Antisense oligonucleotides: modifications and clinical · PDF fileAntisense oligonucleotides:...

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Antisense oligon

DuiUAoDUjhlis

Chemistry, RSC Advances and NucAcids. His research interests areistry, multicomponent reactions an

aDepartment of Chemistry, University of DelbEvalueserve Pvt. Limited, Infospace (SEZ), GcDepartment of Chemistry, Kirori Mal Col

India. E-mail: [email protected]

Cite this:Med. Chem. Commun., 2014,5, 1454

Received 23rd April 2014Accepted 29th July 2014

DOI: 10.1039/c4md00184b

www.rsc.org/medchemcomm

1454 | Med. Chem. Commun., 2014, 5

ucleotides: modifications andclinical trials

Vivek K. Sharma,a Raman K. Sharmab and Sunil K. Singh*c

There has been an upsurge in the number of clinical trials involving chemically modified oligonucleotide-

based drug candidates after the FDA approval of Vitravene, Macugen, and recently, Kynamro. Over the

years, different types of backbone, nucleobase and/or sugar-modified oligonucleotides have been

synthesized because natural DNA/RNA based oligonucleotides pose some limitations, such as poor

binding affinity, low degree of nuclease resistance, affecting their direct use in antisense therapeutics. In

this review article, we discuss in detail different modifications of nucleosides/oligonucleotides along with

the related clinical trials, which demonstrated their potential as drug candidates for antisense and related

nucleic acid based therapeutics.

Introduction

Most of the drugs present in the market interact withproteins; moreover, they oen bind to non-target proteins orexert an adverse effect through unknown interactions.1 Thedream of modern drug research to develop a therapeutictechnology that can act specically only on the targetresponsible for the disease has led to the development ofdrugs that can turn off genes by targeting directly the nucleic

r Vivek K. Sharma received hisndergraduate degree in chem-stry from Hansraj College,niversity of Delhi, in 2007.er receiving his masters inrganic chemistry from theepartment of Chemistry,niversity of Delhi, in 2009, heoined the same department foris PhD. To date, he has pub-ished 11 research papers innternationally reputed journalsuch as The Journal of Organicleosides, Nucleotides & Nucleicbiocatalysis, nucleoside chem-d heterocyclic chemistry.

hi, Delhi-110007, India

urgaon 122001, Haryana, India

lege, University of Delhi, Delhi-110007,

, 1454–1471

acids that code for the proteins. Antisense therapeuticswere introduced aer Paterson et al.2 in 1977 reportedthe utility of nucleic acids in modulating gene expression,and shortly aer, Zamecnik and Stephenson3 demonstratedthe inhibition of viral replication by modied oligonucleo-tides (ONs).4 In the quest of effective antisense candidates,various chemical modications of the natural ONs have beenstudied, such as modications in the phosphodiester back-bone, heterocyclic nucleobase and sugar moiety, which conferhigh affinity and specicity for their target nucleic acidsequences (Fig. 1).5

Dr Raman K. Sharma completedhis BSc from W.R.S. Govt.College Dehri, Kangra, H.P.India and his MSc fromG.N.D.U. Amritsar, PunjabIndia. During MSc he wasoffered the position of MedicinalResearch Chemist in the newdrug discovery division of Ran-baxy (now Sun Pharma), Gur-gaon, Haryana, India, where heworked for one and half yearsaer his MSc. He then joined the

research group of Prof. Ashok K. Prasad at the Department ofChemistry, University of Delhi, India for his PhD, and worked inthe area of biocatalysis and heterocyclic compounds. He haspublished eight research articles and is currently working as aProject Manager at IPRD Evalueserve Gurgaon, Haryana, India.

This journal is © The Royal Society of Chemistry 2014

http://crossmark.crossref.org/dialog/?doi=10.1039/c4md00184b&domain=pdf&date_stamp=2014-09-22

http://dx.doi.org/10.1039/c4md00184b

http://pubs.rsc.org/en/journals/journal/MD

http://pubs.rsc.org/en/journals/journal/MD?issueid=MD005010

Fig. 1 An overview of different chemical modifications of antisense oligonucleotides (AONs); B ¼ nucleobase.

