Managed by the King Baudouin Foundation 20 YEARS OF · Author(s) Stefan Gijssels & Ann Van Gysel...

20 YEARS OFSUPPORT TO BELGIAN RESEARCH

IN CYST IC F IBROS IS

The Fund Alphonse & Jean FortonManaged by the King Baudouin Foundation

Colophon

Title The Fund Alphonse & Jean Forton: 20 years of support to Belgian Research in Cystic Fibrosis

A publication of the King Baudouin Foundation rue Brederodestraat 21B-1000 Brussels

Author(s) Stefan Gijssels & Ann Van Gysel

Coordination King Baudouin

Foundation

Gerrit Rauws, directorAnnemie T’Seyen, senior project coordinatorMichèle Duesberg, project & knowledge managerIsabelle Van Praet, intern

Graphic design & Layout

Kaligram

Photos Shutterstock

This publication can be ordered or downloaded free of charge from www.kbs-frb.be

Legal deposit D/2893/2017/17

Order number 3515

November 2017

TABLE OF CONTENTSExecutive summary of the report 4

Synthèse du rapport 6

Samenvatting van het rapport 8

1 Introduction 11

2 What is cystic fibrosis? 152.1 The science behind the disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162.2 The treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182.3 Challenges and outlook

for cystic fibrosis research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232.4 The cystic fibrosis community

in Belgium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252.5 Living with cystic fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

3 The Fund Alphonse & Jean Forton: A Driving Force in Belgian Cystic Fibrosis Research 313.1 Research supported

by the Fund Alphonse & Jean Forton . . . . . . . . . . . . . . . . . . . . . . . 323.2 Overview of the projects supported

by the Fund Alphonse & Jean Forton . . . . . . . . . . . . . . . . . . . . . . . 33Molecular Biology – Exploring the cause of the disease 33

Microbiology – Research to understand the consequences

of the disease 36

The development of new research methods, techniques and

therapeutic concepts 38

3.3 The Fund Alphonse & Jean Forton gets strong support from the scientific community . . . . . . . . . . . 40Attracting additional funding 41

International visibility and collaboration 43

3.4 Overview of the impact of the Fund Alphonse & Jean Forton for cystic fibrosis research . . . . . . . . . . . . . . . . . . . . 45

4 A supporting network 474.1 The Belgian Cystic Fibrosis Registry . . . . . . . . . . . . . . . . . . . . . . . . 474.2 The voice of the patient:

the Belgian Cystic Fibrosis Association . . . . . . . . . . . . . . . . . . . . . 51

Concluding remarks 55

Appendix 57

Acknowledgements 63

2 0 Y E A R S O F S U P P O R T T O B E L G I A N R E S E A R C H I N C Y S T I C F I B R O S I S4

EXECUT IVE SUMMARY OF THE REPORT Twenty years ago, in 1997, the King Baudouin Foundation launched the

Fund Alphonse & Jean Forton for research into cystic fibrosis. It was

created when Jean Forton, as the last in line of his family, donated his

capital to create this Fund with the sole aim to conduct research into

cystic fibrosis.

Now, twenty years later, the Fund has contributed significantly to what it

was destined to do: advance research.

The Fund Alphonse & Jean Forton has funded 53 projects allocated to

almost all Belgian universities, for a total amount of over 8 million euro.

Cystic fibrosis is a genetic disease, that affects about 70 000 people in the

world, of which 1 400 live in Belgium. In patients affected with the disease,

the gene that regulates the flow of fluids through cells is defective, resulting

in thick and salty fluids in the lungs, pancreas, sweat glands and the male

reproductive organs. In the lungs the mucus clogs the airways and traps

bacteria, leading to infections, extensive lung damage and eventually,

respiratory failure. In the past twenty years, the living conditions of

patients have increased, primarily because of better management of

the symptoms, the avoidance of infections, and lung transplants. The

first treatment that address the cause of the disease, albeit one specific

mutation of the gene, has recently been launched.

The Fund Alphonse & Jean Forton has funded 27 projects that conducted

research into the molecular biology level of the disease, trying to unravel

the causes of cystic fibrosis, 6 research projects looked at the microbiology

of the infections that cystic fibrosis patients are confronted with, and 15

projects conducted research into specific treatments for cystic fibrosis.

Some studies peeked into the pure genetics of the disease, to identify which

genetic regions and variations determine susceptibility to cystic fibrosis.

Several laureates gathered insights into the tissue-specific features of the

defective gene, such as the kidney, lungs and the pancreas. In addition,

the mechanism of inflammation in cystic fibrosis was studied. Several

2 0 Y E A R S O F S U P P O R T T O B E L G I A N R E S E A R C H I N C Y S T I C F I B R O S I S 5

studies were conducted to understand the physiological mechanisms of

the disease. The microbiology space in cystic fibrosis research is mainly

occupied by studies on the pathogens that create infections and disease

complications, with the aim to optimise treatment regiments or to find

suitable alternatives.

The breakthrough area is the research into new treatments with the use of

nanobodies and gene therapy. In both areas, Belgium can be considered a

leader in cystic fibrosis research.

The research supported by the Fund Alphonse & Jean Forton has led to

approximately 300 scientific publications in top-notch journals, several

scientific books as well as countless citations in research publications.

As a general outcome, one might say that the Fund has put cystic fibrosis

on the map in Belgium, almost doubling the available research funds,

creating an informal community of dedicated researchers, and by doing so,

also contributing to the international reputation of Belgium in this area.

At the same time, the Fund Alphonse & Jean Forton was instrumental in

financing the creation of the Belgian

Cystic Fibrosis Registry, which covers

all Belgian patients and which allows

to track the progress of the disease and

its management year after year.

Twenty percent of all cystic fibrosis

clinical trials take place in Belgium,

which is double the average for any

other disease.

Even if Belgium already had a strong

position in cystic fibrosis research,

the Fund Alphonse & Jean Forton

made it more impactful, more flexible

and contributed to our country’s

reputation in the area.

“By investing in Cystic fibrosis research in Belgium

for the past 20 years, the fund Forton has played

an essential role in improving the lives of people

with cystic fibrosis. Although it’s an exercise that

demands a continuous and long engagement, people

with cystic fibrosis are given most opportunities

when the healthcare providers and researchers

that surround them are encouraged to develop

and understand the causes and mechanics of the

disease: the basic defects of the DNA, inflammation,

antibiotic and other treatments. In-depth

knowledge and understanding of cystic fibrosis

improves better care both directly and indirectly”.

Ulrike Pypops, Belgian Cystic Fibrosis Association


SYNTHÈSE DU RAPPORTC’est en 1997 que le Fonds Alphonse & Jean Forton a été constitué, sous

l’égide de la Fondation Roi Baudouin. Cette initiative a été prise par Jean

Forton qui, en tant que dernier descendant de sa lignée, a légué ses biens à

un Fonds chargé de soutenir la recherche contre la mucoviscidose.

Aujourd’hui, nous pouvons affirmer que le Fonds Alphonse & Jean Forton a

apporté une contribution significative à la recherche sur la mucoviscidose.

Pas moins de 53 projets de recherche mis sur pied par des chercheurs belges

ont été financés, pour un total de plus de 8 millions d’euros. Ces projets

ont porté sur les causes génétiques de la mucoviscidose, mais aussi sur

une meilleure compréhension de ses symptômes et de leurs conséquences,

ainsi que sur la mise au point de nouvelles thérapeutiques. Ces recherches

ont généré plus de 300 articles dans des publications de renom, une série

d’ouvrages de référence, et de nombreuses citations dans les grandes

publications scientifiques. Les chercheurs belges ont joué un rôle clé

dans les diverses avancées signées ces dernières années. Nous pensons ici

avant tout à la thérapie génique et à la mise au point de ‘nanobodies’, à

savoir des anticorps très petits et faciles à produire qui peuvent se révéler

particulièrement utiles dans la lutte contre la mucoviscidose. Le Fonds

Alphonse & Jean Forton a par ailleurs contribué à la création du Registre

belge de la Mucoviscidose, une banque de données qui enregistre tous

les patients belges, et qui permet de suivre au quotidien les progrès des

nouvelles thérapies.

La mucoviscidose est une maladie congénitale qui touche environ 70 000

personnes dans le monde. En Belgique, les patients ‘muco’ sont au

nombre de 1 400. La mucoviscidose se caractérise par une anomalie de la

consistance des mucosités organiques, qui les rend épaisses et collantes. Ce

mucus provoque des obstructions des exutoires des voies respiratoires, du

tractus gastro-intestinal, du foie, des glandes sudoripares et des organes

sexuels masculins. C’est surtout dans les poumons que ces agglomérats de

mucus se transforment en foyer bactérien, avec à la clé des infections, des

lésions pulmonaires graves et parfois une défaillance pulmonaire.


Au cours des vingt dernières années, l’espérance de vie et la qualité de

vie des patients ont fortement progressé. Aujourd’hui, le monde médical

est en mesure de mieux maîtriser les symptômes de la mucoviscidose, de

prévenir les infections des voies respiratoires et de réaliser avec succès

des greffes pulmonaires. La recherche est cependant plus nécessaire que

jamais, tant pour comprendre les mécanismes sous-jacents que pour

mettre au point des thérapies innovantes et plus efficaces.

Une étude de l’impact du Fonds Alphonse & Jean Forton révèle à quel point

ce Fonds a contribué à la visibilité de la recherche sur la mucoviscidose en

Belgique. En vingt ans, les moyens mis à la disposition de la recherche

ont pratiquement doublé, le nombre d’études cliniques a augmenté de

manière spectaculaire, et une communauté de chercheurs très active s’est

constituée et s’appuie sur de multiples

ramifications internationales. Grâce

au soutien structurel accordé par

le Fonds à l’asbl Association Muco,

il a aussi été possible de mettre sur

pied une association ‘patients’ pour

un encadrement et une assistance

efficaces autour de ces derniers.

« Au cours des 20 dernières années, le Fonds

Alphonse & Jean Forton a considérablement investi

dans la recherche sur la mucoviscidose en Belgique.

Le Fonds a ainsi contribué de manière substantielle

à l’amélioration de la qualité et de l’espérance de

vie des patients. Vivre avec la mucoviscidose, c’est

mener un combat de toute une vie. Pour gagner

ce combat, les patients doivent se savoir entourés

de soignants et de chercheurs qui sont encouragés

à identifier les causes et les mécanismes de la

mucoviscidose, à mieux connaître la déficience

génétique qui est à la base de la maladie, ses

symptômes inflammatoires, le rôle des antibiotiques

et autres traitements, etc. Pour pouvoir mieux

soigner les patients muco, il est indispensable de

mieux connaître et comprendre la maladie. »

Ulrike Pypops, asbl Association Muco Belgique


SAMENVATT ING VAN HET RAPPORTIn 1997 werd binnen de Koning Boudewijnstichting het Fonds Alphonse

& Jean Forton opgericht. Dit gebeurde op initiatief van Jean Forton

die, als laatste in de lijn van de familie, het familiepatrimonium ter

beschikking stelde om een Fonds te creëren dat onderzoek zou steunen

naar mucoviscidose, ook wel taaislijmvliesziekte genoemd.

