Regenerative medicine in the management of neurological conditions · 2015-06-18 · regenerative...
Transcript of Regenerative medicine in the management of neurological conditions · 2015-06-18 · regenerative...
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Regenerative medicine in the management of neurological
conditions
Horizon Scanning Centre
August 2012
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This report presents independent research funded by the National Institute for Health Research (NIHR). The views expressed in this publication are those of the author(s)
and not necessarily those of the NHS, the NIHR or the Department of Health.
The NIHR Horizon Scanning Centre,
University of Birmingham, United Kingdom
www.hsc.nihr.ac.uk
Copyright © University of Birmingham 2012
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Contents Page Number
Summary 4
Introduction and background 5
Clinical need and burden of disease 5
Aims and objectives 6
Methods 6
Results
Identified products 7
Phase III clinical trial – multiple sclerosis 13
Phase II/III clinical trial – spinal cord injury 13
Phase II clinical trials 14
Phase I/II clinical trials 15
Conclusion 15
Appendices
Appendix 1 UK regenerative medicines, organisations and network 17 Appendix 2 Online search sources 18 Appendix 3 Glossary of terms 20
References 21
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Summary
Aim
To identify and investigate the stage of development of emerging regenerative medicine
technologies that potentially may benefit patients with chronic neurological conditions.
Methods
We conducted an initial search to scope the review and identify appropriate contacts and
organisations in the UK. We followed this with a more detailed online search to identify
developments using pre‐determined search terms. Once potential developments had been
found we searched clinical trial databases to gather further information on products closer to
licensing or launch.
Results
Fifteen emerging products or techniques were identified in late clinical trials for a range of
neurological diseases. One is in phase III clinical trials; one in phase II/III trials and thirteen in
phase II. A total of 76 clinical trials were identified in phase I to III trials. The products nearest
to full clinical use are in development for multiple sclerosis and spinal cord injury. Two of the
fifteen trials identified are industry led and one is a joint collaboration between industry and
researchers.
Conclusion
Developments in regenerative medicine for chronic neurological conditions show signs of
promise but it is likely to be several years before any technology is translated into clinical
practice. Multiple sclerosis appears to be the chronic neurological condition that shows most
promise in research with one phase III trial in progress and five phase II trials identified. Stem
cell technology is at the forefront of research in chronic neurological conditions accounting for
over two thirds of research in phase II or III trials. The challenge of demonstrating effectiveness
and safety to use in routine clinical practice still needs to be proven.
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Introduction and background
Regenerative medicine and in particular cellular therapy is a rapidly developing field that is
being investigated as an option for the restoration of function in many disease areas including
neurological disease. Regenerative medicine may have a significant role in the future
treatment of chronic neurological conditions.
There is considerable interest and research of regenerative medicine technologies in chronic
neurological conditions.1 A recent review of neurorestorative clinical trials activity worldwide
identified 106 ongoing or planned clinical trials.2 Approximately three‐quarters of all clinical
trials targeted one of four disease areas: multiple sclerosis, stroke, Parkinson’s disease and
amyotrophic lateral sclerosis. Cell‐based therapy represented two‐thirds of the clinical trials
focus and almost all trials are in phase I or II of development.
Clinical need and burden of disease
A ‘long term neurological condition’ results from disease of, injury or damage to the body’s
nervous system (the brain, spinal cord and/or their peripheral nerve connections) which may
affect the individual and their family for the rest of their lives.3
Long term neurological conditions encompass many different diseases (approximately 130
conditions) and results in very different experiences for people. Conditions may be present at
birth or be acquired later in life. Some conditions appear in childhood, for example muscular
dystrophy, or develop during adult life, including Parkinson’s disease. Some, such as cerebral
palsy and hydrocephalus may be associated with varying degrees of learning disability. The
prognosis for different conditions also varies widely. The average time between diagnosis and
death for someone with motor neurone disease is 14 months, while someone with multiple
sclerosis may live with the condition for decades.