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Internucleoside linkage or backbonemodified AONs

These are also referred to as the rst generation of chemicallymodied antisense agents. They contain backbone

Dr Sunil K. Singh received hismasters degree in OrganicChemistry from the Departmentof Chemistry, University of Delhi,in 2004. He completed his PhD inChemistry from the samedepartment in 2010. Currently,he is working as an AssistantProfessor in Kirori Mal College,University of Delhi. His currentresearch focuses on the synthesisof nucleosides, biocatalytictransformations, multicompo-

nent one-pot synthesis, etc. To date, he has published 13 researchpapers in internationally reputed journals such as The Journal ofOrganic Chemistry, Nucleosides, Nucleotides & Nucleic Acids,Current Organic Chemistry, and Organic & BiomolecularChemistry.


modications such as 50-N-carbamate, methylene–methylimine(MMI), amide, triazole, phosphorothioate (PS), phosphor-odithioate, thioether, thioformacetal, mercaptoacetamide,methylphosphonate, boranophosphate, N-30-phosphoramidate

Fig. 2 Structures of phosphate backbone modified internucleosideresidues.

Med. Chem. Commun., 2014, 5, 1454–1471 | 1455


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(NP), S-methylthiourea, and guanidinium, and they havebeen designed and synthesized to circumvent the physicaland biological limitations of the natural phosphodiesterlinkage.5,6 These backbone modications can be broadlyclassied as neutral, anionic or cationic internucleosidelinkages (Fig. 2).

Phosphorothioate oligonucleotides (PS-ONs) are the majorrepresentatives of this generation and have been used mostsuccessfully for gene silencing. The introduction of a PSlinkage into ONs confers sufficient resistance to nucleasedegradation, leading to higher bioavailability. In addition tonuclease resistance, PS-ONs form regular Watson–Crick basepairs, activate RNase H, carry negative charge for cell delivery,and display attractive pharmacokinetic properties and cellularuptake due to increased binding to plasma proteins and other

Fig. 3 Structure of phosphorothioate backbone modified drug Vitraven

1456 | Med. Chem. Commun., 2014, 5, 1454–1471

receptor sites as compared to natural phosphodiesters.4d,7

However, their proles for binding affinity to the targetoligonucleotide sequences and specicity are less satisfac-tory.8 Despite these disadvantages, the FDA approved the rstantisense drug Vitravene, a rst generation PS-modied AONfor the treatment of AIDS-related cytomegalovirus (CMV) reti-nitis (Fig. 3).9

Sugar modified AONs

In recent years, there has been a sudden leap in the synthesis ofconformationally constrained nucleoside analogues by modi-fying the sugar moiety in various ways. These include: (a)synthesis of nucleoside analogues containing an electronega-tive atom or substituent at the 20-position of sugar;10 (b)

e.



Fig. 5 Structure of RNA like 20-substituted nucleosides; B ¼nucleobases.

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synthesis of bicyclic nucleoside analogues having an extra ringfused to the sugar moiety;11 (c) synthesis of nucleosideanalogues of varying sugar ring structures;12 and (d) synthesis ofspironucleosides containing a spirocyclic ring at differentpositions of the sugar ring (Fig. 4).13 The problems associatedwith PS-ONs, i.e. poor binding affinity to the target RNA, lack ofspecicity and low cellular uptake, are to some degree solved bythese second generation ONs containing a modied sugarmoiety. 20-O-Methyl (20-OMe), 20-O-methoxyethyl (20-OMOE) andlocked nucleic acid (LNA) are the most important members ofthis class (Fig. 4).

The structural difference between DNA and RNA includesthe 20-substitution on the furanose ring of RNA. Hence, theRNA binding behavior of AONs may be improved bymimicking RNA structures with 20-modied nucleosides(Fig. 5). Electronegative substituents like uorine and oxygeninuence the furanose sugar C 0

3-endo conformation14 due tothe preferred gauche orientation of the 20-substituent and thering oxygen (Fig. 5). As a result, RNA and 20-modied nucleo-sides are found predominantly in the C 0

3-endo conformationthat is exclusively present in A-type duplexes.15 Variousreported 20-substitutions have shown excellent results inantisense therapeutics as they provide high metabolic stabilityand high affinity to target mRNA; for example, 20-OMe-, 20-OMOE- and LNA-containing ONs have entered in humanclinical trials.15,16

The FDA in 2004 approved pegaptanib sodium (Macugen),an anti-vascular endothelial growth factor (anti-VEGF) RNAaptamer for the treatment of all types of neovascular age-related macular degeneration.17 Macugen consists of 20-F and20-OMe substituted sugar moieties (Fig. 6). Aptamers aresingle-stranded ONs (DNA/RNA) that form stable three-dimensional structures and are capable of binding withhigh affinity and specicity to a variety of molecular targets

Fig. 4 Structures of different types of sugar-modified constrainednucleoside analogues.


such as proteins and can modulate their functions. Becausethe targets are in the blood plasma or displayed on thesurface of cells, aptamers are likely to be degraded easily byserum nucleases. Therefore, unmodied aptamers haveshown half-lives in the blood as short as 2 minutes.18 Modi-cations such as the capping of ONs at the 30-terminus, oenfollowed by inverting the nucleotide at the 30-terminus, haveshown increased stability against endogenous serum nucle-ases (Fig. 6).19

