Lancet neurology.
`v. 8, no . 10 (Oct 2009)
`General Collection
`W1 LA453U
`2009-10-22 13:03 :33
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`PROPERTY OF THE
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`LIBRARY OF
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`Articles
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`; ::.:suits from the Carotid
`_;l'rtebral ArteryTranslumin~I
`Angioplasty Study {(/1.\lf.,TA,
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`Hestoration of clwt
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`Review .
`
`Sec page 929
`
`

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`
`THE LANCET r\Jeurology u
`
`Volume 8 · Issue 10 • October 2009
`
`Articles
`889 250 µg or 500 µg interferon beta-lb versus 20 mg
`➔ @\ glatiramer acetate in relapsing-remitting multiple
`sclerosis: a prospective, randomised,
`multicentre study
`P O'Connor and others
`898 Endovasculartreatment with angioplasty or stenting
`➔ @ versus endarterectomy in patients with carotid artery
`stenosis in the Carotid And Vertebral Artery
`Transluminal Angioplasty Study (CAVATAS):
`long-term follow-up of a randomised trial
`J Ederle and others
`908 Long -term risk of carotid restenosis in patients
`➔@ randomly assigned to endovascular treatment or
`endarterectomy in the Carotid and Vertebral Artery
`Transluminal Angioplasty Study (CAVATAS):
`long-term follow-up of a randomised trial
`L H Bonati and others
`Local restoration of dystrophin expression with
`918
`➔ @\ the morpholino oligomer AVl-4658 in Duchenne
`muscular dystrophy: a single-blind,
`placebo-controlled, dose-escalation,
`proof-of-concept study
`M Kina Ii and others
`Review
`929 A reassessment of risks and benefits of dopamine
`agonists in Parkinson's disease
`@
`A Antonini and others
`938 Blood pressure as a prognostic factor after
`acute stroke
`\
`V Tikhono(( and others
`949 Malignant middle cerebral artery infarction:
`clinical characteristics, treatment strategies,
`and future perspectives
`H B Huttner, S Schwab
`959 Cervicogenic headache: an assessment of the
`evidence on clinical diagnosis, invasive tests,
`and treatment
`N Bogduk, J Govind
`
`873
`@
`
`Leading Edge
`869 Pandemic influenza: a priority for the neurological
`community
`Reflection and Reaction
`870 Trials of diminishing relapses for diminishing returns
`@
`AColes
`Poor outcomes after endovascular treatment of
`871
`symptomatic carotid stenosis: time for a moratorium
`@
`PM Rothwell
`Less is more: therapeutic exon skipping for
`Duchenne muscular dystrophy
`A Aartsma-Rus, G-/ 8 van Ommen
`875 Cervicogenic headache: a pain in the neck for some
`neurologists?
`I'/ Goadsby
`877 Can the WATCHMAN device truly PROTECT from
`stroke in atrial fibrillation?
`/1/Wrigl,·y, r, YI/ lip
`Correspondence
`879 Epidural abscesses in Africa
`T /I l/o/>i11; G l'roclilla. IJ Rigamonti
`880 Quality of life in children with CMT type lA
`S 1/amdrnndrl'n anrl others; J Burns
`In Context
`882 When a patient chooses death: divided attitudes
`K Stone
`884 Profile
`Paul O'Connor: from manual labour to multiple
`sclerosis mastery
`RWil/iarm
`885 Ten most wanted
`885 Lifeline
`MM/11ow11
`l3ook
`Unravelling the mysteries of juvenile
`Huntington's disease
`I' (!'nrlcs
`88G Book
`Navigating neuroradiology
`( (rol1'111J, r ( /101J1ckus
`887 Book
`Unveiling the less explored side of Parkinson's disease
`M Mcrl'lln
`888 News in brief
`
`886
`
`➔ 1'1•1•1 11•vi1•w1•d .md f.,..,, 11 ,\l kPd to pllblit,llinn in ,1 -H wnh
`
`@ l'11•vi111"ly p11hll',h1•1!1n1luw
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`att:h,e NUM and mav b,e
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`\
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`'wt' www.tht"l.\llu·t .< c ,111 for Wt·hl xt, ., contrnt
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Li Articles
`
`~ @ +~ Local restoration of dystrophin expression with the
`morpholino oligomer AVl-4658 in Duchenne muscular
`dystrophy: a single-blind, placebo-controlled,
`dose-escalation, proof-of-concept study
`Maria Kinali*, Virginia Arechavala•Gomeza*, Lucy Feng, Sebahattin Cirak, David Hunt, Carl Adkin, Michela Guglieri, Emma Ashton, Stephen Abbs,
`Petros Nihoyannopoulos, Maria Elena Garralda, Mary Rutherford, Caroline Mcculley, Linda Popplewell, Ian R Graham, George Dickson,
`Matthew )A Wood, Dominic J Wells, Steve D Wilton, Ryszard Kole, Volker Straub, Kate Bushby, Caroline Sewry, Jennifer E Morgan,
`Francesco Muntoni
`
`Lanett Neurol 2009; 8: 918•28
`
`Published Online
`August 26, 2009
`DOl:10.1016/S1474·
`4422(09)70211-X
`See Reflection and Reaction
`page 873
`
`'Contributed equally
`
`Summary
`Background Mutations that disrupt the open reading frame and prevent full tr;111sfotion of DMD, the gene that encodes
`dystrophin, underlie the fatal X-linkcd disease Duchcnnc muscular dystrophy. Oligonuclcotidcs targeted to splicing
`clements (splice switching oligonucleotidcs) in DMD pre•rnRNA GIii lead to cxon skipping, restoration of the open
`reading frame, and the production offunctional dystrophin in vitro and in vivo, which could hendit patients with this
`disorder.