Vandaag, twintig jaar later, kunnen we zonder overdrijving stellen

dat het Fonds Alphonse & Jean Forton een significante bijdrage heeft

geleverd aan het onderzoek naar mucoviscidose. Niet minder dan 53

onderzoeksprojecten, opgezet door Belgische onderzoekers, werden

gefinancierd voor een totaal bedrag van ruim 8 miljoen euro. Deze projecten

gingen zowel over de genetische grondslag van mucoviscidose, een beter

begrip van de symptomen en hun gevolgen als over het uitwerken van

nieuwe behandelingsmethoden. Dit resulteerde in meer dan 300 artikels in

toonaangevende tijdschriften, een reeks wetenschappelijke naslagwerken

en talloze citaten in belangrijke wetenschappelijke publicaties. Bij de

belangrijke doorbraken van de afgelopen jaren speelden Belgische

onderzoekers een leidende rol. We denken dan in de eerste plaats aan

gentherapie en aan de ontwikkeling van ‘nanobodies’, dit zijn heel kleine,

vrij eenvoudig te produceren antilichamen die erg nuttig kunnen zijn in

de behandeling van mucoviscidose. Daarnaast stond het Fonds Alphonse

& Jean Forton aan de wieg van het Belgisch Mucoviscidose Register, een

databank die alle Belgische patiënten registreert en opvolgt, en die toelaat

de effecten van nieuwe therapeutische toepassingen op de voet te volgen.

Mucoviscidose is een aangeboren ziekte die wereldwijd ongeveer 70 000

mensen treft. Ongeveer 1 400 daarvan wonen in België. Bij mensen met

‘muco’ is de regulering van de lichaamsslijmen verstoord waardoor deze

taai, dik en kleverig worden. Zo ontstaan verstoppingen in de afvoerkanalen

van de luchtwegen, het maagdarmstelsel, de lever, de zweetklieren en de


mannelijke geslachtsorganen. Vooral in de longen vormen de slijmproppen

een haard voor bacteriën, wat leidt tot ontstekingen, ernstige longschade

en uiteindelijk soms longfalen.

De laatste twintig jaar zijn de overlevingskansen en de levenskwaliteit

van mensen met mucoviscidose er gelukkig sterk op vooruitgegaan. Zo

is men beter in staat om de symptomen onder controle te houden en

luchtweginfecties te voorkomen, en kunnen longtransplantaties met

succes worden uitgevoerd. Toch is nog heel veel onderzoek nodig, zowel

naar een beter begrip van de onderliggende mechanismen van de ziekte,

als naar nieuwe, meer efficiënte therapieën.

Een uitgebreide studie naar de impact van het Fonds Alphonse & Jean Forton

toont overtuigend aan hoe het Fonds het onderzoek naar mucoviscidose op

de Belgische kaart heeft gezet. In twintig jaar tijd zijn de onderzoeksmiddelen

quasi verdubbeld, is het aantal klinische studies spectaculair toe genomen,

en is een zeer actieve ‘onderzoekscommunity’ ontstaan met internationale

vertakkingen. Dankzij de

structurele steun van het

Fonds aan de Mucovereniging

vzw kon ook een zeer aktieve

patiëntenvereniging worden

uitgebouwd die de patiënten in

woord en daad bijstaat.

“De afgelopen 20 jaar heeft het Fonds Alphonse &

Jean Forton sterk geïnvesteeerd in het onderzoek naar

mucoviscidose in België. Zo heeft het Fonds een essentiële

rol gespeeld in de verbetering van de levensverwachting

en de levenskwaliteit van patiënten. Leven met

mucoviscidose vraagt een voortdurend, levenslang

engagement. Dit is beter vol te houden wanneer

patiënten zich omringd weten door zorgverstrekkers en

onderzoekers die aangemoedigd worden om de oorzaken

en mechanismen van de ziekte verder te ontrafelen, om

inzicht te krijgen in het basisdefect dat aan de ziekte ten

grondslag ligt, in de ontstekingsverschijnselen, de rol

van antibiotica en andere behandelingen… Een betere

kennis en begrip van de ziekte zorgen rechtstreeks en

onrechtstreeks voor betere zorg.”

Ulrike Pypops, Belgische Mucovereniging vzw


1


INTRODUCT IONIn 1996 Jean Forton discussed his will with his notary, wondering how to

best invest his family capital, in the knowledge that he was the last in line

of his family, with no remaining descendants or siblings. And although

little is known about Jean Forton as a person, his name will continue to be

associated with the Fund that carries his name, and to be recognised as a

benefactor in the cystic fibrosis research community.

The money available to him was about 11.5 million euro. His final decision

was to donate his legacy to the King Baudouin Foundation, ensuring that

the money was spent on projects to improve well-being of society. When

both men discussed what specific cause they would support, Jean Forton

decided to fund research to find better treatments, and maybe even a cure

for cystic fibrosis, the devastating disease that affects young people and

deprives them of a healthy life. Jean Forton also added that he wished that

his father’s name – Alphonse – should be added to the Fund’s moniker,

so that his memory would live on too. As such, the Fund was set up in

1997, and since then scientific research projects to improve the situation

of cystic fibrosis patients were funded every three years. A panel of

international experts reviews all the submitted projects, a jury of national

experts then makes a proposal for the allocation of the project funding

to the Fund’s management committee which makes the final decision. In

this way, more than 8 million euro has been distributed to 53 research

projects over the last twenty years. Scientists from almost all Belgian

universities have been able to benefit from this Fund that offers additional

opportunities to deepen and broaden their research over and above the

funding they already receive through other channels, such as the Fund

for Scientific Research (FWO/FNRS) and the Belgian Cystic Fibrosis

Association. The Fund Alphonse & Jean Forton offers an important and

effective contribution in the fight against cystic fibrosis.


It is one of the most important of the more than 70 funds in the area of

health research that the King Baudouin Foundation manages, and which

carry out research in very diverse fields such as cancer, rare diseases,

ageing, neurology, cardiology… Most of these Funds have been set up

by individual donors with a clear motivation, for example to support a

specific area of research on the basis of a personal experience or a sense of

gratitude towards a specific institution or department.

One of these other funds was the Fund Crawhez Mucoviscidose, which was

also dedicated to research into cystic fibrosis, and which ceased to exist

in 2015. As can be expected, this Fund was closely cooperating with the

Fund Alphonse & Jean Forton, and between 2005 and 2015, 12 researchers

were supported by the Fund Crawhez Mucoviscidose for a total amount of

240 000 euro. They were all selected within the call for projects of the Fund

Alphonse & Jean Forton.

The 20th anniversary of the Fund Alphonse & Jean Forton is a good

occasion to review what has been realised by the various research projects

that have taken place. In this report, we will try to analyse the nature

of the research conducted and assess its impact, both on patients’ lives

and on the role that Belgian cystic fibrosis research has played on an

international level.

Meanwhile, the Fund continues with its activities. In 2017, 1 550 000 euro

has been made available in a joint call for new cystic fibrosis research

projects, 855 000 euro by the Fund Alphonse & Jean Forton, and 700 000

euro by the Belgian Cystic Fibrosis Association, the Belgian patients

organisation. For this first joint call, both basic as well as clinical research

projects were eligible to receive a grant, covering a research period of three

years. Basic research projects could request up to 275 000 euro, clinical

projects were eligible for grants up to 225 000 euro. Seven projects have

been selected this year.


2


WHAT IS CYST IC F IBROSIS? Cystic fibrosis is a genetic disease caused by mutations in the ‘cystic fibrosis

transmembrane conductance regulator’ (CFTR) gene, coding an ion channel

that regulates the flow of salts and fluids in and out of cells. Secretions

regulated by the channel include sweat, digestive fluids and mucus. With

the defective gene, these secretions – which are usually thin – become less

fluid, resulting in the build-up of thick fluids in the lungs, pancreas, sweat

glands and the male reproductive organs. In the lungs the mucus clogs the

airways and traps bacteria, leading to infections, extensive lung damage

and eventually, respiratory failure. In the pancreas, the mucus prevents

the release of digestive enzymes, which allows the body to break down

food and absorb vital nutrients. This results in bad uptake of fats and

proteins, diarrhea, leading to reduced body weight gain and poor growth.

Because of the lack of fat uptake, the disease also leads to insufficiencies in

vitamins A, D, E and K.

People suffering from cystic fibrosis can have a variety of symptoms,

including:

– Very salty-tasting sweat

– Persistent coughing, at times with phlegm

– Frequent lung infections including pneumonia or bronchitis

– Wheezing or shortness of breath

– Poor growth or weight gain in spite of a good appetite

– Frequent greasy, bulky stools or difficulty with bowel movements

– Male infertility1

Many people carry a mutated version of the CFTR gene, but only when

both parents carry a malfunctioning gene there is a 25% chance that their

child will have cystic fibrosis. Since its discovery in 1989, more than 2 000

different mutations have been identified in the CFTR gene, and more

continue to be found. To date, 281 of these mutations are confirmed to

cause cystic fibrosis and disease severity varies greatly between the various

mutations.

1. Cystic Fibrosis Foundation Website – www.cff.org


2.1 The science behind the diseaseBecause a significant part of the research funded by the Fund Alphonse

& Jean Forton has focused on understanding the mechanisms of cystic

fibrosis, it is good to understand exactly how the disease comes about.

Since the first recognition of cystic fibrosis as a separate disease in 1938,

perception of and research into the disease have gone through some

drastic changes. Research in the mid-20th century mainly focused on

characterising the clinical manifestations and developing symptomatic

treatments to slow down disease progression: the effects of cystic fibrosis

on different organs and physiology of cystic fibrosis patients were closely

studied to devise ways of mitigating damage caused by the disease. This

changed when the field went through a complete overhaul from 1989

onwards with the discovery of the gene that causes cystic fibrosis

when mutated, i.e. the cystic fibrosis transmembrane conductance

regulator (CFTR) gene. While at first only a single mutation was known

(ΔF508) as the cause of the disease, later on a host of different mutations

in the CFTR gene were identified, all resulting in an a malfunctioning

ion channel protein. The importance of this discovery can hardly be

understated, as it lies at the foundation of our understanding of the

disease and the development of novel treatments that restore the mutant

protein in its function. Not only did the CFTR gene place the already

available knowledge on cystic fibrosis in a conceptual framework, the gene

and translated protein provided an essential new research track to fully

explore. Research on the molecular basis of cystic fibrosis has exploded

since, and for good reasons. Fundamental insights into the nature and

function of the CFTR protein and its coding gene offer the perspective of

a cure for the disease.

Under normal conditions the CFTR protein channel is inserted into the

cell surface or plasma membrane where it controls the flow of salt and

fluids in and out of the cells. However, mutations can render the protein

defective or prevent the channel from being inserted in the cell membrane.

In these cases, loss of CFTR-mediated chloride and bicarbonate transport

leads to dehydration of various surface fluid layers and impaired clearance


of bacteria and mucus, especially in respiratory and digestive organs such

as the lungs, pancreas, liver and intestines. While in healthy people,

mucus is a watery and slippery layer that keeps the inner surface of hollow

organs moist, in patients with cystic fibrosis, it is thick and sticky, and

causes obstruction.