Nucleobase modified AONs

Since the nucleobases provide the prime recognition site forWatson–Crick base pairing via specic hydrogen bondinginteractions, the scope of modication of the nucleobase isconned, which can only improve the binding affinity for thecomplementary ON but not the nuclease resistance.20 Althoughless common than backbone and sugar modications, chemi-cally modied heterocyclic nucleobases have also found appli-cations as AONs. Carefully designed nucleobase analogueswhen introduced into ONs can provide information on theimportance of specic functional groups in natural bases. Notethat even a subtle change can have a dramatic effect because ofthe change in size, electronic distribution, nucleoside sugarconformation, tautomeric structure or functional group pKa

values. Representative structures of several modied bases, i.e.pyrimidine and purine modication, and universal bases areshown in Fig. 7. The most attractive sites for substitution of thenucleoside bases are those positions that are exposed tosolvents in the major groove, i.e. the 4- and 5-positions ofpyrimidines and the 6- and 7-positions of purines (Fig. 7).Substitutions at these positions neither interfere with basepairing nor induce steric hindrance and inuence the generalgeometry of the double helix.5,21,22

Natural nucleobases display exquisite selectivity in recog-nizing complementary bases as given by Watson–Crick rules. Auniversal base is an analogue that can be substituted for any ofthe four natural bases in ONs without signicantly impairingthe duplex stability. In general, universal base analogues usearomatic ring stacking, instead of specic hydrogen bonds, tostabilize a duplex (Fig. 7).22

Med. Chem. Commun., 2014, 5, 1454–1471 | 1457


Fig. 6 Structure of the 20-sugar modified drug Macugen (Pegaptanib sodium).

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The stacking interactions between the planar heterocycles ofnucleic acids are largely responsible for the stability of DNA andRNA duplexes. Maximizing stacking interactions throughchemical modication provides a means of creating duplexhelices of greater stability, e.g. tricyclic phenoxazine and G-clamp cytosine derivatives have been shown to enhance stack-ing.23 A tricyclic phenoxazine (Fig. 8) serves as a rigid scaffoldfor the attachment of groups designed to interact with theHoogsteen binding face of a complementary base pairedguanine. Appending an arm with strong hydrogen bond donor,i.e. an aminoethyloxy tether to the phenoxazine, recognizesboth the Watson–Crick and the Hoogsteen sites of guanine;hence, it is termed as a G-clamp (Fig. 8).23

The G-clamp-containing AON displayed dramaticallyenhanced stability. The greatly increased affinity and specicity

1458 | Med. Chem. Commun., 2014, 5, 1454–1471

of the base-modied G-clamp was also conrmed by in vivostudies.23 However, the acyclic derivative lacks the conforma-tional restriction and hence does not demonstrate enhancedaffinity. The G-clamp0s affinity for the complementary guanineis due to the appropriate positioning of the strong hydrogenbond donors (Fig. 8).

Other advanced modified AONs

Although AONs made of only sugar modied building blocksare less toxic than PS-AONs and have slightly enhanced affinitytowards their complementary RNAs, their efficiency to induceRNase H cleavage of the target RNA is a matter of concern.24

Since RNase H cleavage is the most desirable mechanism forthe antisense effect and 20-O-alkyl modications are desirable



Fig. 7 Structures of different types of nucleobasemodified nucleosideanalogues.

Fig. 8 Cytosine nucleobase modified analogues used in hybridizationexperiments and interaction of the G-clamp with guanosine.

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for nuclease resistance and high binding affinity, a hybrid ONconstruct incorporating both characteristics has appeared inthe form of the ‘gapmer’ antisense oligonucleotide.25 A gapmercontains a central ‘gap’ of deoxynucleotides sufficient toinduce RNase H cleavage anked by blocks of 20-O-modiedribonucleotide ‘wings’ that protect the internal block fromnuclease degradation, e.g. 20-OMOE sugar modied nucleo-sides can be further combined with a phosphorothioate (PS)linkage as in Kynamro,26 which is the second antisense drugapproved by the FDA to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein-B, total cholesterol andnon-high density lipoprotein–cholesterol in patients withhomozygous familial hypercholesterolemia (HoFH) (Fig. 9).Kynamro also represents the rst systemic antisense drug andis given as a 200 mg weekly subcutaneous injection as anadjunct therapy to lipid-lowering medications and a controlleddiet. Some serious side effects such as liver toxicity have beenencountered with Kynamro; hence, it is available with awarning on the package citing the risk of hepatic toxicity. Thecommon adverse reactions to Kynamro include injection sitereactions, increased alanine aminotransferase (ALT) and


aspartate aminotransferase (AST) levels, u-like symptoms,and abnormal liver function test results.27 Numerous modiedONs are being tested in multiple clinical trials to explorewhether this ‘gapmer’ type chimera has improved therapeuticproperties (Table 1).