`
`Methods We did a single-blind, placebo•controllcd, dose•escalation study in patients with DMD recruited nationally,
`lo assess the safety and biochemical efficacy of an intramuscular morpholino splice-switching oligonucleotide
`(AVl•4G58) that skips exon 51 in dystrophin rnRNA. Seven patients with Duchc1111e muscular dystrophy with deletions
`in the open reading frame of DMD that are responsive to cxon 51 skipping were selected on the basis of the preservation
`of their extensor digitomm brcvis (EDD) muscle seen on MRI and the response of cultured lihrohlasls from a skin
`biopsy to AV1•4G58. AVl•4G58 was injected into the EDB muscle; the contralatcral muscle received saline. Muscles
`were biopsied between 3 and 4 weeks after injection. The primary endpoint was the safety of AV1•4G58 and the
`secondary endpoint was its biochemical efficacy. This trial is registered, number NCT00J59250.
`
`The Dubowitz Neuromuscular
`Centre, University College
`London Institute of Child
`Health London, UK
`(M Kinali MD,
`V Arechavala-Gomeza PhD,
`L Feng PhD, S Cirak MD,
`Carl Adkin PhD, C Sewry PhD,
`J E Morgan PhD, F Muntoni MD);
`Department of Pediatrics,
`Hammersmith Hospital,
`London, UK (M Kinali,
`F Muntoni); Department of
`Orthopaedics, St Mary's
`Hospital, London, UK
`(D Hunt FRCS); Institute of
`Human Genetics, Newcastle
`University, Newcastle, UK
`(M Guglieri MD, V Straub MD,
`K Bushby MD); DNA Laboratory
`Genetics Centre, Guy's
`Hospital, London, UK
`(f Ashton PhD, S Abbs PhD);
`Department of Cardiology
`(P Nihoyannopoulos MD),
`Division of Neuroscience and
`Mental Health (C Mccull,•y PhD,
`fJ J Well~ PhD), ~nd RobPrt
`Steiner MRI Unit
`(M Rutherford MD),
`Hammersmith Hospital
`Campus, Imperial College
`London, UK; Academic Unit of
`Child and Adolescent
`Psychiatry, Imperial College
`St Mary's Campu1, London, UK
`(ME r.,urald,1 MD);
`H.tmmenmith Hospital
`Campus, Imperial College
`London, UK; Royal Holloway
`University of London, UK
`(L PopplPwrll PhD,
`IR Graham PhD, G Diclsor1 PhD);
`Department of Physiology,
`
`Findings Two patients receivecl 0, 09 mg AV1•4G58 in 900 JIL (0· 9%) saline and live patients received 0, 9 mg AV1·4G58
`in 900 pL saline. No aclverse events related to AV1•4G58 ,ulministration were reported, lnlramusrnlar injection of the
`higher-dose of AVI-4658 resulted in increased clystrophin expression in all lrcakd EDB muscles, although the results
`of the immunostaining of EDB-treated muscle for dystrophin were not 1111ifor111. In the areas of the imrnunostained
`sections that were adjacent to the needle track through which AVl-4658 was given, 44-79% of myolibres had increased
`expression of dystrophin. In randomly chosen sections of treated EDII muscles, the 111ea11 i11tc11sity of dystrophin
`staining ranged from ZZ% to 32% of the mean i11tcnsity or dystrophin in healthy co11trol muscles (mean ZG, 4%), and
`the mean intensity was 17% (range 11-21%) greater tha11 the i11tcnsity in the contralatcral salinc•trc.1ted muscle
`(one-sample paired t test p=0· 00Z). In the dystrophin-positivc fihres, Ilic i11tc11sity of dystrophi11 staining was up to
`42% of that in healthy muscle, We showed expression of dyslrophi11 al Ilic expcfled molecular weigh! ill !he
`AVI,4658-lrcalcd muscle by i1111111111oblol.