In the skin, the sweat glands transport water together with chloride and

sodium, the components of salt, to the surface. In normal skin, most of

the sodium and chloride is reabsorbed. Not so with cystic fibrosis patients,

where the sodium and chloride stay on the surface of the skin, resulting

in very high salt levels in the sweat. The salt content is so high compared

to healthy individuals that the “sweat test” is one of the most reliable

diagnostics to identify the presence of the disease.

The same process of defective fluid secretion has the most dramatic

effect in the lungs. Under normal circumstances the airway epithelium

is covered with a thin, moist film called airway surface liquid, a salt-

containing liquid and a mucus gel layer. This liquid traps bacteria and

foreign particles, and helps to move them out of the lungs into the mouth.

At the same time, the liquid contains a lot of substances that neutralise or

destroy invading organisms without damaging the lungs2. This process

protects the lungs from infection in healthy people. In patients affected by

cystic fibrosis, decreased chloride transport into the airway surface liquid

is coupled with excess sodium reabsorption. Because water follows the

flow of sodium, the surface liquid loses volume and the mucus gel layer

becomes dehydrated. As a result, the mucus thickens, stays in the lungs

and increases the need to cough. Bacteria cannot be cleared efficiently,

leading to chronic infections (commonly with Pseudomonas aeruginosa),

and finally bronchiectasis (permanent enlargement and scarring of the

airways). These events cause severe airway inflammation and eventually

result in severe and irreversible lung damage, which is the principal cause

of death or reason for lung transplantation in these patients3.

2. Based on the Johns Hopkins Cystic Fibrosis Center Website – http://www.hopkinscf.org

3. End-stage cystic fibrosis lung disease is characterised by a diverse inflammatory pattern: an immunohistochemical analysis, Respiratory Research, January 2017


The same process takes place in the pancreas, the organ that produces

enzymes for digesting food. The pancreatic duct cells secrete bicarbonate

via the CFTR channel into the intestines to neutralise stomach acid. In

patients with cystic fibrosis this secretion is defective4. Furthermore, due

to disturbed chloride, bicarbonate and fluid secretion, the pancreatic

secretions become viscous, leading to obstructions in the pancreatic ducts.

Therefore, pancreatic enzymes cannot reach the intestine where they play

a crucial role in food digestion (sugars, proteins and fats) into smaller

absorbable particles. This leads to bad absorption of fat and proteins,

resulting in excessively fatty stools and growth retardation.

2.2 The treatmentAlthough there is no cure for cystic fibrosis today, the clinical side of

better understanding the disease has seen tremendous progress over

the years Current therapies mainly still address the symptoms of the

disease, by focusing on the respiratory system: physiotherapy, inhalation

therapy and antibiotics play a role in facilitating the removal of mucus

in the lungs and avoiding infections. To treat the digestive pathology,

pancreas enzyme supplements are given and a diet rich in calories.

These tremendous improvements in symptomatic treatment have led to

a significant increase in both life quality and life expectancy of patients.

Fifty years ago, very few patients made it past early childhood. Today, the

average life expectancy is more than 40 years depending on the type of

CFTR gene mutations present. For patients, their disease requires constant

attention. They have to avoid getting infections and they have to eat more

food than other people, but if well-managed, patients can live fulfilling

lives. The continuing increase in survival for cystic fibrosis patients

means that that the predicted median survival of more than 50 years for

4. Johns Hopkins University – Cystic Fibrosis website – http://www.hopkinscf.org


individuals born in 2000 starts looking realistic, even in the absence of

proven efficacy of therapies aimed at correcting the basic cystic fibrosis

gene defect5.

Although the treatment of cystic fibrosis does not change significantly

as a child ages, there are additional age-related factors that must be put

into context. Around 40 to 50% of adult cystic fibrosis patients develop

diabetes. They also have increased chances of developing joint pain and

bone disease as they age. In addition to health concerns, many cystic

fibrosis patients now reach the reproductive age due to better treatment.

Fertility in cystic fibrosis patients differs greatly depending on gender. For

example, the genetic mutation which causes the disease leads to infertility

in men, but only sometimes in women. Since cystic fibrosis is a genetic

condition, helping patients make well-informed decisions when it comes

to reproduction (reduced fertility, chances of passing cystic fibrosis on

to their children, possibilities of screening for CFTR mutations in the

pre-implanted embryo or developing fetus) will likely become increasingly

important6.

About 80% of people with cystic fibrosis are colonised with a pathogen

called Pseudomonas aeruginosa. Pseudomonas is found everywhere,

and it commonly grows in water. People with cystic fibrosis are at much

greater risk for infection with Pseudomonas, and this bacterium can

cause progressive destruction of the lungs, which can result in respiratory

insufficiency and death.

With the relatively recent discovery of the CFTR gene in 1989, cystic

fibrosis is a research field in full development. Many recent breakthroughs

in the field have substantially contributed to patient well-being and

research progress. Although by no means a cure, lung transplantation has

become a viable treatment option and many patients have tremendously

5. Rate of improvement of CF life expectancy exceeds that of general population—Observational death registration study

Matthew N. Hurley, Tricia M. McKeever, Andrew P. Prayle, Andrew W. Fogarty, Alan R. Smyth

J Cyst Fibros. 2014 Jul; 13(4): 410–415. doi: 10.1016/j.jcf.2013.12.002

6. Medical Daily, 2015


benefited from it. Lung transplantation often becomes necessary for cystic

fibrosis patients as lung function and exercise tolerance decline. Although

single lung transplantation is possible in other diseases, individuals with

cystic fibrosis must have both lungs replaced because the remaining lung

might contain bacteria that could infect the transplanted lung. Even with

single lung transplantations, this risk isn’t fully removed, as nasal sinuses

remain a reservoir of resistant bacteria that can cause infection after

transplantation. Even if very rare, a pancreatic or liver transplant may

be performed at the same time to alleviate liver disease and/or diabetes7.

However, organ donors are scarce and many patients die while on the

waiting list.

Thanks to the genetic and molecular knowledge available on the CFTR

gene and its protein counterpart, a new revolution for cystic fibrosis

patients is close. Small molecule drugs that are able to help the mutant

CFTR protein fold better and get inserted into the plasma membrane or

restore function to the CFTR ion channel are commercially available and

many more are in clinical development. These so-called correctors and

potentiators have sent the powerful signal to the cystic fibrosis research

community that effective treatment for the disease is not a far-fetched

unrealistic concept, but a solution that is within reach.

Vertex Pharmaceuticals developed the first of these commercially available

drugs with major support from the American Cystic Fibrosis Foundation,

setting an example of how NGO’s can significantly contribute to progress

in cystic fibrosis treatment. Ivacaftor (tradename Kalydeco), one of the

drugs developed by Vertex, potentiates chloride/bicarbonate transport

through the mutant CFTR protein and is already available for patients

with gating or conductivity defects (currently approved for 38 different

mutations, from age two onwards). Other treatments are now available

for the F508del mutation, the most common mutation. The Lumacaftor/

Ivacaftor combination therapy (Orkambi) is prescribed for people aged six

7. Fridell JA, Vianna R, Kwo PY, Howenstine M, Sannuti A, Molleston JP, Pescovitz MD, Tector AJ (October 2005). “Simultaneous liver and pancreas transplantation in patients with cystic fibrosis”. Transplant. Proc. 37 (8): 3567–9. doi: 10.1016/j.transproceed.2005.09.091. PMID 16298663


and older who have two copies of the F508del mutation. Several problems

are caused by the F508del mutation that prevents the CFTR protein from

achieving its correct shape and reaching the cell surface. The combination

therapy works to correct this in two ways. Lumacaftor helps the defective

CFTR protein in better folding and inserting it at the correct place on the

cell surface, while Ivacaftor increases the protein’s channel activity once

it is in place.

Together, Kalydeco and Orkambi are able to provide treatment for

approximately 50% of the cystic fibrosis patients (Kalydeco for 38

approved mutations with gating, conductivity or splicing defects (~12%),

Orkambi for F508del homozygous patients (~38%))8. Although Kalydeco

can significantly improve lung function and as a result life quality, the

clinical benefits of Orkambi are more limited. Therefore, biotech and

large pharma companies focus their development on developing improved

modulators for F508del homozygous patients. The company has eight

more compounds in clinical development at the moment.

While Vertex was the first to bring pharmacological therapies for cystic

fibrosis to the market, it certainly isn’t the only. Galapagos, the Belgian-Dutch

biotech company, has been actively pursuing new small molecule therapies

in collaboration with AbbVie. Galapagos

currently has seven different molecules in

the pipeline of which five are in clinical

trials. The company aims at delivering a

triple combination therapy, consisting of one

potentiator and two corrector molecules.

The challenge of the continuously increasing life expectancy requires a

totally different way of how to perceive this disease and finance it. In the

first study of its kind, published in the European Respiratory Journal (19

March 2015), researchers have provided predictions on the number of

adults that will be living with the disease in 34 different European countries

8. US Food & Drug Administration – 1 August, 2017

“The discovery of correctors and potentiators,

molecules that are able to restore CFTR

protein function, is one of the most significant

breakthroughs of the past 20 years.”

Prof. Charles Pilette (UCL, Laureate in 2014)


by the year 2025. For example, the cystic fibrosis patient population

of 18 years or older will increase with 77% in Belgium by 2025

The dramatic increase of this number will require large investments in

adult cystic fibrosis services to be able to provide sufficient healthcare for

this growing adult CF population.

Professor Pierre-Régis Burgel, one of the

co-authors of this study from Cochin Hospital,

Paris, elaborates: “The estimations we have

made show very positive news for cystic fibrosis

patients as the average survival age is increasing.

We are now concerned that there are insufficient

specialist centres to provide optimal care to

adults with the disease. Healthcare systems

will need to adapt to this change, particularly in countries with less

well-established adult services.” The research is part of a joint task force

between the European Respiratory Society (ERS) and the European Cystic

Fibrosis Society (ECFS). The members of the task force are now calling on

healthcare professionals and policymakers to be aware of these expected

increases and to develop adult services to meet this demand.

However, when considering a sustainable approach to cystic fibrosis

therapy, the field is still in its early days. Scientific knowledge on the

CFTR protein has enabled researchers to come up with the first

curative strategies, but further fundamental research is necessary to

bring these to the patients Many experts in the field claim that a more

comprehensive scientific basis is needed before moving to applications

and therapy.

“There is still a need to evaluate the

molecular CFTR network and identify

additional factors. This will be the basis

of novel pharmacological treatments.”

Prof. Bernd Nilius

(KU Leuven, Laureate 1998)


2.3 Challenges and outlook for cystic f ibrosis research

As research on cystic fibrosis continues, major hurdles still need to be

overcome to guarantee the ongoing improvement of the lives of cystic

fibrosis patients. Basic knowledge on the disease still needs to be expanded

to devise new and improved therapeutic options, and also research itself

is faced with significant challenges. Although there has been tremendous

progress in cell and animal models of cystic fibrosis and its features, these

are still not commonplace and further developments are required to lift

the brakes on both fundamental research and drug development.

Also technical impracticalities associated with molecular research are

being addressed in academia, shown by multiple research groups focusing

solely on devising new research tools, such as techniques to measure

electrical current through ion channels in innovative ways.