Neurological conditions affect people of all ages, although the prevalence of neurological
conditions increases with age. Over the next two decades it is predicted that the number of
people with neurological conditions will increase significantly due to factors including
improved survival rates, improved general health care, increased longevity and improved
diagnostic techniques.3
A review undertaken in the United Kingdom (UK) estimated that there are in excess of 10 million people living with a neurological condition that has a significant impact on their lives.4 Over 1 million people (approximately 1 in 60 people of the UK populationa) are disabled by their neurological condition.2 Typically disability means people may need help with some daily
a Applying Office for National Statistics (ONS) mid‐2010 UK population estimate of 62.3 million
http://www.ons.gov.uk/ons/rel/pop‐estimate/population‐estimates‐for‐uk‐‐england‐and‐wales‐‐scotland‐and‐
northern‐ireland/mid‐2010‐population‐estimates/index.html
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tasks and are likely to be out of full time employment. This figure includes most people living with cerebral palsy, those who have recently had a brain injury or illness, those who have had a stroke, some people living with motor neurone disease (MND), multiple sclerosis (MS), Parkinson’s disease and forms of dementia.4 It also includes some of those with epilepsy or migraine. Annually, an estimated 1% of the UK population are newly diagnosed with a neurological condition equating to 600,000 people.4 In primary care, 17% of GP consultations are for neurological conditions, and in secondary care, 10% of accident and emergency visits and 19% of hospital admissions are for neurological conditions.4
The NHS spend on neurological conditions has increased by 38% in real terms, from £2.1 billion
in 2006‐07 to £2.9 billion in 2009‐10. Spending on social services for people with neurological
conditions has remained at an estimated £2.4 billion for the period 2005‐06 to 2009‐10.5
Currently there are no curative therapies or interventions for the majority, if not all, long term
neurological conditions and the aim of health and social care is to maximise quality of life for
people.2 The majority of treatments currently available help to reduce symptoms of disease
rather than affect progression. The hope is that regenerative medicine techniques and
products may restore the function of diseased or damaged tissues or organs through a variety
of approaches.6
Aims and objectives
The aim of this review is to identify and to investigate the stage of development of emerging
regenerative medicine technologies that potentially may benefit patients with chronic
neurological conditions.
Methods
We undertook an initial search of online sources to scope the review.
Detailed online search
We conducted an online search to find developments using combinations of pre‐determined
search terms including: neurological, nervous system, stem cells, gene therapy, tissue
engineering, biomedical technology and transplants.
Sources used (see appendix 2) included:
Medline, Embase and the Cochrane research database
Regulatory authorities
UK research councils
EU framework programme research consortia
Global trial registries
UK regenerative medicine organisations and networks (see appendix 1)
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Once we had identified potential developments we searched clinical trial databases to identify
developers and specific technologies that are in clinical trials closer to licensing and launch.
We initially searched for any cell therapy, tissue engineering and regenerative technique
products being developed for any neurological indications in any clinical trial phase. We then
excluded any that were in, or had reported results from proof of concept or phase I trials, but
had no indication or evidence of ongoing phase II trials. Trials that were listed as phase I/II
were excluded if they were essentially proof of concept trials. For technologies in phase II or III
trials additional information about complete or ongoing trials was collected. Stroke is classified
as a long term neurological condition but is excluded from this review due to its inclusion in the
published cardiovascular disease review.
Results
Identified Products
We identified 76 relevant clinical trials of regenerative medicine techniques and products
across 14 neurological conditions (table 1). Two principal therapy approaches were identified;
cellular therapy and gene therapy. Cellular therapy was the research approach used in 68 of
the clinical trials. Eighty per cent of the trials were in phase I or II, 17% in phase II, and one
each in phase II/III and phase III stages.
Multiple sclerosis and spinal cord injury were the two most researched conditions with 20 and
19 clinical trials identified respectively. Parkinson’s disease and amyotrophic lateral sclerosis
both had nine clinical trials identified. The four most researched conditions totalled 57 (75%) of
the clinical trials identified. The remaining nine chronic neurological conditions had fewer than
five clinical trials identified per condition.
Table 2 details the approach or intervention under investigation, indication, sponsors and
collaborators, and any relevant trial information for those in phase II and III clinical trials.
Stem cell therapy was almost exclusively the cellular therapy of choice, with adult stem cells
being used predominantly. Hematopoietic or mesenchymal stem cells were used in trials with
sources including bone marrow, peripheral blood and umbilical cord. Autologous and
allogeneic stem cells were investigated, with a similar number of trials under investigation at
phase II. The procedures of extracting and inserting the stem cells in to humans varied, as did
the use of immunotherapy. Six of the eight clinical trials utilising gene therapy were focused on
Parkinson’s disease.
Research was undertaken or involved collaboration with industry in twenty one clinical trials
(27%). Three of the phase II trials involved industry, the remaining eighteen trials were all at an
earlier phase.
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Table 1: Summary of clinical trials identified for chronic neurological conditions by condition, therapy type and phase.