`
`Interpretation Intramuscular AVl-4658 was safe and induced the cxprcssio11 of dystrophin loc:1lly withi11 treated
`muscles. This proof.of.concept sludy has lt•d Jo an ongoing systemic di11kal trial ofAVl-4651! i11 palicnls with DMD,
`
`Funding UK Department of Health.
`
`Introduction
`Duchenne muscular dystrophy (DMD) affects 1 in
`3500 newborn boys, causing eventually progressive
`muscle weakness, cardiomyopathy. and
`respiratory
`failure. Patients arc diagnosed when they arc toddlers,
`become wheelchair-dependent in their early teens, and
`<lie in their 20s. With improvements in standards of care,
`including non.invasive venlilation and gl11cocorlicoid
`and cardioprotective treatment, many i11divid11als with
`DMD survive beyond their mid-20s'' dcspi(c having
`scwre and disabling weaknesses.
`
`DMD is caused by the absence of the protein <lrstrophin.
`Dystrophin associates with other sarcolcmmal proteins
`of the dystrophin glycoprotein complex and connects the
`cytoskclcton to the extracellular matrix. The ahse11ce of
`dystrophin reduces the stability of the sarcolemm,1 and
`increases intracellular calcium influx, which is followl'd
`by dcgcneralion of the muscle lihrl's. Drstrophin is
`encoded by DMD. Dl'll'tions (in ;1ho11t (,5?b of p;1ti1•111s).
`d11plicatio11s (in about 10% or patirnts), point 11111t;1tio11s
`(in about l0%ofp;1tie11ts), orotlins111alln 11-;11 r;111g('lll<'t1ts
`GIil disnipt tlil· open 1r;1dit1g fr;11111· of /)/\1/), il';tding lo
`
`918
`
`Th is material wascop,ied
`
`www tl11·l,1111 ,·t, 0111/11,•1,rnl'"JY Vot 8 Oclohrr 2009
`
`

`

`J J u
`
`Articles
`
`Anatomy and Genetics,
`University of Oxford, UK
`(M J A Wood MD); Centre for
`Neuromuscular and
`Neurological Disorders,
`University of Western
`Australia, Perth, WA, Australia
`(SD Wilton PhD); AVI
`Biopharma, Corvallis, Oregon,
`USA (R Kole PhD); Centre for
`Inherited Neuromuscular
`Disorders, Robert Jones and
`Agnes Hunt NHS Trust,
`Oswestry, UK (C Sewry)
`
`Correspondence to:
`Francesco Muntoni, Oubowitz
`Neuromuscular Cl'ntre,
`University College London
`lnstillM of Child Health,
`30 Guilford Street, London,
`WC!N l EH, UK
`f.muntoni @ich.ucl.ac.uk
`
`studied the safety and biochemical efficacy of AVJ-4658, a
`PMO designed to target exon 51 that is delivered by
`intramuscular injection. Here, we report the results of a
`single-blind, placebo-controlled, dose-escalation safety and
`efficacy study of PM Os in patients with DMD.