In order to further enhance target affinity, nuclease resis-tance, biostability and pharmacokinetics, an advanced thirdgeneration of AONs was developed mainly by modications ofthe furanose ring of the nucleotide. Peptide nucleic acid (PNA)and phosphorodiamidate morpholino oligomer (PMO) are themost well studied third-generation AONs.28

Peptide nucleic acid (PNA) is a non-charged nucleotideanalogue in which the phosphodiester backbone is replaced bya exible pseudopeptide polymer N-(2-aminoethyl)glycine andthe nucleobases are attached to the backbone via methyl-enecarbonyl-linkage (Fig. 1). PNAs can hybridize withcomplementary DNA or RNA strands with higher affinity andspecicity than natural oligonucleotides. PNA is not asubstrate for RNaseH and exerts its antisense effect by forminga sequence-specic duplex with mRNA, causing sterichindrance of translational machinery, leading to proteinknockdown.29

In phosphorodiamidate morpholino oligomer (PMO), theribose sugar is replaced by a six-membered morpholino ring,whereas the phosphodiester bond is replaced by a phosphor-odiamidate linkage (Fig. 1).30 Like PNAs, this modication alsodoes not activate RNase H; hence, it acts only as a steric blockerfor specic inhibition of gene expression. PMO provide excel-lent nuclease stability in comparison to that of the unmodiedAONs. PMO has demonstrated antisense efficacy in animalmodels in vivo and in human clinical trials.31–34

Clinical trials of modifiedoligonucleotides

The last 35 years have witnessed an explosive growth in thenumber of modied ON-related clinical trials. We havecollated the data for 76 oligonucleotide drug candidates thathave been tested in the clinical trials for treatment of variousdiseases, and the majority of them have shown promisingpotential. Please note that we have considered only those ONdrugs that have been tested in a minimum of phase I clinicaltrials or onwards. Most of these chemically modied ONsinvolve phosphorothioate (PS) chimera and are designed tospecic inhibition of gene expression through an antisensemechanism (Table 1). Antisense technology led to the foun-dation of ON based therapeutics and has now been con-junctured for use in more potent strategies, e.g. antigene, RNAinterfering (RNAi), aptamer, ribozyme and decoy ON, all ofwhich utilise the knowledge gained from the difficult effortsmade in developing the antisense technology.112 These ON-based approaches target different sites in the central dogmaof molecular biology in order to exert their therapeutic effects.Antigene and decoy ONs bind to DNA and hence block thetranscription process. Antisense, ribozyme and RNAi inhibitprotein synthesis (transcription) by blocking the

Med. Chem. Commun., 2014, 5, 1454–1471 | 1459


Fig. 9 Structure of FDA approved antisense drug Kynamro having 20-OMOE chimera.

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corresponding RNA, whereas aptamers directly bind to theprotein target (Fig. 10).

From the Table 1, it is quite clear that ISIS pharmaceuticals,which is a pioneer in antisense technology, has contributedabout �20% of all modied ON based drugs that are in clinicaltrials. Sarepta Therapeutics had six drug candidates in clinicaltrials involving PMO chemistry. A brief representation of thenumber of drugs in clinical trials for different assignees is

1460 | Med. Chem. Commun., 2014, 5, 1454–1471

provided in Fig. 11. Please note that assignees having one or twodrugs are grouped together as ‘others’ assignees in the graph.

To see the pattern in the number of drug candidates thatentered Phase 1 clinical trials over time (2 year intervals), weretrieved the corresponding data for these drug candidates fromvarious sources113 and prepared a graph to showcase thispattern (Fig. 12). From the graph, it is clear that aer the rsttwo drug candidates entered clinical trials in 1997–1998 (both



Tab

le1

Modifiedolig

onucleotidesin

clinical

trialsforvariousdiseasesa

S. no.

Prod

uct

Chem

istry

Disease

Target

Mod

eof

action

Status

(phase)

Com

pany

1Fo

mivirsen35

(Vitravene,

ISIS-292

2)PS

CMVretinitis

Immed

iate-early

2(IE2)

gene

Antisense

App

roved

ISIS

Pharma

2Mipom

ersen36

(Kyn

amro,ISIS-30

1012

)20-OMOEch

imera

Hom

ozygou

sfamilial

hyp

erch

olesterolemia

(HoF

H)

Apo

lipo

proteinB

Antisense

App

roved

ISIS

Pharma

3Pe

gaptan

ib37,17

(Macug

en)

Phosph

odiester

with20-O-

methylated

purines

and20-

F-mod

ied

pyrimidines

Neo

vascular

age-related

macular

degeneration

(AMD)

Vascu

laren

dothelialgrow

thfactor

(VEGF)

RNAap

tamer

App

roved

OSI

Pharma

4Oblim

ersen38

(Gen

asen

se,

Aug

merosen

,G-313

9)

PSChronic

lymph

ocytic

leuk

emia

(CLL

),malignan

tmelan

oma,

multiple

myeloma,

non

-smallcell

lungcancer(N

SCLC

),acute

myeloid

leuk

emia

(AML)

Bcelllymph

oma(Bcl2)

Antisense

III

Gen

taInc.