Condition Therapy Clinical trial phase
Cellular therapy Gene therapy I I/II II II/III III Total
Alzheimer's disease 2 2 2 1 1 0 0 4
Amyotrophic lateral sclerosis† 9 0 4 4 1 0 0 9
Cerebral palsy 4 0 1 2 1 0 0 4
Encephalopathy 1 0 0 1 0 0 0 1
Hereditary ataxia 1 0 0 1 0 0 0 1
Hereditary cerebral ataxia 1 0 1 0 0 0 0 1
Huntington's disease 1 0 0 0 1 0 0 1
Multiple sclerosis 20 0 5 9 5 0 1 20
Neurological 1 0 1 0 0 0 0 1
Parkinson’s disease 3 6 2 6 1 0 0 9
Myasthenia gravis 1 0 1 0 0 0 0 1
Spinal cord injury 19 0 7 8 3 1 0 19
Epilepsy 1 0 1 0 0 0 0 1
Brain injury 4 0 1 3 0 0 0 4
TOTAL 68 8 26 35 13 1 1 76
† The most common form of Motor neurone disease (also known as Lou Gehrig’s disease).
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Table 2: Products in Phase II and/or III clinical development
Indication Approach/Intervention Sponsor/Collaborator Phase Trial information Route/method of delivery
Multiple sclerosis
Autologous unmanipulated peripheral blood stem cell therapy.
Northwestern University, USA
III Hematopoietic stem cell therapy for patients with inflammatory multiple sclerosis failing interferon: a randomized study (NCT00273364).7 Estimated enrolment 110 patients, estimated primary completion December 2012.
Not stated
Spinal cord injury
Bone marrow derived adult stem cells (unknown if autologous or allogeneic)
Bansal Foundation, India
II/III An open label, randomised, multicentre, prospective, clinical study to determine the safety and therapeutic effectiveness of bone marrow derived adult stem cells via multiple routes of administration in the treatment of patients with complete spinal cord injury (CTRI/2010/091/001469).8 Estimated enrolment 100 patients, estimated duration of trial 2 years from commencement in February 2011.
Intrathecally below the site of lesion, intravenously or directly at the site of lesion
Alzheimer’s disease
Gene therapy: CERE‐110: adeno‐associated virus delivery of nerve growth factor
Ceregene, USA II A double‐blind, placebo‐controlled (sham surgery), randomized, multicenter study evaluating CERE‐110 gene delivery in subjects with mild to moderate Alzheimer's disease (NCT00876863).9 Estimated enrolment 50 patients, estimated primary completion December 2013.
Injection into brain during surgery
Amyotrophic lateral sclerosis
Allogeneic umbilical cord mesenchymal stem cells
General hospital of Chinese armed police forces
II The clinical study on the use of umbilical cord mesenchymal stem cells in amyotrophic lateral sclerosis (NCT01494480).10 Estimated enrolment 30 patients, estimated primary completion January 2013.
Intrathecal injection ‐ lumbar puncture
Cerebral palsy
Allogeneic umbilical cord blood
Bundang CHA Hospital, Republic of Korea
II FLT(3'‐Deoxy‐3'‐[F‐18]Fluorothymidine)‐PET activity change after allogeneic umbilical cord blood cell therapy in cerebral palsy (NCT01486732).11 Estimated enrolment 40 patients, estimated primary completion April 2012. Study suspended.
Infusion intravenously or intraarterially under non‐myeloablative immunosuppression
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Indication Approach/Intervention Sponsor/Collaborator Phase Trial information Route/method of delivery
Huntington’s disease
Intracerebral graft of homologous foetal neurons
Assistance Publique ‐Hôpitaux de Paris
II Multicentric intracerebral grafting in early Huntington's disease(NCT00190450).12 Estimated enrolment 60 patients, estimated primary completion May 2013.
Intracerebral graft
Multiple sclerosis
Autologous mesenchymal stem cells
Albert Saiz, hospital clinic of Barcelona
II Autologous mesenchymal stem cell transplantation in a randomized, double‐blind, crossover with placebo phase II study (NCT01228266).13 Estimated enrolment 16 patients, estimated primary completion June 2012.
Single infusion
Multiple sclerosis
Autologous CD34+ hematopoietic stem cell transplant
National institute of allergy and infectious diseases (NIAID), USA
II High‐dose immunosuppressive therapy (HDIT) using carmustine, etoposide, cytarabine, and melphalan (BEAM) and thymoglobulin, and autologous CD34+ hematopoietic stem cell transplant (HCT) for poor prognosis multiple sclerosis (NCT00288626).14 Estimated enrolment 25 patients, estimated primary completion September 2014.
Not stated
Multiple sclerosis
Autologous hematopoietic stem cell transplant
National institute of neurological disorders and stroke (NINDS), USA
II Immunological mechanisms of immune ablation and autologous hematopoietic stem cell transplantation in secondary progressive multiple sclerosis (NCT00342134).15 Estimated enrolment 34 patients, estimated primary completion May 2011. Completed.