`
`Methods
`Patients
`TI1is
`single-site,
`non-randomised,
`single-blind
`(investigator) study was done at Imperial College NHS
`Trust, London, UK. in patients with DMD who were
`recruited nationally. Participants were boys with a classic
`clinical diagnosis of DMD"· who were aged between 10
`and 17 years inclusive when the study drug was given. All
`participants had a deletion that can be rescued by the
`skipping of exon 51 (cg, deletion of exons 45-50, 47-50,
`48-50, 49-50, SO; 52, or 52-63); had fewer than 5%
`revertant fibres seen in a muscle biopsy; had the extensor
`digitorum brcvis (EDIJ) muscle sufficiently preserved
`(grade I to 3: grade 1 is near normal; grade 2 is 30-60% of
`the muscle is normal; and grade 3 is muscle is almost all
`abnormal but some normal muscle still present at the
`periphery), as determined by MRI of the fcet; 1
`' " had a
`forced vital cap:icity of 25% or more and a normal
`overnight sleep stttdy before 3 months from the day of
`injection; were able to comply with all study assess ments
`and return for all study visits; and had adequate
`
`premature termination of its
`translation/' whereas
`deletions or duplications that maintain the open reading
`frame can lead to truncated but functional dystrophin,
`which underlies the milder disorder Becker muscular
`dystrophy (BMD). 1 The spectrum of severity for BMD
`varies, ranging from difficulties in walking in the late
`teens to preserved walking ability into late adulthood and
`a normal lifespan.'
`Up to 50% of patients with DMD have sporadic
`dystrophin-positive revertant fibres. ' This dystrophin
`expression arises from alternative processing of DMD
`pre-mRNA that skips some exol!S, leading to restoration
`of the open reading frame.' Revertant dystrophin is
`correctly localised to the sarcolcmma and mediates the
`assembly of other proteins of the dystrophin glycoprotein
`complex, suggesting that it is physiologically functional.
`The ocrnrrencc of rcvertant fibres and the mild symptoms
`of some individuals with BMD with in-frame deletions
`suggest that it might be f\:asilile to modify the splicing of
`the DMD transcript and, by skipping the mutated cxons,
`produce functional dystrophin (figure 1).
`Some exon deletions arc more co11J111011 than others.''
`Deletions of exons 50, 52, 52-(,3, 45-50, 47-50, and 49-50
`cumulatively account for 13% of all the deletions in
`DMD." Skipping of exon 51
`in patients with these
`deletions should restore the open reading frame of DMD
`and !cad to the expression of functional dystrophin.
`Antisense oligonucleotides have been used
`for
`experimental gene silencing and recently as splice(cid:173)
`switching oligonuclcotides to modify splicing and
`induce exon skipping," partirnlarly in rnyoblasts from
`patients with DMD in vitro,""' and in mouse and dog
`models of DMD."·" One patient with DMD who had
`a deletion of exon 20 received an intravenous infusion
`of a splice-switching oligo11uclcotidc with a phos(cid:173)
`phorothioatc backbone, which induced skipping of
`exon 19 aml restored the VM V open reading frame in
`lymphocytes but had 110 clli·ct in skeletal 111uscle.1·• A
`recent phase I clinical study rl'portl'd encouraging
`results in four boys with DMD who rl'ccived a single
`intramusrnl:ir
`injection of a 2'O-ml'lhyl-ribooligo-
`11ucleosiclt·-pl10sl10pl10rothio:1tl' spliu•-switcl1i11g oligo-
`1111cleotide that was largl'lcd lo skip c•xon 51. This
`treatment led to apprcciahlc l'xprcssion of dystrophin
`am! was well toll'rated.1"
`Other cl1emically 111odilil'd oligo1111ch-01id<·s h:t\'l' hl'l'II
`used
`in
`preclinical modl'ls
`and diniral
`trials.
`Phosphorodi:1111idatc• 111orphnli110 oligoml'rs
`(l'MOs;