Continuous improvements in molecular and cell biological research

allow further unravelling the molecular complexity of defects caused by

mutations in the CFTR gene. Patient derived primary airway or intestinal

cultures obtained from lung explants, nasal brushings or rectum biopsies

allow studying CFTR mutations in their natural environment, which is

often even patient-specific due to modifier genes etc. Intestinal organoids

grown from rectal biopsies is one such example. These ‘mini guts’ resemble

the human intestine based on morphology and CFTR protein function.

Organoids from patients can be incubated with drug candidates to assess

their effect on CFTR protein function. It is becoming increasingly clear

that individual mutations require different therapies, and that even for

the same mutation (mainly F508del), different responses to therapy are

noted. The above points out the importance of a personalised medicine

approach in cystic fibrosis. Both primary airway cultures as well as

intestinal organoids will likely play a very important role in identifying

individual patient responders to existing or emerging modulator therapies,

or will help in the development of novel therapies with different mode-of-

action. The fact that personalised medicine is gaining momentum is also

reflected in a paradigm shift in medicine prescription. More specifically,


the ‘prescription for use’ of Kalydeco now specifies that this treatment can

be approved for any CFTR gene mutation that shows in vitro activity in a

laboratory setting in cystic fibrosis-based cell models. In other words, it

can only be prescribed in patients for whom the models indicate that the

drug matches the genetic mutation the patient has.

About 15% of cystic fibrosis patients carry more than 1 800 different

ultra-rare and uncharacterised CFTR gene mutations (these patients

are without a single copy of either a gating or F508del mutation). It is

unknown which of these will respond to which of the drugs present in

the development pipeline. Due to very low prevalence, rare mutations are

not the first focus of pharma industry for development of novel therapies.

In that regard, evaluating existing or emerging drugs on their efficacy to

restore CFTR protein function of these rare mutations (‘repurposing’),

is of major interest as currently these specific patient groups are without

causal treatment to date.

A final step will be translating this knowledge into novel therapies

that benefit the patient. The research community agrees that, in a first

phase, this will come from small molecules and other pharmacological

approaches. In the longer term, gene therapy and genetic engineering

will also claim its space in cystic fibrosis therapy. A clear challenge in

the therapeutic area will be to design universal cystic fibrosis treatments,

applicable to all cystic fibrosis patients with a broad range of different

mutations at the basis of their disease. Although most therapies are rather

mutation-specific, gene addition therapy (introducing a healthy CFTR

gene into affected cells) offers a mutation-independent treatment. In the

end, most likely a combination of pharmacological and genetic solutions

will be necessary to provide a causal therapy to all cystic fibrosis patients.

The recent evolution of CRISPR ‘gene editing’ technology holds promise of

correcting the mutations themselves on the gene level. This kind of genetic

therapy uses so called ‘nuclear scissors’ to ‘cut and paste’ in the patient’s

DNA containing all genetic information, and more specifically correct the

genetic mutations in the CFTR gene that cause cystic fibrosis.


2.4 The cystic f ibrosis community in Belgium

Approximately 70 000 patients worldwide live with CF9, of which

more than 1 400 live in Belgium About 60% of patients are older

than 18 years, 14% older than 40, and 11% has had a lung transplant

Every year, 40 to 50 new patients are known to the Belgian Cystic

Fibrosis Association The overall patient population increases year after

year, not so much because of new patients, which is relatively stable, but

because mortality decreases and patients live longer.

Belgium is well organised to tackle the problem of cystic fibrosis. There

are seven reference centres for the disease and two specialised revalidation

centres. Belgium is also well represented at the European scientific

congresses, based on the number of participants, posters and presentations.

Belgian experts have leading roles in Cystic Fibrosis Europe, the European

cystic fibrosis patient organisation, and in the European Cystic Fibrosis

Society, which represents the medical experts. Belgian physiotherapists

have also played a leading role in developing new therapies, which are now

applied across the world10.

Cystic fibrosis is the most common genetic disorder in Belgium, with the

F508del mutation the most common mutation. For 17% of patients the

diagnosis was made after neonatal screening, despite the absence of official

screening programs in Belgium. End 2016, the Flemish Parliament approved

a program for neonatal screening for cystic fibrosis in Flanders. In March

2017, a proposal for the implementation of a federal neonatal screening was

submitted to the Belgian Federal Parliament. These initiatives are mainly

the result of the very active cystic fibrosis community in Belgium, formally

represented by the Belgian Cystic Fibrosis Association, on which more

attention will be focused later in this report.

9. Cystic Fibrosis Foundation What you need to know, 2012

10. Translated from the Belgian Cystic fibrosis Association’s website


In 2014, there were 1 230 patients included in the registry in Belgium. The

median age of patients is 21.3 years. This is a significant increase

compared to the median age of 14.9 years fifteen years ago. The oldest

patient in Belgium was 76 years old in 2014. In the overall population,

there appears to be better nutritional management, better lung function,

and with infections slightly decreasing or increasing depending on the

nature of the bacteria. The main reasons for diagnosis of cystic fibrosis

are “acute or recurrent respiratory problems” (42.7%) and “failure to

thrive11” (24.2%). About 12.3% of the patients in the registry are living

with a transplant.

2.5 Living with cystic f ibrosisEven though the life expectancy of people with cystic fibrosis has

increased significantly in the past decades, the disease remains a

heavy burden for the affected patients, who easily spend three to

four hours a day simply managing their disease

Already from an early age, patients suffer from a variety of discomforts

that may vary from one patient to the other. Their inability to gain weight

and malfunctioning nutrient absorption gives rise to impaired growth

and various bowel symptoms. These include diarrhea, severe constipation

causing stomach ache, bloating and gas accumulation, nausea, appetite

loss and foul smelling stools. Also respiratory problems such as coughing,

nasal congestion (nasal polyps), pneumonia, shortness of breath, fever,

and phlegm can seriously diminish quality of life. Additionally, many

adolescents and adults with cystic fibrosis will develop cystic fibrosis-

related diabetes.

To partially relieve them of their symptoms, patients are required to

adhere to an extensive set of treatments. Hours of physiotherapy are

needed to clear the lungs of mucus, together with the use of nebulised

treatments to make their mucus secretions easier to cough up. To this end,

11. Failure to thrive (FTT) is a term used in pediatric and adult medicine to indicate insufficient weight gain or inappropriate weight loss


both DNAse enzyme therapy and vaporised high salt concentration fluids

are inhaled to reduce mucus viscosity. Also inhaled antibiotics are used,

both for prevention and treatment of lung and sinus infections. Because

of the increased risk of infection, patients are often taken up in hospital

to treat these bacterial infections with antibiotics. Additional treatments

include flu and bacterial vaccines, oxygen therapy, percussion vests and,

in some cases, a lung transplant.

The decreased uptake of fats and calories in patients with cystic fibrosis

requires a lot of attention to diet on a daily basis. The low efficiency of

properly digesting food into absorbable nutrients, means that they require

more than 1 000 extra calories a day, spread over several more meals, and

with a high fat content and mineral supplement. Even then, many patients

remain skinny. Gastrointestinal therapies are of importance to increase

the absorption of nutrients. Patients often rely on pancreatic enzymes to

aid in digestion and absorption of fats and proteins, vitamin supplements

and anti-constipation drugs.

Given the many facets of the disease and separate treatment of each of

the symptoms, it is not uncommon for patients to have to take 50 pills a

day. Even aside from medication, the disease requires a lot of attention for

patients to stay healthy from a more general point of view: not smoking

and avoiding tobacco smoke are quite obvious implications, but also

washing hands often to lower the risk of infection, exercising regularly

and drinking lots of fluids are part of these general measures.

Even though patients may find it difficult to remain physically active, there

is a lot of evidence that keeping active has a myriad of benefits. Increased

exercise tolerance, respiratory muscle endurance, sputum expectoration,

reduced residual lung volume and rate of decline in pulmonary function,

improvements in fluid balance and retention of serum electrolytes, a lower

risk of death12: it definitely pays to keep working out and be physically

active for the cystic fibrosis patient.

12. Sources: Cystic Fibrosis Foundation, Cystic Fibrosis Trust


“By investing in Cystic fibrosis research

in Belgium for the past 20 years, the

fund Forton has played an essential role

in improving the lives of people with

cystic fibrosis. Although it’s an exercise

that demands a continuous and long

engagement, people with cystic fibrosis

are given most opportunities when the

healthcare providers and researchers

that surround them are encouraged to

develop and understand the causes and

mechanics of the disease: the basic defects

of the DNA, inflammation, antibiotic and

other treatments. In-depth knowledge and

understanding of cystic fibrosis improves

better care both directly and indirectly”.

(Ulrike Pypops,

Belgian Cystic Fibrosis Association)

While patients with cystic fibrosis do not have any barrier to a healthy sex

life, the majority of men afflicted by the disease are infertile and women

may have difficulties in conceiving. However, modern fertility treatments

can help in this process. In addition to these complications, patients also

face challenges in different aspects of their lives like traveling. Cystic

fibrosis does not prevent people from traveling, but proper preparation

and planning are needed in advance. Patients need to anticipate potential

symptoms or exacerbations, and provide the necessary medication to treat

this. Further, they need to make sure all immunisations are up to date and

check out the possibility of specialised care at the holiday location.

The constant focusing on the disease and

the special attention that family and schools

have to provide for affected patients, might

isolate young patients and influence their

self-esteem. The impact on mental health

is less obvious at first sight and is generally

underestimated in cystic fibrosis patients.

Attention to this aspect of the disease is

nonetheless important. Although moments

of sadness and anxiety due to the uncertainty

may come and go, depression and persistent

anxiety should be treated as part of overall

health and emotional wellness.

Although the factors to keep in

consideration are many, most individuals

will only experience a handful of these

complications in their lifetime and a lot

of support is available. More than 50% of

adults with cystic fibrosis are professionally

active, achieving their ambitions despite the

challenges they face.


Living with the disease is very demanding, as it requires a constant effort

by the patient and his or her family. It is a constant struggle to remain in

control of a healthy lifestyle and avoid infection, together with the choices

of interacting in social environments, including travel and being exposed

to possible contaminations. It is a life filled with uncertainty about the

immediate activities to be planned for the coming days and weeks, as

well as about the longer-term choices of life, such as studying, working,

marrying or getting children. Scientific research is absolutely essential

to better understand the complex mechanisms of the disease and find

treatments that address the cause of the disease itself. The first steps in

that direction have been set.


3


THE FUND ALPHONSE & JEAN FORTON: A DR IV ING FORCE IN BELGIAN CYST IC F IBROSIS RESEARCHIn order to assess the impact the Fund Alphonse & Jean Forton has had

up until now in fostering scientific research into the disorder, we got in

touch with the cystic fibrosis experts we know best: our laureates from

1997 until 2014. We contacted every one of the Fund Alphonse & Jean

Forton’s beneficiaries since the very beginning and asked them about the

disease, trends in research and treatment and the impact the Fund has had

on their work and the cystic fibrosis field in general. We gathered insights

into what types of research are popular, where the biggest challenges lie

and what Belgium’s position is in the scientific world on an international

level.