Not stated
Multiple sclerosis
Autologous CD34 selected hematopoietic stem cell transplant
Ottawa hospital research institute, Canada
II Intensive immunoablative therapy and immunological reconstitution: a potential curative therapy for patients with a predicted poor prognosis (NCT01099930).16 Estimated enrolment 24 patients, estimated primary completion December 2012.
Not stated
Multiple sclerosis
Hematopoietic CD34 stem cell transplant
Baylor college of medicine, USA
II Intensive immunosuppression followed by rescue with CD34 elected, T cell depleted, leukopheresis products (NCT00040482).17 Estimated enrolment 10 patients. Completion August 2005. No recent trial activity and no results identified.
Intravenous via central line in to neck or chest
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Indication Approach/Intervention Sponsor/Collaborator Phase Trial information Route/method of delivery
Parkinson’s disease
Gene therapy: AAV‐GAD Neurologix, Inc., USA II Safety and efficacy study evaluating glutamic acid decarboxylase gene transfer to subthalamic nuclei in advanced Parkinson's disease (NCT00643890).18 Estimated enrolment 44 patients, estimated primary completion December 2010. Terminated due to financial reasons.
Infusion into the subthalamic nucleus
Spinal cord injury
Mesenchymal stem cells derived from umbilical cord transplant
General hospital of Chinese armed police forces
II Efficacy difference between rehabilitation therapy and umbilical cord derived mesenchymal stem cells transplantation in patients with acute or chronic spinal cord injury in China (NCT01393977).19 Estimated enrolment 60 patients, estimated primary completion May 2012.
Lumbar puncture directly into subarachnoid
Spinal cord injury
Autologous incubated macrophages (Procord)
Proneuron Biotechnologies, USA
II Multicenter, randomized‐controlled study to evaluate the safety and efficacy of autologous incubated macrophages for patients with complete spinal cord injuries (NCT00073853).20 Estimated enrolment 61 patients. Commenced September 2003. Study has been suspended.
Injection into spinal cord
Spinal cord injury
Umbilical cord mesenchymal stem cell transplantation
General hospital of Chinese armed police forces
II The safety and efficacy of umbilical cord mesenchymal stem cell transplantation (ChiCTR‐ONC‐12002005).21 Estimated enrolment 20 patients, estimated primary completion December 2013.
Femoral artery interventional procedure
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Phase III clinical trial – multiple sclerosis
One clinical trial (NCT00273364) in the United States researching autologous unmanipulated
peripheral blood hematopoietic stem cell therapy for multiple sclerosis (n=110) was
identified at phase III. The trial aims to demonstrate the efficacy of stem cell transplant with
a conditioning therapy of cyclophosphamide and anti‐thymocyte globulin (rATG) compared
to Food and Drug Administration (FDA) approved standard of care (interferon, copaxone or
mitoxantrone) for patients with inflammatory (relapsing) multiple sclerosis failing interferon
therapy. Patients will be followed up every six months for five years. Researchers hope that
stem cell therapy may provide a mechanism of preventing progressive disease disability,
which current immune therapy is not proven to achieve.
A previous phase I/II clinical trial (n=21) investigating the use of autologous non‐
myeolablative haemopoeitic stem cell transplantation in relapsing‐remitting multiple
sclerosis suggested that for patients with relapsing‐remitting multiple sclerosis, neurological
deficits may be reversed.22 The authors state that after 37 months (range 24‐48 months) all
patients were free from progression and 16 were free from relapses.
Clinical investigation of autologous haemopoeitic stem cell transplantation as therapy for
multiple sclerosis has been ongoing for over a decade.23 Due to its risk profile,
immunodepletion followed by autologous haemopoeitic stem cells has been restricted to
patients with highly active, rapidly deteriorating, treatment refractory primary or secondary
progressive forms of multiple sclerosis.24 The safety and efficacy outcomes published to‐
date cannot therefore be transferred to other forms of multiple sclerosis. The question of
which conditioning regimen offers the optimal risk/benefit ratio remains unanswered.24 A
recent systematic review concluded that patients with secondary progressive multiple
sclerosis refractory to conventional medical treatment have longer progression‐free survival
(up to 3 years post treatment) following autologous stem cell transplant with intermediate‐
intensity conditioning regimens than with high‐intensity conditioning regimens.25
A phase III multicentre randomised controlled trial is currently in development to establish
the role of haemopoeitic stem cell transplantation for the treatment of severe, active forms
of multiple sclerosis.26 ‡
Phase II/III clinical trial – spinal cord injury
There is a phase II/III clinical trial (CTRI/2010/091/001469, n=100) ongoing for people with a
complete spinal cord injury. Bone marrow derived adult stem cells are to be administered
intrathecally below the site of lesion, intravenously or directly at the lesion site. Researchers
aim to demonstrate that the procedures are safe and therapeutically effective. Neurological
‡ It is unclear whether this trial is the same trial as NCT00273364 as reported above.