&Aventis

Pharma

5Trabe

dersen39

(AP-12

009)

PSOncology-gliob

lastom

aTransforminggrow

thfactor

beta

2(TGF-b2)

Antisense

III

Antisense

Pharma

6Aga

nirsen40(G

S-10

1)PS

Cornealneo

vascularization

Insu

linreceptor

subs

trate-1

(IRS-1)

Antisense

III

Gen

eSign

al

7Affinitak

41(ISIS-35

21,

LY-900

003,

aprinocarsen)

PSNSC

LCProteinkinaseC-a

(PKC-a)

Antisense

III

ISIS

Pharma&EliLilly

Pharma

8Cus

tirsen

42(O

GX-011

,ISIS-112

989,

TV-101

1)20-OMOEch

imera

NSC

LC,p

rostatean

dbreast

cancer

Clusterin

Antisense

III

OncoGen

eX

9Drisape

rsen

43(PRO-

051,

GSK

-240

2968

)20-OMech

imera

Duc

hen

nemus

cular

dystroph

y(D

MD)

Dystrop

hin

Antisense

III

Prosen

saTherap

eutics

&Glaxosm

ithkline

10Bevasiran

ib44(Can

d-5)

RNA

AMD

VEGF

RNA

interferen

ce(RNAi)

III

Opk

ohealth(formerly

Acu

ity)

11De

brotide4

5Ran

dom

mixture

ofsingle-

strande

doligod

eoxyribo

nuc

leotides

derivedfrom

porcine

muc

osal

DNA

Hep

atic

veno-occlus

ive

disease(VOD)

Com

plicationsresu

ltinga

ermyeloab

lative

chem

otherap

yUnkn

own

III

Gen

tium

&Dan

a-Fa

rber

12ProM

une4

6(CPG

-790

9,PF

-351

2676

)PS

NSC

LCToll-likereceptor

9(TLR

9)Im

mun

e-active

III

Pzer

1310

18-ISS

47

PSRag

weedallergy,

hep

atitis

B,n

on-H

odgk

in's

lymph

omaan

dcolorectal

neo

plasms

TLR

9Im

mun

e-active

III

Dyn

avax

Technolog

ies

14Alicaforsen

48(ISIS-

2302

)PS

Crohn'sdisease

Intercellularad

hesion

molecule-1(ICAM-1)

Antisense

III

ISIS

Pharma

15AVI-41

26(ref.4

9)(Resten-NG/Resten-M

P)PM

ORestenosis,c

anceran

dkidn

eydiseases

C-m

ycmRNA

Antisense

II/III

SareptaTherap

eutics

16Edifoligide5

0(E2F

decoy)

PSde

coyON

Atherosclerosis

Transcriptionfactor

(E2F

)Decoy

ON

II/III

Duk

eClinical

Research

Institute

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Tab

le1

(Contd.)

S. no.

Prod

uct

Chem

istry

Disease

Target

Mod

eof

action

Status

(phase)

Com

pany

17LY

-218

1308

(ref.5

1)(ISIS-23

722)

20-OMOEch

imera

Survivin

Solidcancer

Antisense

IIISIS

Pharma&EliLilly

Pharma

18Eteplirsen52(AVI-46

58)

PMO

Duc

hen

nemus

cular

dystroph

yDystrop

hin

Antisense

IISa

reptaTherap

eutics

(Earlier

AVIBioph

arma)

19LY

-227

5796

(ref.5

3)(ISIS-EIF4E

Rx)

20-OMOEch

imera

NSC

LC,p

rostatecancer

andsolidtumou

rcelllines

Euk

aryotictran

slational

initiation

factor

4E(EIF4E

)Antisense

II/I

ISIS

Pharma&EliLilly

Pharma

20ALN

-TTR02

(ref.5

4)siRNAform

ulationus

ing

lipidnan

oparticle

tech

nolog

y

Transthyretin-m

ediated

amyloido

sis(ATTR)

Transthyretin

(TTR)

RNAi

IIAlnylam

Pharma

21Miravirsen55(SPC

-364

9)LN

Ach

imera

Hep

atitis

Cvirus(H

CV)

microRNA12

2RNAi

IISa

ntarisPh

arma

22Excellair56

dsRNA(unkn

own)

Asthma

Spleen

tyrosinekinase(Syk)

RNAi

IIZa

BeC

orPh

arma

23Cen

ersen57(Aezea,E

L-62

5)PS

Can

cer

Tum

orprotein53

(P53

/TP5

3)Antisense

IIEleos

Inc.