Over the last 20 years, the Fund Alphonse & Jean Forton provided

grants to 53 projects, shared among 31 research groups from six Belgian

universities (Université Libre de Bruxelles, Vrije Universiteit Brussel, KU

Leuven, Université Catholique de Louvain, Universiteit Gent, Université

de Liège). The research supported by the Fund Alphonse & Jean Forton led

to approximately 300 scientific publications in top-notch journals, several

scientific books13 as well as countless citations in research publications.

13. Books – Molecular Pathology of Liver Diseases edited by Satdarshan P. S. Monga, Article F.P. Lemaigre, Springer Verlag, 2011

Development, Differentiation and Disease of the Para-Alimentary Tract, Academic Press, 2010 (F.P Lemaigre)

Ion Channel Localization: Methods and Protocols, edited by Anatoli N. Lopatin, Colin G. Nichols (Jan Eggermont)


From our contact with the laureates, it has become clear that the Fund

Alphonse & Jean Forton has put cystic fibrosis on the research agenda of

many Belgian scientists and has subsequently put Belgium on the map as

a cystic fibrosis research hub. The Fund Alphonse & Jean Forton was also

instrumental in the foundation of the Belgian Cystic Fibrosis Registry,

and as such also directly interacts with patients and support groups.

Below, we present an overview of the various research topics and projects

supported by the Fund Alphonse & Jean Forton, delve into the impact it

has had on scientific development in all its aspects and show how it enabled

the creation of one of Belgium’s most extensive patient organisations.

3.1 Research suppor ted by the Fund Alphonse & Jean For ton

All the previously discussed challenges and topics are a good indicator of

the things moving in the field of cystic fibrosis and are all well represented

in the different research projects supported by the Fund Alphonse & Jean

Forton. While every project contributes something unique to the cystic

fibrosis field, three major categories of research supported by the Fund

can be discerned:

– Molecular biology of cystic fibrosis and the CFTR gene

– Microbiology in cystic fibrosis

– The development of new research methods, techniques and therapeutic

concepts

The majority of cystic fibrosis research in Belgium is situated in the first

category, which answers the outspoken need for a deeper understanding

of cystic fibrosis on the molecular level. Many academics hold a deep

appreciation for the Fund Alphonse & Jean Forton for supporting

fundamental research efforts. The laureates express concern about the

general trend in life sciences of research investments shifting away from

basic research to clinical research.


Since infection is one of the primary causes of death in cystic fibrosis

patients and therapy with antibiotics is a mainstay of cystic fibrosis

treatment, a focus on microbiology should be of no surprise. The fact that

novel approaches are being pursued so actively is a sign that new impulses

are necessary, but also a testament to

the innovativeness of the cystic fibrosis

research area.

While true translational efforts are

still scarce, the first pioneers in the

field are definitely present. The Fund

Alphonse & Jean Forton has supported

projects evaluating all kinds of novel

biotechnological tools such as gene

therapies, oligonucleotides, single-

domain antibodies (nanobodies) and

stem cells for their potential in cystic

fibrosis therapy.

Over the last twenty years, the research

projects have been spread over these

three major categories without any

significant shifts in subject area.

3.2 Overview of the projects suppor ted by the Fund Alphonse & Jean For ton

Molecular Biology – Exploring the cause of the disease

As mentioned before, central to understanding cystic fibrosis is the CFTR

gene. Although discovered almost 30 years ago, not all of its functional

intricacies have been elucidated yet. Since the gene is the key component to

“A major bottleneck in drug development for

the treatment of Cystic fibrosis has been the

electrophysiological evaluation of compounds in

primary cultures of human bronchial epithelial

(hBE) cells. Demonstrating efficacy in cystic

fibrosis hBE cells is considered critical in the

drug development pathway. We developed an

automated workstation to measure transepithelial

equivalent currents (Ieq) in primary cultures of

CF hBE cells. Automated Ieq measurements with

this format can now be used to evaluate up to

500 compounds per week in CF hBE cells, further

accelerating drug discovery for the treatment of

cystic fibrosis.”

Prof. Willy Van Driessche

(KU Leuven, Laureate 2011)


understanding and ultimately curing the disease, research into its structure,

function and behaviour is extensive. The gene is a very popular research

topic, also among the laureates of the Fund Alphonse & Jean Forton.

Some studies peeked into the pure genetics of the disease. Which genetic

regions and variations determine susceptibility to cystic fibrosis? A very

relevant question, since the severity of cystic fibrosis can vary significantly

between affected siblings. Together with other labs in Europe, one of our

laureates located regions of the genome that carry genetic causes of such

variation and developed a methodology to do so applicable for many

genetic diseases apart from cystic fibrosis. Another laureate unveiled how

mutations in the CFTR gene gives rise to a specific form of male infertility,

and characterised these mutations from the level of the DNA, through

the RNA and finally to its manifestation in the protein. Additionally,

this project identified genes modulating the cystic fibrosis phenotype,

influencing the course of disease and potentially providing alternative

therapeutic angles.

Several laureates gathered insights into the tissue-specific features of the

CFTR gene and protein. One project zoomed in on the kidneys, where

the CFTR gene is expressed but a disease phenotype is seemingly absent.

Through the use of innovative mouse models, this research characterised

the expression, subcellular localisation and processing of the CFTR protein

in the kidneys. New pathophysiological characteristics of cystic fibrosis

were unveiled, together with novel insights on tissue-specific processing

of the CFTR protein.

A second project characterised the activity of the CFTR protein in the

pancreas and how its defect influences pancreatic function. This work

showed that the CFTR channel was active in the islets of Langerhans, the

groups of cells within the pancreas responsible for glucose homeostasis,

which connected CFTR function in these cells to cystic fibrosis-related

diabetes. This research changed the view that cystic fibrosis-related

diabetes was due to destruction of the exocrine pancreas and cemented

the notion that it rather emerged because of CFTR dysfunction in the

endocrine pancreas.


A third project explored the role of anion channels, such as the CFTR

protein, play in the development of polycystic liver disease. Again, novel

mouse models were developed to study how anion channels function and

are regulated in the liver’s bile ducts.

In addition, the mechanism of inflammation in cystic fibrosis was studied.

One research project revealed that the lungs already become inflamed in

foetuses suffering from cystic fibrosis and that a mutated CFTR gene is

sufficient to cause chronic lung inflammation. Next to this, gene mutations

in African children with cystic fibrosis-like symptoms were characterised

and the way they contributed to the cystic fibrosis phenotype described.

Another project studied the impact of genetic CFTR defects in inflammatory

cells such as macrophages, fibroblasts and fibrocytes. A lack in functional

CFTR protein might be responsible for an over activation of serum- and

glucocorticoid-inducible kinase (SGK). Mononuclear precursor cells from

cystic fibrosis patients tend to differentiate to inflammatory cell types at

higher rates compared to those from healthy individuals, and it is believed

that SGK overexpression is the source of this imbalance.

Several studies were conducted to understand the physiological

mechanisms of the disease, trying to identify how the CFTR protein

channel interacts with other chloride channels or lipid microdomains.

Studies were conducted to elude how mutations give rise to protein

defects. This enabled the creation of a method to test hypotheses for

chloride channel rescue, opening new avenues for therapeutic use.

Pharmacological approaches use these insights to treat cystic fibrosis and

are based on restoring function to the CFTR channel by nullifying the

defect caused by the mutation.


Microbiology – research to understand the consequences of the disease

The microbiology space in cystic fibrosis research is mainly occupied by

studies on the pathogen Pseudomonas aeruginosa, the bacterium that

causes infections and disease complications in cystic fibrosis patients

most frequently. Since antibiotics are currently the only way of treating

infections that accompany cystic fibrosis, a lot of research is done to

optimise their regimen or to find suitable alternatives to avoid generating

antibiotic resistance among frequently recurring pathogens.

Pseudomonas aeruginosa is very difficult to treat and severely impairs

the quality of life and life expectancy of patients. A proper immune

response is obviously essential to clear the pathogen from the infection

site. However, many pathogens including Pseudomonas aeruginosa have

developed mechanisms to modulate the immune response and create a

unique niche for their survival and propagation. One study found that

IgA antibodies are produced upon infection, indicating that it is not a

lack of them that contributes to pathogenesis. Infection is thus detected in

the body, however, IgA antibodies do not seem to contribute to clearance

of the pathogen in the lungs as it normally should. One of our laureates

identified exactly how Pseudomonas bacteria escape the normal immune

response in the lungs in infected cystic fibrosis patients. By injecting

macrophages with the toxin ExoS, Pseudomonas interferes with the white

blood cells’ capacity to produce and secrete the cytokine IL-1b, a mediator

of inflammation. This insight could provide a gateway to innovative

antibiotic-independent treatment of the most common infection and

cause of death in cystic fibrosis patients.

The explant cystic fibrosis lung research project took a more zoomed-out

view of the cystic fibrosis lung and the microbiota present. Lungs were

frozen solid and techniques such as CT-scans, immunostaining and

16SrRNA analysis were used in various lung regions to map structural

abnormalities, histopathological changes and local microbiota. This study

suggested a correlation between the spatial heterogeneity of lung damage

with tissue remodeling, inflammation or the presence of certain bacteria.


Because infections are such a threat to cystic fibrosis patients, antibiotics

are obviously a cornerstone of cystic fibrosis treatment. Knowledge on these

antibiotic agents, their effect on bacterial populations and the emergence of

resistance is therefore of great value. With the aim of optimising antibiotic

therapies, one laureate initiated a project studying the pharmacokinetics

of frequently used antibiotics by using mass spectrometry-based

monitoring of their concentrations in serum and sputum. With these

techniques, a drug monitoring analytical methodology was developed for

the inhaled antibiotics tobramycin and aztreonam-lysine and the efficacy

of piperacillin/tazobactam was evaluated. These experiments are hugely

relevant when considering the possibility of more personalised antibiotic

regimens for different patients and improved clinical outcomes.

However essential antibiotics may be in cystic fibrosis treatment, these

compounds are a fundamentally unsustainable way to treat infections as

resistances arise. With this in mind, there is a continuously ongoing search

for alternative and more efficient and precise ways to treat infections. One

of the Fund Alphonse & Jean Forton’s laureates proposed that so-called

pyocins might just do the trick. These are toxins produced by various

Pseudomonas strains to compete within its own species. Strains producing

a type of pyocin also express a protein that renders them immune for their

own pyocin type while sensitive strains are killed. Since these substances

only kill Pseudomonas aeruginosa and are non-toxic to the host, they

might provide a viable alternative to antibiotics. By characterising

various pyocin receptors, weaknesses of different strains can be mapped.

Afterwards, chimeric pyocin toxins were designed to be broadly applicable

to a spectrum of Pseudomonas strains, offering a specific way to combat

Pseudomonas infections in cystic fibrosis patients.


The development of new research methods, techniques and therapeutic concepts

The scientific landscape is constantly progressing and evolving. New

technologies become available that provide a platform for innovative

therapies or novel research techniques and methodologies. This is no

different for cystic fibrosis research and the Fund Alphonse & Jean Forton

is proud that its laureates have contributed significantly to this area over

the years.