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and urinary bladder functions will be clinically assessed to determine efficacy. The study
requires the injury to have occurred from one month up to a year before inclusion.
A recent systematic review highlighted the paucity of studies carried out in more clinically
relevant models of spinal cord injury, with current clinical trials justified primarily on the
basis of pre‐clinical studies conducted predominantly in thoracic models to determine safety
and feasibility of the cellular interventions.27
Phase II clinical trials
Thirteen phase II clinical trials were identified covering seven chronic neurological
conditions. Cellular therapy accounted for 11 of the trials and stem cells used as the
intervention in nine. Two other cellular based approaches were identified.
A clinical trial in people with early Huntington’s disease in France is substituting
degenerated striatal neurons using a bilateral intracerebral graft of homologous foetal
neurons. The clinical effect of this approach will be assessed using the Unified Huntington
Disease Rating Scale (UHDRS). The other cellular approach was investigating the benefits of
autologous incubated macrophages (Procord) injected into the spinal cord for complete
spinal cord injury. The theory behind this approach was to circumnavigate the biochemical
mechanism known as immune privilege and support the regeneration of axons through the
injury site and enable the recovery of neurological function. However, this study has been
suspended with the company stating that it is not due to any clinical or safety concerns. A
phase I open label nonrandomised trial had previously been conducted to assess the safety
and tolerability of incubated autologous macrophages administered to patients with spinal
cord injury.28 The authors concluded the therapy to be well tolerated with further
evaluation warranted.
Two trials were investigating the use of gene therapy, one for Alzheimer’s disease and the
other for Parkinson’s disease (terminated due to funding). The Alzheimer’s disease trial
(mild to moderate disease) uses CERE‐110, an experimental technology that is designed to
help nerve cells in the brain function better. CERE‐110 uses an adeno‐associated virus to
transfer a gene that makes nerve growth factor (NGF), a protein that may make nerve cells
in the brain healthier and protect them from dying. CERE‐110 is injected into the brain
during a surgical procedure. The Alzheimer's disease assessment scale ‐ cognitive subscale
(ADAS‐Cog) will be used to assess the outcome of the trial. This follows a phase I trial
(NCT00087789) that indicated CERE 110 gene therapy delivery was safe in six patients with
mild‐to‐moderate Alzheimer’s disease and warranted further investigation. The results of
the Parkinson’s disease phase II trial have been published with the authors suggesting that
the efficacy and safety of bilateral infusion of AAV2‐GAD shows promise for gene therapy.29
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The phase I open‐label trial of AAV‐GAD had been interpreted as showing gene therapy of
the subthalamic nucleus to be safe and well tolerated.30
Of the thirteen phase II trials identified, two have been suspended and one terminated due
to financial reasons, and a fourth trial was completed in 2005 but has not had any results
published.
Phase I/II clinical trials
Cellular therapy, particularly stem cell transplantation, dominates the approaches being
trialled in the phase I trials. Information available infers that stem cells in trials are often
used unchanged but may have been expanded/enriched/activated prior to being
administered.
There is a variation in the approach to using immunosuppression (conditioning regimes)
between the trials. Researchers are looking into the theory that no or partial
immunosuppression may be as effective as immunoablation due to the phenomenon known
as graft versus tumour effect. The additional benefit if successful is that it may be better
tolerated and potentially available to a wider group of patients.
An ongoing trial is the first to investigate the use in humans of fetal‐derived neural stem
cells transplanted into the spinal cord in the treatment of amyotrophic lateral sclerosis. This
trial design was one of escalating risk, where each group of patients is progressively less
impaired by the disease. Another trial is investigating intramedullary transplantation of
human central nervous system stem cells in people with thoracic (T2‐T11) spinal cord injury.
A phase I trial by Geron, the first to use differentiated human embryonic stem cells for
spinal cord injury has been withdrawn for commercial reasons.
Conclusion
Chronic neurological conditions cover a wide and diverse range of diseases, including those
that are rare and common. People living with these diseases often have poor prognosis,
with degeneration and/or loss in body function over the short to long term. For most
conditions current treatment, if available, may at best reduce symptoms rather than target
the cause of disease. It is not surprising that there is great interest in the potential of
regenerative medicine for these conditions.
The majority of research identified by this review is unsurprisingly focused on the more
common diseases, including multiple sclerosis and spinal cord injury. This finding agrees
with a previous review of neurorestorative clinical trials activity.5 The majority of clinical
trials focus on cellular therapy and are in phase I or II of development. Where results are
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available investigators often suggest that safety and efficacy has been demonstrated and
further trials are warranted. However, the trials are usually open‐label, non‐randomised
with small patient numbers. Until larger comparative studies are undertaken and results
published, questions around the use and place of cellular therapy in neurological conditions
remain unanswered.