`figure• I) ;ire 11011-loxic, and in IIH• 111dx 111011st' 111odt•I of
`DMD tlr\'y wen• tire• 1110st dkctiv1• oligonl<'r dl<'111ist1y for
`i11Jud11g c·xon skipping and rC'storing lo11g-bsting (Wl'l'ks)
`dyslrophi11 <'Xpn·ssio11 alh-r i11lra,·1·11011s or i11lra11111srnlar
`i11jl'ctior1.11 "
`l'MOs,
`1111lik1· otl1t•t anlisc·tts<' oligo•
`llttrl<'olidt's,
`:111• 1111rltargl'cl. 1101 11u·l:1bolisc·d. a11d
`ill
`Jli<'diniral or diniral studit•s W<'l<' 1101 asscH iah·d with
`artivat ion oft Ill' i1nn1111u· S)'Sh'lll. ;111;1ph)'laxis. lr}'poh·11sio11,
`or a11li•anh)'tl1111ias,,.· 011 1111' basis of tl1<·s,· dat:1, w,· haw
`
`A
`
`B
`
`Dystrophin
`Dyslrophin pre-mRNA
`I EIJ- lmJ-m:11-mJJ-lm)-:mD-mJ> __,. 0 -c::Dc=::::D CZD-c:t::>
`II :lmJ-lmJ-m:11-mJJ,/_..L--:mD-mJ)- -► o--c:Dc::::::D
`Ill m!l-mzJ-IZI]]-mIJ-,1_,L--]mJ-mJ)- -► C ) - c :D~
`IV EIJ-mzJ-IZI]]---1'/---lEID-lm>- -► C)-c:::::J)-c::=:=D c:::::t:::>
`V lmJ-mzJ--r,:::L----lmJ--lm>- -► o--c:De::::::::I)-c=i::::>
`v1 m----------0,,__--mu-mi>- -► o-e:o-c:::o c:::>
`
`AVl -4658
`
`AVl -4658
`
`AVl -46S8
`
`AVl -4658
`
`I i~urt 1: llrl,·tlon\ ,111d pt<•dict,·d rriult\ nf ,•xon sklppi119 In tin' p,1tie11t\ who W<'re studit•d
`(A) l'1t• ml\NA 11,111,uiph ,uuldy,llophin p10h•i11 p1od11d\ f1tllll (ull lt•lltjlh PMI>, in fl.ltil'nh wilh P11du•111w
`11u,,,ul.u dy,lmphy, ,mtl p1t·dit h•d pmlt•in wqtH'lllt'\ ,,fh•r t>xon ,~ippin1_J (I) lht• 110,m,11 dy,1 1ophi11 IJt'Ol' p1rnl11u•\
`1l11• f1,ll lc·1H1th dy,l1llphl11 prlldll(!, (11) l'.1lil'nl11 ,rnd] 11,\11 ,1 ,kll'lin11i111•xn11 50 lh,11 di\l llj)IS 1111• "1"'11 ll'.ldirHJ
`lr,\1111', l,•,1<l111q to ,1 !1llm,11t•d ,111d ll11,1,1hlc• dy,11ophi11. (Ill) ~~ippinq nf ,•xnn r, l 1t•,1rn,•1 thl' ll'.1llil1lJ f1,111w, prodlldnq
`,t t1ll11< .11t·d hlll !1111<1lll11,1I dy,lrt1phi111h,1t l,H~1 ,•xort, 'JO ,111d ', 1. (IV) l'.1li,•11I / ii 111il1i1HJ <'xon~ ~•) ,111d ',O.
`(VJ 1·.,1 1,•111\ j ,111d-t ,\It' 111i\\i11q ('Xlll1\ -IB ',ll. (VI) 1•,11i,•111, ', ,111d (, ,lit' llli\\ilUJ <'XOl11 ,1',-',ll. All 111,, lrtllll,lll'"
`cly,t1(1pl1111, p1t1d111 t·d ,d11•1 ~Jippinq or t')(()ll !)1 ,lll' mi,<iinq tlw hirnj(' 3 H.'(jillll .md \Ollll' of llll' 1rnl tlo m ,1in but h,lVl'
`ht•r11,1\\rn i,,11•1lwith 1lw mil111•r llMI> plwnolyp1•_,. ,., (II) \ltlll t111t•o(lhC' pho,phormli,u11id,11t• nunpholino
`r111i1l1ln,1ti,1n c,11'11• ,11 1t i,1·11,l' 11/iq111111·1
`
`www1l11•l.111trl «1111/11,·1110l,111y Vol 8 0ctnlll'r 200')
`
`Th is m ateria I w as co-,pied
`atthe N Uvl a nd m ay b,e
`
`919
`
`

`

`u Articles
`
`DMD deletion
`
`Mobility
`
`Age at
`enrolment
`(years)
`
`Steroids Age at Dystrophin-positive MRI
`fibres in original
`first
`grading
`ofEDB
`biopsy
`biopsy
`(years)
`muscle
`
`EDBfibrosis
`
`Amplicon
`Time between PCR
`injection and primers to sizes (bp)
`exons
`EDBbiopsy
`(weeks)
`
`Saline injected Treated
`
`Low dose
`16
`
`13
`
`14 bp deletion in intron 49 Wheelchair for N
`that included the exon 50
`11 years
`acceptor splice site
`Exon 50
`
`Wheelchair for N
`10 years; rides
`static bike for
`10 min daily
`
`High dose
`11
`
`Exons 48-50
`
`4
`
`15
`
`Exons 48-50
`
`Wheelchair for
`lOyears
`Walks indoors
`
`11
`
`Exons 45-50
`
`Walks unaided
`
`6
`
`12
`
`Exons 45-50
`
`Walks unaided
`
`7
`
`10
`
`Exons 49-50
`
`Walks unaided
`
`y
`
`y
`
`y
`
`y
`
`y
`
`8
`
`7
`
`7
`
`3
`
`7
`
`3
`
`4
`
`++
`
`+++
`
`+++
`
`A few revertant fibres, 2a
`(-1-2% ); traces on a
`few fibres
`No revertant fibres;
`no traces
`
`2b/3
`
`No revertant fibres;
`no traces
`One revertant fibre;
`traces on many fibres
`No revertant fibres;
`traces on a few fibres
`No revertant fibres;
`traces on many fibres
`No revert.mt fibres;
`traces on many fibres
`
`2b/J
`
`2a/2b
`
`2a
`
`++
`
`48 and 52
`