In a collaboration between two of the Fund Alphonse & Jean Forton’s

laureates, single-domain antibodies produced by camelids such as

llamas and alpacas, also known as nanobodies, were assessed for their

therapeutic potential in cystic fibrosis. As nanobodies are relatively small,

they are able to bind certain protein epitopes that are inaccessible for

conventional antibodies. Making use of this characteristic, nanobodies

can be developed to stabilise the CFTR channel to keep it functional. As

this could be a potentially revolutionary new way to treat cystic fibrosis,

the method was swiftly protected by intellectual property.

Another of these technology platforms are the antisense oligonucleotides

(AONs), shorts strings of natural or chemically modified RNA or DNA

strands that bind mRNA in the cell and inhibit translation in a sequence-

specific fashion. As cystic fibrosis is not only characterised by a reduced

absorption of chloride but also an excessive absorption of sodium ions,

one of our laureates designed AONs to inhibit the epithelial Na+ channel

(ENaC) and demonstrated its functional relevance in a cellular cystic

fibrosis model.

Of course, no overview of cystic fibrosis would be complete without the

inclusion of gene therapy.

For a long time, gene therapy was considered the ultimate cure for cystic

fibrosis due to its genetic origin. Although gene therapy still has many

hurdles to overcome in terms of practical application, research into the

subject has been booming for quite some time, also in cystic fibrosis

research. A Fund Alphonse & Jean Forton laureate made use of modified

viral particles, or viral vectors, as a mechanism to administer a functional


CFTR gene to replace the defect copy present. Viruses are a perfect vehicle

to bring DNA into cells, as it is their natural replication mechanism.

By administering an adeno-associated viral vector via the airways,

the research team was able to rescue CFTR channel function in both a

mouse model of cystic fibrosis and patient-derived intestinal organoids,

providing a powerful proof of concept for the technique. However, many

years of research are still required before such an application enters

clinical validation.

Next to novel therapeutic strategies, new research tools and disease

models are needed to sustain progress in cystic fibrosis research. One

of such practical tools is human embryonic stem cells (hESC) derived

from cystic fibrosis patients and thus carrying naturally occurring CFTR

gene mutations. Once a cell line with these characteristics is established,

it provides cystic fibrosis researchers with a new model, or enables them to

grow organoids from the stem cells to use in research or drug development.

Another example is the development of novel methods to measure

the flow of currents through ion channels, as this is a measure of how

well the CFTR channel is functioning. This allows researchers to assess

the potential of different drugs to correct defect CFTR channels by

measuring improvements in current. One of our laureates designed an

automated electrophysiological workstation that allows for the screening

of cystic fibrosis drugs in human bronchial epithelial cells by means of

transepithelial current measurements. This platform can now be used

to screen up to 500 compounds per week, drastically accelerating drug

discovery and development.


3.3 The Fund Alphonse & Jean For ton gets s trong suppor t from the scientif ic community

Laureates of the Fund Alphonse & Jean Forton have praised its support

and consider it to be invaluable for their research projects. In fact, 100% of

the respondents said the grants received were significant for their research.

With the resources of the Fund Alphonse & Jean Forton, researchers are

able to pursue different, perhaps more risky research avenues. This can

lead to unexpected but no less valuable outcomes.

By providing the resources to scientists already active

in the cystic fibrosis field to try out new ideas, the

Fund Alphonse & Jean Forton enables high risk high

gain research that might remain untapped otherwise

On top of empowering existing cystic fibrosis scientists,

the Fund Alphonse & Jean Forton also actively attracts

researchers from outside the cystic fibrosis field. Many

laureates confirm that the Fund Alphonse & Jean Forton

initiated their interest in cystic fibrosis and motivated

them to start research on the disease. As such, the Fund

Alphonse & Jean Forton plays an active role in expanding

the Belgian cystic fibrosis research community. Laureates

indicate that much of the Fund Alphonse & Jean Forton’s financing is spent

on academic personnel: numerous technicians, postdoctoral researchers

and doctoral students are able to become part of the cystic fibrosis research

community thanks to the Fund Alphonse & Jean Forton. As an indication,

among all research groups more than half the money received from the

grants went to additional personnel working on the project.

One third of all respondents moved into the cystic fibrosis research area

because the Fund Alphonse & Jean Forton made grants available, triggering

the interest among molecular biologists and geneticists to further use their

scientific knowledge in this domain. Secondly, it created collaborations

within universities across disciplines, among universities in Belgium,

“Although the initial

hypothesis of our project has

not materialised, our work

has nevertheless sparked two

complementary research lines,

connecting two different topics

within Cystic fibrosis research.”

Prof. Jan Eggermont

(KULeuven, Laureate 1999)


and at the international level. Thirdly, it

created a community of expertise, which

did not exist before. As one respondent

put it: “The Fund Alphonse & Jean Forton

plays an important role: it coordinates

activities in cystic fibrosis research

without consciously doing so”. Finally,

because of its broad scope, the Fund

Alphonse & Jean Forton granted very

complementary areas of research, which

results in specialisations in many areas

from early basic research over clinical

trials to a patient registry.

Attracting additional funding

For all respondents in our survey, the Fund Alphonse & Jean Forton was

critical in funding their cystic fibrosis research. We asked respondents

to give a rough estimate of the importance of the grants. For 27% of

the respondents, the Fund provided less than 25% of the cystic fibrosis

research grants they received, for 33.3% it represented between 25 and

50% of their revenue, for 16.6% it represented between 50 and 75% of

their revenue, and for 22,2% it represented more than 75%. This again

demonstrates that the existence of the Fund Alphonse & Jean Forton has

a strong orientation of academic research

to areas in which they were probably not

active before, with 38% of the laureates

obtaining more than 50% of their cystic

fibrosis funds from the Fund Alphonse &

Jean Forton.

“Thanks to the fund we were able to recruit an

additional full-time employee in our group.

The research supported by the fund resulted in

important findings about the genetic basis and

mechanisms of CF and CFTR-related diseases,

as published in numerous international peer-

reviewed scientific journals. The importance of

these findings is underscored by the fact that the

Principal Investigator, and his research group,

became an internationally recognised group in the

Cystic Fibrosis Scientific and Medical Society.”

Prof. Harry Cuppens

(KULeuven, Laureate 2008 and 2011)

“The Fund Alphonse & Jean Forton provided us

with startup financing to start research in this

area. We will soon have a PhD student who will

continue the research and have applied for other

continuing funding on this topic.”

Prof. Alain Verstraete (UGent, Laureate 2014)


While the direct support of the Fund Alphonse & Jean Forton provides

scientists with necessary resources, many ‘secondary’ benefits of the Fund

can be observed. For instance, an endorsement by the Fund opens doors

to additional financing. Many laureates indicate that the grant has acted

as a leverage for additional funding, further attracting financial means

to cystic fibrosis research. These include grants from various government

levels, with the EU being a major source of funding, but also from industry

and other private organisations involved in the cystic fibrosis field.

Like the Fund Alphonse & Jean Forton, some of

these funding initiatives have a very strong focus

on providing financial means for cystic fibrosis

research, which could provide an opportunity

for overarching collaboration. Many national

cystic fibrosis initiatives exist, such as Vaincre la

Mucoviscidose in France and the Italian Cystic

Fibrosis Research Foundation (FFC). As these

organisations are willing to look across borders

to provide assistance to cystic fibrosis researchers,

partnerships between likeminded organisations

have the potential to lead to a more structural

approach to cystic fibrosis research funding.

“The results obtained thanks to the

support of the Fund Alphonse &

Jean Forton allowed us to obtain

complementary funding from

Vaincre la Mucoviscidose (France),

Association Luxembourgeoise

de Lutte contre la Mucoviscidose

(Luxemburg) and Welbio (Belgium).”

Prof Cédric Govaerts

(ULB, Laureate 2011 & 2014 & 2017)

Percentage of total funding represented by Fund Forton grants

25 – 50%

50 – 75%

< 25%> 75%


International visibility and collaboration

Does this put Belgium on the map internationally? Although this is a

difficult element to assess quantitatively, Belgium is internationally well

reputed for its cystic fibrosis research. On the other hand, even though

the Fund Alphonse & Jean Forton has a significant budget, the enormous

amounts of money invested in research in the United States still make that

country the global leader in cystic fibrosis research. As a comparison: the

four leading cystic fibrosis researchers in the US each have 8 million dollar

in annual budgets at their disposal.

When we look at clinical trials in Europe, there are currently no

less than 69 clinical trials taking place in Belgium in the area of

cystic fibrosis, which is 20% of all cystic fibrosis studies conducted

in Europe14. Since Belgium conducts approximately 10% of all clinical

studies in Europe across all disease areas, we can conclude that the relative

weight of cystic fibrosis research is twice the average, but it is impossible

to assess to which extent this is a derivative result from the funding by

the Fund Forton. However, we can conclude that cystic fibrosis clinical

research in Belgium is flourishing.

These Belgian trials include studies for the first

pharmaceutical treatments by Vertex and drugs

in development by Galapagos. The fact that this

cystic fibrosis knowledge is available at our

universities has an effect on collaboration with

pharmaceutical companies, although a direct

link with the Fund Forton is hard to make.

Belgian researchers and clinicians have played leading roles in the

international cystic fibrosis community. The actual chairman of the

European Cystic Fibrosis Society, Prof. Dr. Kris De Boeck, is of Belgian

origin, and other Belgians have been chairmen of international scientific

congresses or chief reporters of WHO meetings on the subject.

14. clinicaltrials.gov

“Thanks to the Fund, we were able

to participate in a large European

consortium on Cystic fibrosis.”

Prof. Rudi Beyaert

(UGent, Laureate 2004)


Next to financial aid, laureates were

able to set up long-term collaborations

with internationally respected cystic

fibrosis research groups. By setting

up networks and lasting partnerships

with other research groups, hospitals

or patient organisations, many

groups were able to link fundamental

research with other aspects of the

cystic fibrosis field. This includes

gaining access to patient samples, participating in clinical trials or sharing

data to increase relevance of ongoing investigations. By enabling this kind

of high-level interaction with the international cystic fibrosis research

community, researchers are able to position themselves on the forefront

of cystic fibrosis research. By fostering international collaboration over

the years, Belgium is currently respected as an international hub for

cystic fibrosis research

Not only for the principal investigators, but clearly for their PhD

students or postdoctoral collaborators, the Fund was an excellent

springboard. Dr. Marianne Carlon received the Cystic Fibrosis Young

Investigator Award in 2011.

“The Fund Alphonse & Jean Forton helped in setting up lasting collaborations with clinical

centres in Belgium and France, with whom we obtained international grants. Importantly,

it helped build the careers of students who obtained their PhD and got jobs in the

pharmaceutical and biomedical industry, and of post-doctoral researchers who, after their

stay in our lab, obtained prestigious academic positions in France.”

Prof. Frédéric Lemaigre (UCL, Laureate 2008 & 2011)

“After starting the project at the UZ Leuven

I continued and extended the work as a full professor

at the University of Muenster (Germany). The

initial grant helped me tremendously to establish

an international network on cystic fibrosis research.

Furthermore, the grant was a clear facilitator to many

other grants from a great variety of sources.”