There are numerous clinical trials for neurological conditions conducted with adult stem
cells, with only one trial investigating embryonic stem cells, which has now been withdrawn.
The trial for Huntington’s disease uses foetal neurons, however there is debate as to
whether this is truly classed as stem cell therapy. The focus for gene therapy research in
neurological conditions appears to be on Parkinson’s disease, however the most advanced
trial at phase II has been terminated due to funding.
A number of completed phase I and phase I/II trials indicate that stem cell therapy may be
safe and tolerated in people with neurological conditions. However, at present there are
many approaches being investigated across different diseases which indicates that a
commonly agreed best approach has not yet been identified. The fact that the majority of
trials for neurological conditions are still at an early phase assessing safety and efficacy
suggests that the reality of using such approaches in everyday healthcare is many years
away.
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Appendix 1: UK regenerative medicines organisations and networks
UniverCell Market https://www.univercellmarket.com/
Source of up‐to‐date information for the global stem cell and regenerative medicine community.
Renger8 http://www.regener8.ac.uk/home.html
The translational centre for regenerative medicine that brings together the work of UK scientists
with UK and international industry to advance the development of tools and technologies to
accelerate therapies through to clinic.
East of England Stem Cell Network (EESCN)
http://www.cambridgenetwork.co.uk/directory/orgprofile/default.aspx?objid=67752
EESCN is the UK's largest regional stem cell network, representing the interests of world class
researchers, clinicians and businesses involved in regenerative medicine and stem cell science, as
well as providing opportunities for public engagement.
London Regenerative Medicine Network (LRMN) http://www.lrmn.com/
The London Regenerative Medicine Network is the world's largest cell therapy and regenerative
medicine network with in excess of 5,500 members representing all the stakeholder groups
including: the general public, patients, patient advocates, students, scientists, engineers, clinicians,
charities, government organisations and business people.
Merica Stem Cell Alliance (previously Northeast England Stem Cell Institute)
http://www.msca.ls.manchester.ac.uk/
Alliance’s collaborators have established notable regional Centres of Excellence, lead major science‐
driven companies, and collectively maintain a skill set which supports the translation of basic
research to innovative therapies.
Scottish Stem Cell Network (SSCN) http://www.sscn.co.uk/
The aim of the network is to bring together scientists and clinicians in order to improve the rate at
which laboratory research translates into therapeutic benefits for patients. The SSCN works with the
entire stem cell community in Scotland, including academic institutions, clinical and industry‐based
research groups, as well as suppliers in the field.
The Social Science Stem Cell Initiative http://www.york.ac.uk/res/sci/introduction.htm
The ESRC Social Science Stem Cell Initiative was set up in 2005 with the broad aim of supporting a
range of activities to build research capacity and raise awareness in the UK social science community
regarding the emerging field of stem cell science.
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Appendix 2: Online search sources
Regulatory authorities Web Address European Medicines Agency (EMEA)
http://www.ema.europa.eu/ema/index.jsp?curl=/pages/home/Home_Page.jsp&jsenabled=true
Human Fertilisation and Embryology Authority (HFEA) http://www.hfea.gov.uk/
Human Tissue Authority (HTA) http://www.hta.gov.uk/
Medicines and Healthcare Products Regulatory Agency (MHRA)
http://www.mhra.gov.uk/index.htm
US Food and Drug Administration (FDA) http://www.fda.gov/
UK government departments Web Address Department of Health (DH) http://www.dh.gov.uk/en/index.htm
Department for Business, Innovation and Skills (BIS) http://www.bis.gov.uk/
UK research councils Web Address Biotechnology and Biological Sciences Research Council (BBSRC)
http://www.bbsrc.ac.uk/
Economic and Social Research Council (ESRC) http://www.esrc.ac.uk/
Engineering and Physical Sciences Research Council(EPSRC)
http://www.epsrc.ac.uk/pages/default.aspx
Medical Research Council (MRC) http://www.mrc.ac.uk/index.htm
Science and Technology Facilities Council (STFC) http://www.stfc.ac.uk/
Technology Strategy Board (TSB) http://www.innovateuk.org/
Learned Societies Web Address Academy of Medical Sciences (AMS) http://www.acmedsci.ac.uk/