`519-286
`
`+++
`
`4
`
`48 and 52
`
`519-286
`
`4
`
`4
`
`4
`
`4
`
`46 ,rnd 52
`
`570-337
`
`46and52 570-337
`
`43 and52
`
`486-253
`
`43 .,ml 52
`
`486-253
`
`47 ,1ml 52
`
`539.306
`
`Numbers are patient number. EDB,extensor digitorum brevis. bp,base pair. Y•yes. N,no. "'•Asymmetrical EDB Involvement on mu,cle MRI grading. +•Moderate incre,1se of perlmyslal and tndomysial
`connective tissue; some areas had a severe increase in perimysial and endomysial connective tissue. ++•Most fibres were surrounded by l.uge amounts of connective tlm,e, but some areas h,1d less and were
`compact. +++•All fibres surrounded by connective tissue; severe fibrosis throughout sample. EDB 0 extensordigitorum brevis. bp•b,1se pairs. PCR 0 polymeme chain reaction.
`
`Table 1: Baseline characteristics, exons targeted by PCR primers, and predicted amplicon sizes
`
`psychosocial
`supportive
`adjustments,
`psychiatric
`circumstances, and full understanding of the study aims,
`process, and likely outcomes.
`Exclusion criteria were: absence of EDB muscles or
`advanced pathology ofEDB muscles (grade 4) on muscle
`MRI; left ventricular shortening fraction of 25% or less,
`an ejection fraction of less
`than 35% seen by
`cchocardiography within 3 months of visit one, or both;
`respiratory insufficiency defined by the need for invasive
`or non-invasive ventilation; severe cognitive dysfunction
`that meant the patient was unable to understand and
`collaborate with the study protocol; immune deficiency
`or autoimmune disease; bleeding disorders or chronic
`anticoagulant treatment within 3 months before study
`entry; medication with anabolic steroids, crcatinc protein
`supplementation, albuterol, or other beta agonists, and
`intranasal, inhaled, or topical steroids for a disorder other
`than muscular dystrophy within 1 week before study
`entry; surgery within 3 months before study entry or
`planned for anytime <luring the study; inability to
`undergo MRI (cg, owing to metal implants); known
`allergies to products likely to be used in the study (cg,
`antiseptics or anaesthetics); and participation in another
`experimental study within 4 weeks of study entry.
`Standard-of-care treatment, including glucocorticoids
`and car<lioprotcctivc drugs, was continued in all patients.
`All study participants were informed before enrolment of
`the procedures, risks, and possibility of 110 benefit, All
`participants provided written assent, and their parents
`
`gave written informed consent before enrolment in this
`study, This trial was designed and <lone in compliance
`with UK good clinical practice, International Conference
`on I Iarrnonisation (ICI I) EC,, and all applicable regulatory
`requirements were met (UK Medicines and Healthcare
`Products Regulatory Agency, UK Gene Therapy Advisory
`Committee, and local research ethics committees).
`Trial activities and adverse events were monitored by a
`safety monitoring committee. The safety monitoring
`committee rnet on the following occasions: before recruit(cid:173)
`ment of' the first patient; to authorise the recruitment of
`the second patient afier the first patient was biopsied:
`and aficr the second p:itient was studied but before
`recruitment of the first patient in the high-dose cohort
`without use of an intermediate <lose (0-27 mg). The
`safety monitoring committee also met to discuss and
`authorise a proposed change to the protocol, which
`enabled us to increase the <lose directly to the higher
`dose, to authorise the recruitment of the last two patients
`in the high-dose cohort, and to discuss a severe adverse
`event (bilateral surgical wound infection after the muscle
`biopsies) in one of the patients in the second cohort.
`The