Prof. Wolf-Michael Weber

(KULeuven, Laureate 1999)


3.4 Overview of the impact of the Fund Alphonse & Jean For ton for cystic f ibrosis research

8 million euro

> 300 scientific publications

For the benefit of all cystic fibrosis patients

30 research groups

53 research projects

Cause of cystic fibrosis

Microbiology of cystic fibrosis

Better treatment of cystic fibrosis

National Patient Registry


4


A SUPPORT ING NETWORK4.1 The Belgian Cystic Fibrosis RegistryAlready in 1995, members of the medical committee of the Belgian

Cystic Fibrosis Association decided to set up a national patient registry.

Existing functioning cystic fibrosis registries in the US, Canada, France

and Germany were studied, contacts were made and a pilot project with

the clinical data of 100 patients from different academic Belgian cystic

fibrosis centres was set up. The university hospital of the University of

Brussels (VUB – UZ Brussel) was chosen as coordinator. The results were

very encouraging and the decision was made to create the Belgian Cystic

Fibrosis Registry. The supervision of the project was entrusted to the

same committee. The initial location and funding were provided by the

UZ-Brussel. This project was set up as a collaboration between different

universities, academic and general hospitals, private practitioners and

possibly IT departments.

The launch of the Fund Alphonse & Jean Forton by the King Baudouin

Foundation offered a perfect opportunity to turn this fledgling initiative

into a more solid project.

The initial goals of the cystic fibrosis registry were numerous. First, to

observe the natural course of the disease, such as age and conditions

at diagnosis, prevalence, morbidity and mortality. Second, to gather

additional data to provide support to scientific clinical and basic research,

such as the study of infection patterns, the study of the heterogeneity of

the presentation of cystic fibrosis like mild cases and older patients, the

study of genotype/phenotype relationships, the study of indications for

lung transplantation or gene therapy. Third, to provide data to optimise

patient health and well-being. And finally to provide families, healthcare

providers and the community with quality and verified patient data.

Initially, there was a heated debate whether this project could fit within

the scope of the Fund Alphonse & Jean Forton. Could a registry be

considered part of scientific research? Should the money not be spent

on basic research? In today’s era of big data collection and analysis, the


discussion might appear to be futile but technology and priorities change

over time. Luckily, common sense prevailed and the Fund Alphonse &

Jean Forton provided the Belgian Cystic Fibrosis Registry with its first

large funding, essentially dedicated to hiring scientific personnel.

The registry, a national and centralised database,

gathers a broad range of patient data, with more than

200 parameters per patient every year. The treating

physician collects demographic and clinical data

from medical records once a year. These include the

age at diagnosis, the mutations, the clinical follow-up

data such as length, weight, body mass index, lung

capacity, types of lung infections etc. The treatment

regimen (antibiotics, physiotherapy, etc) and the

occurrence of lung transplants are of course also

monitored. Co-morbidities and complications such

as diabetes, gastro-intestinal problems, liver disease

and psychological problems are mentioned as soon

as they occur. In the early years, all information was

collected by completing a pre-printed paper form. A

manually processed data report was issued every year

under the supervision of the medical committee. It

contained summary tables (e.g. microbial infections, therapeutics) and

statistical calculations (e.g. BMI, lung function tests). The data report

was systematically sent to the provider of the patient data. It served as a

determinant tool to promote the Belgian Cystic Fibrosis Registry not only

in the medical world (national and international medical conferences) but

also within the cystic fibrosis community.

The whole system was re-configured in 2004. Data were first collected

via CD-ROM, and later, between 2011 and 2013 through a web-based

application. Since 2015 the registry uses, like many other registries,

the generic services of the Healthdata.be platform for data collection,

validation and analysis. Through these 20 years the general structure of

the Belgian Cystic Fibrosis Registry has undergone only limited changes.

“The Fund Alphonse & Jean Forton

started precisely at the right moment

for the development of the Belgian

Cystic Fibrosis Registry. With the

financial support of the Fund, we

got the opportunity to hire highly

educated collaborators, familiar with

epidemiology and automation, very

precise in their work and all of them

highly motivated. Today, our initial

project has become a crucial part of the

cystic fibrosis treatment landscape.”

Prof. em. C. Sevens,

VUB and UZ Brussel, first coordinator

Belgian Cystic Fibrosis Registry

(Laureate, 1997 and 2001)


The first registry in 1998 collected data from 534 patients to reach over

1 200 today, an impressive figure covering almost all Belgian cystic fibrosis

patients, making Belgium one of the best performing countries in Europe.

In 1999, seven cystic fibrosis reference centres were accredited by the National

Institute for Health and Disability Insurance (INAMI – RIZIV). An annual

care and revalidation agreement for patients with cystic fibrosis was signed

between each reference centre and the National Institute for Health and

Disability Insurance from which the former received financial support.

This relationship is still in effect. Each centre has to have specific expertise

in cystic fibrosis care and be able to ensure multidisciplinary follow-up of

the patients in order to provide optimal medical, paramedical, psychological

and social care to the patients and their relatives. The Belgian Cystic

Fibrosis Registry works since 2006 within the framework of this agreement.

Participating in data collection for the Belgian Cystic Fibrosis Registry is one

of the compulsory tasks of the reference centres. The objective of the National

Institute for Health and Disability Insurance was to be informed about the

epidemiological aspects of cystic fibrosis in Belgium and get unbiased data

about the quality of care provided to patients. In addition they wanted to

participate in a database able to provide essential data for scientific research

and to function as a support for the development of new drugs. They also

participate in the European Cystic Fibrosis Patient Registry, an opportunity

created from the start in 1998. Today 27 countries are part of the European

Cystic Fibrosis Patient Registry. This initiative took an active part into the

mapping of more than 2 000 mutations causing the defective gene.

Nowadays each year a national data report15 with results and updated

clinical guidelines is published and made available on the website of the

Scientific Institute of Public Health16. The cystic fibrosis reference centres

receive benchmarking results for their own centre. This procedure allows

each of them to compare them with other centres in order to improve and

optimise the care to their patients.

15. Annual report Belgian cystic fibrosis registry 2014 | www.wiv-isp.be

16. Wetenschappelijk Instituut Volksgezondheid (WIV) / Institut Scientifique de Santé Publique (ISP)


The Belgian Cystic Fibrosis Registry was unmistakably highly funded by

the Alphonse & Jean Forton Fund (above 60%) at different stages of its

development between 1998 and 2005. Apart from its financial support, the

Fund contributed to the scientific credibility of the registry which became a

reference for cystic fibrosis registries in the European Union. The quality of

the data was largely recognised and the level of patients included served as

an example in Europe. It also paved the way for other registries in Belgium

such as the Belgian Neuromuscular Disease Registry. After 2006, the

Belgian Cystic Fibrosis Registry benefited from a more structural funding

from the National Institute for Health and Disability Insurance, allowing

for ongoing continuity. Today, it is managed by the Scientific Institute of

Public Health, which ensures the collection and management of data under

the supervision of a board with the guidance of a scientific steering group.

Thanks to the Belgian Cystic Fibrosis Registry we know how many

patients there are, how their treatments evolve, how their life expectancy

improves and how Belgium compares to other countries The Registry

participated in identifying different mutations across a large geographic

area in Europe, and also locally in Belgium It makes it possible to

benchmark the quality of care on national and international levels, to

distinguish between effective and ineffective therapies After these 20

years of existence its influence on clinical practice has been remarkable

It serves as an evaluation tool for the treatment of lung infections and

offers a better view on the indications for lung and liver transplants The

Registry has given a good picture of how cystic fibrosis was diagnosed

and revealed the heterogeneity of patients Clinical trials make good use

of the registry’s data for patient selection and drug development Taken

together, the registry provides data that can be used as reference points

for research, an invaluable asset


4.2 The voice of the patient : the Belgian Cystic Fibrosis Association

The Belgian cystic fibrosis association (Muco Vereniging vzw/Association

Muco asbl17) has been involved in research for many years. For the last

call of the Fund Alphonse & Jean Forton, it joined forces with the King

Baudouin Foundation and launched a joint call. This allowed combining

support for clinical research with a more direct impact for patients

with the Fund Alphonse & Jean Forton, focused on advancing basic

and translational research. This joint call resulted in a very broad and

complementary support towards the cystic fibrosis community.

The Fund Alphonse & Jean Forton has always been attentive towards

patients In fact, the Belgian Cystic Fibrosis Association receives a

yearly dotation to provide support to patients. They were one of the

first associations to receive support from the King Baudouin Foundation,

which has been incremental to develop the services they are offering today

to patients and families. The organisation does not receive government

subsidies, so it depends fully on membership fee and private fundraising.

The grant it receives from the Fund Alphonse & Jean Forton is substantial

and very important.

The Belgian Cystic Fibrosis Association’s tasks are very broad: one

of these is to help patients in covering their medical costs. For some

families the costs associated with cystic fibrosis care are too high and

the organisation helps these families in covering excess costs so they can

also benefit from optimal care. Another task is to provide information

and education to different audiences, such as going to schools to create

more awareness and understanding. Patients can also contact the

association for psychosocial support. Treatments can weigh heavily on

patients and their family and to have someone to talk to can mean so

much. Of course, the Cystic Fibrosis Association also lobbies for the

rights of the patients, collectively or for individual patients that run into

17. www.muco.be


problems at school or at work. For the official bodies in Belgium, the

Belgian Cystic Fibrosis Association definitely is the voice of the cystic

fibrosis patients. Of course, they continue to support research, and

through its collaboration with the King Baudouin Foundation and the

Fund Alphonse & Jean Forton, the impact will only increase… And last

but not least, the organisation offers very practical support by providing

specific medical materials that are vital for patients.

Patients are the core of the organisation, and they also turn to the

association for more information. The educational material provided can

help them in making more informed decisions.


5


CONCLUDING REMARKSIt is clear that over the past 20 years the Fund Alphonse & Jean Forton

has been a powerful force for progress in the cystic fibrosis field in

Belgium By providing financial means to cystic fibrosis researchers,

elevating local research to international levels, attracting talented

scientists and creating financial leverage for increased cystic fibrosis

research, the Fund can be regarded as a key facilitator in the

generation of a Belgian cystic fibrosis research network

We have seen that the financial support allowed research to be conducted on

trying to understand the cause of the disease, providing better symptomatic

treatment, tackling microbiological infections or development of new

research methods and even more importantly, new treatment options that

tackle the basic defect on the protein, RNA or gene level.

The Fund has had a stronger impact than the individual contributions

by the researchers. It has created a research option that one third of the

laureates had not considered prior to its existence. It has advanced the

collective understanding of the disease and created a loose community

of expertise, which would otherwise not have existed. This includes the

collaboration with the patient organisation and the cystic fibrosis registry.

When asked, 75% of participants suggest not changing anything to the

working of the Fund. It appears to work well in its current format, with the

additional advantage of being flexible and un-bureaucratic. Interestingly

the suggestions for improvement are not related to the current grant, but

about taking up additional responsibilities and creating means to bring

the researchers and stakeholders together, to open up collaboration with

international partners, and to even make international calls.

If anything, they want the Fund to continue as it operates today, and they

see a lot of future research that still needs to be further investigated (and

funded), and this in all areas, from a better understanding of the disease

at its molecular level, to finding innovative treatments in the area of gene

therapy, nanobodies of pharmacological compounds.