British Pharmacological Society (BPS) http://www.abpi.org.uk/Pages/default.aspx
British Society for Cell Biology (BSCB) http://www.bscb.org/
British Society for Developmental Biology (BSDB) http://www.bms.ed.ac.uk/services/webspace/bsdb/welcome.htm
International Society for Cellular Therapy (ISCT) http://www.celltherapysociety.org/
International Society for Stem Cell Research (ISSCR) http://www.isscr.org//AM/Template.cfm?Section=Home
International Society of Differentiation (ISD) http://www.isdifferentiation.org/
Royal Academy of Engineering http://www.raeng.org.uk/
Royal College of Surgeons of England (RCS) http://www.rcseng.ac.uk/
Royal Pharmaceutical Society of Great Britain (RPSGB) http://www.rpharms.com/home/home.asp
Royal Society http://royalsociety.org/
Tissue and Cell Engineering Society (TCES) http://www.tces.org/
Tissue Engineering International & Regenerative Medicine Society (TERMIS)
http://www.termis.org/
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EU Framework Programme Research Consortia
Web address
ES TOOLS http://www.estools.eu/
EuroStemCell http://www.eurostemcell.org/
Miscellaneous Web address Association of the British Pharmaceutical Industry (ABPI)
http://www.abpi.org.uk/Pages/default.aspx
BioIndustry Association (BIA) http://www.bioindustry.org/
California Institute for Regenerative Medicine (CIRM)
http://www.cirm.ca.gov/
Centre of the Cell http://www.centreofthecell.org/
Stem Cells for Safer Medicines Ltd http://www.sc4sm.org/
Stem Cell Patents http://www.stemcellpatents.com/
UK Intellectual Property Office (UKIPO) http://www.ipo.gov.uk/
Free Patents Online Search Engine http://www.freepatentsonline.com/
UK charitable organisations Web address Action Duchenne http://www.actionduchenne.org/
Alzheimer’s Research Trust http://www.actionduchenne.org/
Alzheimer’s Society http://www.alzheimers.org.uk/site/index.php
Association of Medical Research Charities
http://www.amrc.org.uk/homepage/
The Cure Parkinson’s Trust http://www.cureparkinsons.org.uk/
Motor Neurone Disease Association (MNDA)
http://www.mndassociation.org/
Multiple Sclerosis Society http://www.mssociety.org.uk/
Muscular Dystrophy Campaign http://www.muscular‐dystrophy.org/
Parkinson’s UK http://www.parkinsons.org.uk/
UK Stem Cell Foundation (UKSCF) http://www.ukscf.org/
Research Publications and Trials in progress
Web address
ClinicalTrials.gov http://www.clinicaltrials.gov/
WHO International Clinical Trials Registry
http://www.who.int/trialsearch/Default.aspx
EU Clinical Trials Register https://www.clinicaltrialsregister.eu
Current Controlled Trials http://www.controlled‐trials.com/mrct/
UKCRN Portfolio Database http://public.ukcrn.org.uk/search/
ClinicalStudyResults.org http://www.clinicalstudyresults.org/home/
The Cochrane Library (Clinical trials) http://www.cochrane.org/
PubMed, Medline & Medline in Progress, & EMBASE
http://www.elibrary.bham.ac.uk/
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Appendix 3: Glossary of terms
Allogeneic: stem cells from a genetically similar, but not identical donor.
Autologous: .stem cells originating from the recipient rather than from a donor Embryonic stem cells: pluripotent stem cells derived from the inner cell mass of the blastocyst, an early‐stage embryo.
Mesenchymal stem cells: multipotent stem cells that can differentiate into a variety of cell types, including: osteoblasts (bone cells), chondrocytes (cartilage cells) and adipocytes (fat cells).
Pluripotent stem cells: can give rise to any fetal or adult cell type. However, alone they cannot develop into a fetal or adult animal because they lack the potential to contribute to extra embryonic tissue, such as the placenta.
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References
1 Mancardi G. Autologous haematopoietic stem‐cell transplantation in multiple sclerosis. The Lancet 2008: 7;
626‐636. 2 Bednar M.M. Neurorestoration therapeutics for neurodegenerative and psychiatric disease. Neurological
Research 2012: 34; 129‐142. 3 Department for Health. The National Service Framework for Long‐term conditions. London: Department of
Health, 2005. 4 The Neurological Alliance. Neuro numbers.
http://www.neural.org.uk/store/assets/files/20/original/NeuroNumbers.pdf Accessed 2 July 2012. 5 House of Commons Committee of Public Accounts. Services for people with neurological conditions:
Seventy‐second Report of Session 2010–12. London: The Stationery Office Limited. 2012. http://www.publications.parliament.uk/pa/cm201012/cmselect/cmpubacc/1759/1759.pdf Accessed 2 July 2012.
6 Parliamentary Office of Science and Technology (POST). Postnote: Regenerative medicine. May 2009. http://www.parliament.uk/documents/post/postpn333.pdf Accessed 2 July 2012.