24QPI-100

2(ref.5

8)(15N

P)ds

RNA(chem

ically

mod

ied

)Delayed

gra

function

(DGF)

andacutekidn

eyinjury

(AKI)

P53(TP5

3)RNAi

IIQua

rkPh

arma

25GTI-20

40(ref.5

9)(LOR-

2040

)PS

AML

R2compof

ribo

nuc

leotide

redu

ctase(RNR)

Antisense

IILo

rusTherap

eutics

26Archexin

60

PSPa

ncreaticcancer

AKT-1

proteinkinase

Antisense

IIRexah

nPh

arma

27TPI-ASM

8(ref.6

1)PS

Alle

rgic

asthma

CCR3,ILreceptor-3

and-5,G

M-

CSF

Antisense

IITop

igen

Pharma

28AEG-351

56(ref.6

2)20-OMech

imera

B-celllymph

oma,

AML,

CLL

XlAP(caspa

seinhibitor)

Antisense

I/II

AegeraTherap

eutics

29ATL/TV-110

2(ref.6

3)(ISIS-10

7428

)20-OMOEch

imera

Multiplesclerosis

Verylate

antigen-4

(VLA

-4)

Antisense

IIAntisense

Therap

eutics;

Teva&ISIS

Pharma

30ALN

-RSV

-01(ref.6

4)ds

RNA(unmod

ied

)Respiratory

syncytial

virus

Nuc

leocap

sidN

gene

RNAi

IIAlnylam

Pharma

31PF

-045

2365

5(ref.6

5)(PF-65

5)ds

RNA(m

odied

)AMD

anddiab

etic

macular

edem

aDNA-dam

age-indu

cible

tran

script

4(REDD-1,R

TP8

01)

RNAi

IIQua

rkPh

arma&P

zer

32ISIS-513

2(ref.6

6)(CGP-

6984

6A)

PSNSC

LC,s

olid

andovarian

cancers

c-raf-1kinase

Antisense

IIISIS

Pharma

33ISIS-148

03(ref.6

7)PS

HCV

Internal

ribo

someen

trysite

(IRES)

ofHCV

Antisense

IIISIS

Pharma

34GEM-231

(ref.6

8)(H

YBO-165

)20-OMech

imera

Solidcancers

PKA(protein

kinaseA)

Antisense

IIHyb

rido

n

35GTI-25

01(ref.6

9)PS

Lymph

omas

andsolid

cancers

R1compo

nen

tof

RNR

Antisense

IILo

rusTherap

eutics

36ATL-11

03(ref.7

0)2n

dgeneration

Acrom

eagly

Growth

hormon

ereceptor

Antisense

IIAntisense

Therap

eutics

&ISIS

Pharma

37AVI-51

26(ref.7

1)PM

OCardiovascu

lardisease

C-m

ycinhibitor

Antisense

IISa

reptaTherap

eutics

38Mon

arsen72(EN-101

)20-OMech

imera

Myasthen

iagravis

Acetylcholineesterase

Antisense

IIEster

Neu

rosciences

39Hep

tazyme7

3(LY-

4667

00)

20-OMech

imera

Hep

atitis

CHCVIRES

Antisense

IISirna(formerly

Ribozym

e)40

ISIS-250

3(ref.7

4)PS

NSC

LC,b

reastcolorectal

andpa

ncreaticcancer

H-ras

Antisense

IIISIS

Pharma

1462 | Med. Chem. Commun., 2014, 5, 1454–1471 This journal is © The Royal Society of Chemistry 2014

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Tab

le1

(Contd.)