All these scientific evolutions are very promising for patients. Twenty

years ago, when Jean Forton created the Fund that carries his and his

father’s name, patients, all children still, with cystic fibrosis had meagre

prospects, living from one infection to the other, spending more time on

controlling their disease than on playing, and having a very short life

expectancy. He would be surprised to learn that now, life expectancy has

more than tripled, that the disease is now better understood and that the

first treatments have reached the market. He would be proud that a vibrant

research community in Belgium has benefited from his capital and that

it has been put to good use. A causal treatment is not yet available to all

patients, but as the Fund Alphonse & Jean Forton continues to exist, it can

continue to initiate and support impactful studies and research outcomes.


APPENDIXLaureates and projects supported by the Fund Alphonse & Jean Forton 1997-2014

PI Affiliation Year Project title

Renaud Bauwens ULB 1997 The CFTR protein: comparison with the P-glycoprotein or other ABC-transporters

1999 Function and processing of the natural and mutant CFTR protein as well as of other ABC-transporters

2001 Pathophysiology of epithelial chloride channels and depending anion exchanges. Special emphasis on inherited diseases involving mutations of these chloride channels and transporters (Cystic Fibrosis, Dent’s disease and Pendred Syndrome)

2004 Role of the phosphatidlinositol 3-kinase in the trafficking of normal and mutant CFTR protein

2008 The critical role of bicarbonate in physiology and pathophysiology with special emphasis on Cystic Fibrosis and Pendred syndrome.

2011 Mechanisms of HCO3-transport across cell membrane in Cystic Fibrosis target tissues and with special emphasis on intracellular controlling pathway IRBIT and WNK-SPAK/OSR1

Jean-Marie Ruysschaert

ULB 1998 Membrane structure of the Cystic Fibrosis Membrane conductance regulator

2001 Identification of structural states involved in CFTR mediated transport: a prerequisite to a molecular description of its biological activity

Jean-Marie Boeynaems

ULB 1998 Characterisation of the P2Y receptors involved in the therapy of cystic fibrosis by nucleotides

2001 Modulation of the airway epithelium immune function by nucleotides: implication for cystic fibrosis



Marc Abramowicz

ULB 1997 Mapping of Genetic Factors involved in modifying pulmonary disease severity in CF patients

1999 Viral vector-free gene therapy for cystic fibrosis using chimeric RNA/DNA oligonucleotides

Marc Estenne ULB No Call

Subside pour recherche clinique utilisant un stimulateur magnétique

Alain Boom ULB 2014 Impact of serum- and glucocorticoid-inducible kinase (SGK) overactivation/expression on Cystic Fibrosis with emphasis on regulation of chloride channels

Claude Sevens VUB 1997 Het Belgisch register voor mucoviscidose

2001 Belgian Cystic Fibrosis Registry (BRM-RBM) 2002-2004, further developments

Cedric Govaerts VUB 2011 Restoring mutant CFTR Function with Nanobodies

2014 Restoring mutant CFTR Function with Nanobodies

Jan Steyaert VUB 2011 Restoring mutant CFTR Function with Nanobodies

Inge Liebaers VUB 1997 Preimplantation genetic diagnosis for cystic fibrosis and early expression of the CFTR gene

1998 Preimplantation genetic diagnosis for cystic fibrosis: development of strategies applicable to different genetic situations

2004 Derivation of human embryonic stem cells carrying cystic fibrosis and study of factors influencing the derivation of lung epithelial cells from normal human embryonic cells

Pierre Cornelis VUB 1998 New targets for therapeutic intervention against Pseudomonas aeruginosa in cystic fibrosis patients

Christophe Ampe

UGent 1997 Development of mutant actin binding protein as mucolytic agents for cystic fibrosis sputum



Alain Verstraete UGent 2014 Optimisation and application of UPLC-MS/MS based monitoring of antibiotics in sputum of cystic fibrosis patients

Rudi Beyaert UGent 2004 Role of caspase-1 modulation by specific Pseudomonas aeruginosa effector proteins as a novel mechanism of immune escape

Sophie Claeys UGent 2001 Innate Immunity and the role of staphylococcus aureus enterotoxines in cystic fibrosis

Jean-Jacques Cassiman

KULeuven 1997 Structural and functional studies of the R-domain of the CFTR protein

1999 A search for modulating mutations/poymorphisms in genes that encode proteins that are part of the CFTR network

2004 A search and characterisation of mutations/genes in which a CF-causing mutation cannot be indentified on both CFTR genes of CF patients, and a search on characterisation of mutations/genes modulating the CF phenotype, and their involvement in other CFTR-related diseases

Harry Cuppens KULeuven 2008 Generation of a functional CFTR-‘mutatogram’ and search for rescuing mutations of F508del

2011 Exomic and transcriptomic profiling by highly parallel sequencing in patients with CF, CF-like, and CFTR-related diseases

Bernd Nilius KULeuven 1998 Links of CFTR to volume-regulated (VRAC) and calcium- activated (CACC) chloride channels: molecular biology and functional consequences

Wolf-Michael Weber

KULeuven 1999 Correction of excessive Na+ absorption in cystic fibrosis with antisense oligonucleotides

Willy Vandriessche

KULeuven 2001 Investigation of ATP release in relation to Cl secretion in airway surface epithelia



Zeger Debyser KULeuven 2011 Development of an animal model for fetal gene therapy of cystic fibrosis

KULeuven 2014 Viral vector technology as a gene therapeutic tool in search for a cure for cystic fibrosis

Jan Eggermont KULeuven 1999 Caveolin-dependent repression of CFTR activity in an intestinal epithelial cell line: functional and structural analysis

Peter Carmeliet KULeuven 2001 Generation of new Cystic Fibrosis mouse models on defined inbred genetic backgrounds with more severe or restricted lung disease and use of bone-marrow-derived stem cells for treatment of CF lung disease in mice

Lieven Dupont KULeuven 2008 The role of adaptive immune response in the pathogenesis of airways inflammation and lung disease in cystic fibrosis

2014 Correlating ultrastructural abnormailties, histopathological changes and local microbiota throughout the explanted CF lung

Paul Tulkens UCL 1999 Setting up an optimised home-therapy of lung infectious episodes and basic research on the mechanism of altered pharmacokinetics of antibiotics in cystic fibrosis patients



Olivier Devuyst UCL 1997 Relationship between genotype and phenotype in cystic fribrosis: expression patterns, intracellular processing and specific functions of CFTR isoforms

1999 Processing and function of CFTR in the kidney as a model for differential tissue penetrance of the cystic fibrosis phenotype

2001 The role of chloride channels in proximal tubule endocytosis and vesicular acidification

2008 Project title: CFTR and ClC-5 in the kidney: pathophysiology of epithelial cell diseases

2014 Functions and comparative ontogeny of the endosomal chloride channel, CIC-5

Charles Pilette UCL 2014 Impaired secretory IgA and mucosal immunity in cystic fibrosis: contribution to lung pathology and impaired defence against bacterial infection, and role of CFTR-related epithelial changes in the regulation of the receptor- mediated IgA transcytosis

Fredéric Lemaigre

UCL 2008 Regulation and role of anion channels in biliary development

2011 Role of anion channels in hereditary polycystic liver disease

Michel Jadot Université de Namur

1997 Intracellular trafficking ad fate of ΔF508 CFTR

1999 Expression and intracellular trafficking of CFTR

Vincent Bours ULG 2001 Mechanisms of bronchial inflammatory reaction in cystic fibrosis: role of NF-kB activation and oxidative stress



Françoise Mascart

ULB 2017 Development of immuno-assays to diagnose infection with atypical mycobacteria in patients with Cystic Fibrosis and investigation of their potential for monitoring treatment success

Cedric Govaerts ULB 2017 Development of CFTR-stabilizers as therapeutics for cystic fibrosis.

Françoise Van Bambeke

UCL 2017 Efflux as a mechanism of intrinsic and acquired resistance to antibiotics in Achromobacter xylosoxidans

Marianne Carlon KULeuven 2017 Development of drug based therapies to target rare mutations causing severe cystic fibrosis

Lieven Dupont KULeuven 2017 Dynamics of cystic fibrosis airway microbiota: application of next-generation sequencing in a long-term cohort study to characterize bacterial and viral components prior to and during acute exacerbations.

Peter Witters UZ Leuven 2017 The endothelium as the central mediator of cystic fibrosis associated liver disease.

Coenye Tom UGent 2017 Developing a personalized approach for antimicrobial susceptibility testing in cystic fibrosis

Laureates and projects supported in the framework of the first joint call of the

Fund Alphonse & Jean Forton and the Belgian Cystic Fibrosis Association 2017


ACKNOWLEDGEMENTSThe King Baudouin Foundation wants to thank all the laureates for

their excellent research and time investment. We also want to thank

the members of the Jury and of the Management Committee for their

insights and support, as well as the international experts who reviewed

all the submitted project proposals over the last twenty years. Without

their time, open and frank evaluations, the selection of the best research

projects would not have been possible.

The editors of this report would also like to thank the members of our

“reading committee” for their valuable insights and time investment:

– Professor Joseph Martial, Chairman of the Jury of the Fund Alphonse

& Jean Forton, Prof. Em. ULg

– Professor Renaud Beauwens, Laboratory of Molecular and Cellular

Physiology, ULB

– Dr. Marianne Carlon, Molecular Virology and Gene Therapy,

KU Leuven

– Ms Ulrike Pypops, Belgian Cystic Fibrosis Association

– Ms Annemie T’Seyen, King Baudouin Foundation

– Ms Bénédicte Gombault, King Baudouin Foundation

A special thanks goes to Professor Emeritus Dr. Claude Sevens, head of

the Clinical Chemistry Lab of the University of Brussels (VUB) from

1977 till 2002, who set up the Belgian Cystic Fibrosis Registry and who

managed it for many years.


King Baudouin FoundationWorking together for a better society

The King Baudouin Foundation’s mission is to contribute to a better

society.

The Foundation is an actor for change and innovation, serving the public

interest and increasing social cohesion in Belgium and Europe. We seek

to maximize our impact by strengthening the capacity of organizations

and individuals. We also stimulate effective philanthropy by individuals

and corporations.

The Foundation’s key values are integrity, transparency, pluralism,

independence, respect for diversity, and promoting solidarity.

The Foundation’s current areas of activity are poverty and social justice,

philanthropy, health, civic engagement, developing talents, democracy,

European integration, heritage and development cooperation.

The Foundation was set up in 1976 on the occasion of the 25th

anniversary of King Baudouin’s reign.

With thanks to the Belgian National Lottery and to all donors for

their valued support.

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King Baudouin Foundation, public benefit foundation

Rue Brederodestraat 21 B-1000 Brussels [email protected] +32-2-500 45 55

Donations of 40 euros or more made to our account:

IBAN: BE10 0000 0000 0404 – BIC: BPOTBEB1 give rise to a tax

reduction of 45% on the amount actually paid.

http://www.bonnescauses.be/ – https://www.goededoelen.be/

Managed by the King Baudouin Foundation 20 YEARS OF · Author(s) Stefan Gijssels & Ann Van Gysel...

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Transcript of Managed by the King Baudouin Foundation 20 YEARS OF · Author(s) Stefan Gijssels & Ann Van Gysel...