7 Stem Cell Therapy for Patients With Multiple Sclerosis Failing Interferon A Randomized Study. http://clinicaltrials.gov/ct2/show/NCT00273364. Accessed 19 June 2012.
8 An open label, randomised, multicentre, prospective, clinical study to determine the safety and therapeutic effectiveness of bone marrow derived adult stem cells via multiple routes of administration in the treatment of patients with complete spinal cord injury. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=2258. Accessed 19 June 2012.
9 Randomized, Controlled Study Evaluating CERE‐110 in Subjects With Mild to Moderate Alzheimer's Disease. http://clinicaltrials.gov/ct2/show/NCT00876863. Accessed 19 June 2012.
10 The Clinical Trial on the Use of Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis. http://clinicaltrials.gov/ct2/show/NCT01494480. Accessed 19 June 2012.
11 FLT‐PET Activity Change After Allogeneic Umbilical Cord Blood (UCB) Therapy in Cerebral Palsy. http://clinicaltrials.gov/ct2/show/NCT01486732. Accessed 19 June 2012.
12 MIG‐HD: Multicentric Intracerebral Grafting in Huntington's Disease. http://clinicaltrials.gov/ct2/show/NCT00190450. Accessed 19 June 2012.
13 Mesenchymal Stem Cell Transplantation in MS (CMM‐EM). http://clinicaltrials.gov/ct2/show/NCT01228266. Accessed 19 June 2012.
14 High‐Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT MS) Study. http://clinicaltrials.gov/ct2/show/NCT00288626. Accessed 19 June 2012.
15 Immunological Mechanisms of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis. http://clinicaltrials.gov/ct2/show/NCT00342134. Accessed 19 June 2012.
16 Autologous Stem Cell Transplant for Multiple Sclerosis (MS/BMT). http://clinicaltrials.gov/ct2/show/NCT01099930. Accessed 19 June 2012.
17 High Dose Chemo/Radiotherapy and Hematopoietic Stem Cell Transplant for Patients With Multiple Sclerosis. http://clinicaltrials.gov/ct2/show/NCT00040482. Accessed 19 June 2012.
18 Study of AAV‐GAD Gene Transfer Into the Subthalamic Nucleus for Parkinson's Disease. http://clinicaltrials.gov/ct2/show/NCT00643890. Accessed 19 June 2012.
19 Difference Between Rehabilitation Therapy and Stem Cells Transplantation in Patients With Spinal Cord Injury in China. http://clinicaltrials.gov/ct2/show/NCT01393977. Accessed 19 June 2012.
20 Autologous Incubated Macrophages for Patients With Complete Spinal Cord Injuries. http://clinicaltrials.gov/ct2/show/NCT00073853. Accessed 19 June 2012.
21 The safety and efficacy of umbilical cord mesenchymal stem cell transplantation through femoral artery interventional procedure in spinal cord injury patients. http://www.chictr.org/en/proj/show.aspx?proj=2636. Accessed 19 June 2012.
22 Richard K Burt. Autologous non‐myeloablative haemopoietic stem cell transplantation in relapsing‐remitting multiple sclerosis: a phase I/II study. The Lancet Neurology 2009:8; 244‐53.
23 Pasquini M. Hematopoeitic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and EBMT to facilitate international clinical studies. Biol Blood Marrow Transplant 2010: 16;1076‐1083.
21
24 Atkins H. Autologous hematopoietic stem cell transplantation for autoimmune disease – is it now ready for
prime time? Biol Blood Marrow Transplant 2012: 18;S177‐S183. 25 Reston J. Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review.
Multiple sclerosis journal 2011: 17(2);204‐213. 26 Saccardi R. A prospective, randomised, controlled trial of autologous haematopoietic stem cell
transplantation for aggressive multiple sclerosis: a position paper. Multiple sclerosis 2012: 18;825‐834. 27 Tetzlaff W. A systematic review of cellular transplantation therapies for spinal cord injury. J Neurotrauma
2011: 28;1611‐1682. 28 Knoller N. Clinical experience using incubated autologous macrophages as a treatment for complete spinal
cord injury: phase I study results. J Neurosurg Spine 2005: 3(3);173‐181. 29 LeWitt P. AAV2‐GAD gene therapy for advanced Parkinson’s disease: a double‐blind, sham‐surgery
controlled, randomized trial. The Lancet Neurology 2011: 10;309‐319. 30 Kaplitt M. Safety and tolerability of gene therapy with an adeno‐associated virus (AAV) borne GAD gene for
Parkinson’s disease: an open label, phase I trial. The Lancet 2007: 369;2097‐2105.