S. no.

Prod

uct

Chem

istry

Disease

Target

Mod

eof

action

Status

(phase)

Com

pany

41LE

rafAON-ETU75

PSAdv

ancedcancer

c-rafkinase

Antisense

I/II

Neo

Pharm

42MG-98(ref.7

6)20-OMech

imera

Head,

neckan

dmetastatic

renal

cancers

DNAmethyltran

sferase1

Antisense

IIMethylgene

43EPI-201

0(ref.7

7)PS

Asthma

Ade

nosineA1receptor

Antisense

IIEpiGen

esis

44GEM-92(ref.7

8)2n

dgenerationPS

HIV

HIV-1

gag

Antisense

IIHyb

rido

n45

ISIS-CRP R

x(ref.7

9)20-OMOEch

imera

Cardiovascu

lar,

inam

mation

C-reactiveprotein

Antisense

IIISIS

Pharma

46OGX-427

(ref.8

0)20-OMOEch

imera

Oncology

Heatsh

ockprotein27

(Hsp

27)

Antisense

IIOncoGen

eX47

ISIS-113

715(ref.8

1)20-OMOEch

imera

Diabe

tes

Proteintyrosineph

osph

atase-

1B(PTP-1B

)Antisense

IIISIS

Pharma

48iCo-00

7(ref.8

2)20-OMOEch

imera

Macular

degeneration

c-rafkinase

Antisense

IIiCoTherap

eutics

49PF

-064

7387

1(ref.8

3)(EXC-001

)20-OMOEch

imera

Surgeryrelatedbrosisan

dde

rmal

scarring

Con

nective

tissue

grow

thfactor

(CTGF)

Antisense

IIP

zeran

dExcaliard

Pharma

50SP

C-299

6(ref.8

4)LN

Ach

imera

CLL

Bcl-2

Antisense

I/II

SantarisPh

arma

51OHR-118

(ref.8

5an

d86

)(AVR-118

)PN

ACachexia

associated

with

cancer

Cytop

rotective

Immun

e-Active

IIOhrPh

arma

52ARC-177

9(ref.8

7)DNAan

d20-O-m

ethylwitha

singlePS

linka

geconjuga

tedto

20kD

aPE

G,

30-in

verted

dT

vonWillebran

ddisease

Platelets

Aptam

erII

Archem

ix

53AVI-40

65(ref.8

8)PM

OHep

atitis

CNS3

(HCVprotease)

Antisense

IISa

reptaTherap

eutics

54AVI-45

57(ref.8

9)PM

ODrugmetab

olism

CytochromeP4

503A

4(CYP3

A4)

Antisense

I/II

SareptaTherap

eutics

55HGTV-43(ref.9

0)DNA

HIV-1

infection

Viral

replicationgenes

Antisense

IIEnzo

Therap

eutics

56Im

etelstat

91(G

RN16

3L)

Thio-phosph

oram

idate

CLL

andsolidtumor

malignan

cies

Telom

eraseribo

nuc

leic

acid

(hTR)templatean

tago

nist

Antisense

I/II

Geron

57IM

O-205

5(ref.9

2)Ph

osph

odiester

(con

tainingun

methylated

CpG

dinuc

leotides)

Ren

alcellcarcinom

aan

dNSC

LCToll-likereceptor

(TLR

9)Im

mun

e-active

IIIderaPh

arma

58IM

O-212

5(ref.9

3)DNA

Hep

atitis

CTLR

9Im

mun

e-active

IIIderaPh

arma

59HYB-205

5(ref.9

4)(IMOxine)

Phosph

odiester

(con

taining

immun

ostimulatorymotif

CpR

;R¼

20-deo

xy-7-

deazag

uan

osine)

HIV-1

infection

TLR

9Im

mun

e-active

IIIderaPh

armaan

dHyb

rido

n

60ISIS-104

838(ref.9

5)20-OMOEch

imera

Rheu

matoidarthritis,

Crohn'sdiseasean

dps

oriasis

Tum

ornecrosisfactor

(TNF)-

alph

aAntisense

IIISIS

Pharma

61Veglin96(VEGF-AS)

PSKap

osi's

sarcom

aan

dmesothelioma

Vascu

laren

dothelialgrow

thfactor

receptor

(VEGFR

)Antisense

I/II

VasGen

eTherap

eutics

62AGN-211

745(ref.9

7)(AGN-745

,SIRNA-027

)RNA

AMD

andch

oroida

lneo

vascularization

VEGFR

-R1

RNAi

I/II

Sirna&Alle

rgan

Pharma

63ATL-11

01(ref.9

8)20-OMOEch

imera

Prostate

cancer

Insu

lin-like

grow

thfactor-1

(IGF-1R

)Antisense

IAntisense

Therap

eutics

&ISIS

Pharma

This journal is © The Royal Society of Chemistry 2014 Med. Chem. Commun., 2014, 5, 1454–1471 | 1463

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Tab

le1

(Contd.)

S. no.

Prod

uct

Chem

istry

Disease

Target

Mod

eof

action

Status

(phase)

Com

pany

64EZN

-296

8(ref.9

9)LN

Ach

imera

Lymph

omaan

dsolid

tumou

rsHyp

oxia-in

duciblefactor-

1alpha(H

IF-1a)

Antisense

IEnzo

Therap

eutics

65AVI-40

20(ref.1

00)

PMO

WestNilevirus

WestNilevirus

Antisense

ISa

reptaTherap

eutics

66EZN

-304

2(ref.1

01)

LNAch

imera

Oncology

Survivin

Antisense

IEnzo

Therap

eutics

67ALN

-VSP

102

Mod

ied

dsRNAin

lipo

someform

ulation

Livercanceran

dsolid

tumou

rsVEGFan

dkinesin

family

mem

ber11

RNAi

IAlnylam

Pharma

68CALA

A-01(ref.1

03)

dsRNAin

nan

oparticle

form

ulation

Solidtumou

rsM2su

bunitof

ribo

nuc

leotide

redu

ctase(RRM2)

RNAi

ICalan

doPh

arma

69OMJP-GCGRRx(ref.1

04)

20-OMOEch

imera

Diabe

tes

Sodium

-dep

ende

ntgluc

ose

tran

sporter2

Antisense

IISIS

Pharmaan

dOrtho-

McN

eil-Jan

ssen

Pharma

70ISIS-SGLT

2 Rx(ref.1

05)

(ISIS-38

8626

)20-OMOEch

imera

Diabe

tes

Sodium

-dep

ende

ntgluc

ose

tran

sporter2

Antisense

IISIS

Pharma

71OGX-225

(ref.1

06)

20-OMOEch

imera

Prostate

andbreast

cancer

Insu

lingrow

thfactor

binding

protein,IGFB

P2AND

5Antisense

IOncoGen

eX

72LR

-300

1(ref.1

07)(G

-44

60)

PSCML

C-m

ybAntisense

IGen

taInc.

73ISIS-345

794(ref.1

08)

20-OMOEch

imera

Solidtumou

rcelllines

Sign

altran

sduc

eran

dactivatorof

tran

scription3

(STAT-3)

Antisense

IISIS

Pharma

74AIR-645

(ref.1

09)(ISIS-

3696

45)

20-OMOEch

imera

Asthma

Interleu

kin4receptor

alph

a(IL4

R-alpha)

Antisense

IISIS

Pharma

75TKM-080

301(ref.1

10)

(TKM-PLK

1)20-OMe

Adv

ancedsolidtumors

Polo-like

kinase(PLK

1)RNAi

ITek

miraPh

arma

76ARC-520

(ref.1

11)

20-OMe,

20-F,P

San

d30-3

0 -phosph

odiester

HBV

Con

served

region

sof

HBV

RNAi

IArrow

headResearch

a20-OMOE

chim

era,

20-O-m

ethoxyethyl-DNA

chim

eric

oligon

ucleotides

with

phosph

orothioatelinka

ges;

20-O-M

ech

imera,

20-O-m

ethyl-DNA

chim

eric

oligon

ucleotidewith

phosph

orothioate

linka

ges;

LNAch

imera,

locked

nucleicacid-DNAch

imerawithph

osph

orothioatelinka

ges.

1464 | Med. Chem. Commun., 2014, 5, 1454–1471 This journal is © The Royal Society of Chemistry 2014

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Fig. 11 Number of modified ON drugs in clinical trials according todifferent assignees.

Fig. 10 General functional representation of different oligonucleotide based therapeutic approaches in the central dogma of molecular biology.

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drugs in 1998), there was an increase in the number of drugcandidates entering clinical trials and a maximum of 34 drugcandidates entered between 2005–2008. From then, there was adecrease in the number of drug candidates, and only two drugsentered clinical trials in 2011–2012. A maximum of 18 drugcandidates entered clinical trials in 2007–2008, which was fol-lowed by 16 drugs in 2005–2006. Out of these, a maximum of 12drug candidates entered Phase 1 clinical trials in 2005.

Fig. 12 Number of modified ON drugs in clinical trials in different years


Conclusion

The recent approval of Kynamro by the FDA has added a muchneeded boost to research on antisense based therapeutics,which since 1998 was thought to be directionless and futile.Chemical manipulations of natural oligonucleotides arerequired as the direct use of these nucleotides as therapeuticagent suffers from some limitations such as low binding affinityto the complementary nucleic acid and poor nuclease stability.Hence, in the search for suitable antisense drug candidates,vast number of modications have been carried out, e.g. back-bone, nucleobase and sugar moiety modication of the naturalDNA/RNA, leading to the development of three FDA-approveddrugs. Furthermore, with persistent promising clinical trialsinvolving these modied oligonucleotides, it can be anticipatedthat more new potent antisense drugs may appear in the nearfuture.

Acknowledgements

VKS thanks CSIR, New Delhi, for award the Junior/SeniorResearch Fellowships.

.

Med. Chem. Commun., 2014, 5, 1454–1471 | 1465


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