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From darkness to light: prospects for therapy for childhood retinal disease Anthony T Moore Moorfields Eye Hospital and Institute of Ophthalmology UCL. Retinal dystrophies: pathways to therapy. clinical phenotype. gene mapping. protein function. animal models. Human treatment trials. UCL. - PowerPoint PPT Presentation
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From darkness to light: prospects for therapy for childhood retinal disease
Anthony T Moore
Moorfields Eye Hospital and Institute of Ophthalmology UCL
Retinal dystrophies: pathways to therapy
clinical phenotype
gene mapping
protein function
animal models
Human treatment trials
Clinical trial of gene therapy for early-onset severe retinal degeneration caused by defects in RPE65
UCL
JWB Bainbridge, AJ Smith, SS Barker, S Robbie, R Henderson, K Balaggan, A Viswanathan, GE Holder, A Stockman, N Tyler, S Petersen-Jones, SS Bhattacharya, AJ Thrasher, FW Fitzke, BJ Carter, GS Rubin, AT Moore, RR Ali
and the Moorfields Eye Hospital and UCL Eye Gene Therapy Study Group
Institute of Ophthalmology, University College LondonMoorfields Eye Hospital NHS Foundation Trust, LondonNIHR Biomedical Research Centre for Ophthalmology, University College London and Moorfields Eye Hospital LondonDepartment of Civil and Environmental Engineering , University College LondonMichigan State University, MIInstitute of Child Health, University College LondonTargeted Genetics Corporation, Seattle
Bainbridge J et al N Eng J Med 2008 April [Epub]
Lebers amaurosis• first described 1869• infantile onset rod-cone
dystrophy• 2-3 per 100,000 live births• 5% of congenital blindness• AR inheritance • genetically heterogenous• poor vision from infancy• nystagmus • non-recordable ERG
LCA GenesLCA Genes
CPE290
Lebercilin
RDH12
Courtesy of Professor Birgit Lorenz
RPE65 1p31.2
• 14 exons• Encodes a 65 KD protein within RPE• Crucial to Vit A metabolism in retina• responsible for isomerisation of all-trans
retinol to 11-cis retinol• Mutations cause disease in man (6% LCA)
• mouse knockout• Canine model• Gene therapy rescue in mice and dogs
Phenotype associated with RPE65 mutations
– Infantile onset of visual impairment– Light staring – Profound night blindness– Useful vision at young age– Absent rod function– Residual cone function– Progression to severe visual loss in
late teens– Late cell death
Subject RJ age 21
VA Rt 2/48 (1.38) Lt 2/60 (1.48)
Poor colour vision
Visual field loss
Non recordable ERG
• Single gene loss-of-function defect
• Condition is severe and has predictably poor prognosis
• Window of opportunity for intervention
• Intervention might improve function
• Target RPE cells can be transduced efficiently by rAAV
• Principle is proven in experimental models
• UK human trial funded by 970K grant from Department of Health gene
therapy intiative
RPE65 gene therapy for LCA
• Aim: to determine whether gene therapy for retinal dystrophy caused by RPE65 mutations is safe and effective in humans
• Study design phase I/II open-label single-centre dose-escalation study
• IMP rAAV2.hRPE65p.hRPE65
• Primary outcome safety
• Secondary outcome evidence of visual benefit
Design of clinical trial of RPE65 gene therapy for LCA
Inclusion criteria:
• early-onset severe retinal dystrophy
• missense mutations in RPE65
• between 8 and 30 yrs of age
• in each case, the eye with the worse acuity was selected as the study eye
Exclusion criteria:
• visual acuity better than 20/120 in the study eye
• null mutation in RPE65
• contra-indications for systemic immune suppression
Design of clinical trial of RPE65 gene therapy for LCA
Stage 1 of the trial involved:
• 3 young adults (aged 16 to 30 years) with advanced degeneration
• subretinal injection involving up to 1/3 the total retinal area
Subsequent stages will involve:
• 9 subjects younger than 16 yrs
• dose escalation involving larger areas of the retina
Trial stages and dose-escalation
Baseline characteristics of subjects
Age (yrs
)
Sex Mutation Amino acid change
VA (Log-MAR)
Ref. error
ERG
Rods Cones (30Hz flicker)
Macula (PERG/
Multifocal)
1 23 M Homo-zygous
[1102T>C]
p.Tyr368His 1.16 -3.75/-0.50 x170
No definite respons
e
Residual Undetectable
2 17 F c.[11+5G>
A] +[118G>
A]
Splice site p.Gly40Ser
1.52 +1.50/
-1.00 x 90
Residual
Very reduced
and delayed
(4.0uV;41ms)
Untestable (nystagmus
)
3 18 M c.[16G>T]
+ [499G>T]
p.[Glu6X] + [Asp167Tyr]
0.76 -0.25/-2.00 x 52
No definite respons
e
Very reduced
and delayed
(10uV;42ms)
Undetectable
Subretinal injection of rAAV2.hRPE65p.hRPE65 (1x1011/ml; 1ml)
QuickTime™ and aAnimation decompressor
are needed to see this picture.
Resolution of induced retinal detachment
# 1
# 2
# 3
pre-op +1 day +4 monthsduring surgery
Resolution of induced retinal detachment
scan unrecordable
Pre-op
+1 day +2 days
# 1
# 2
# 3
Adverse events
Transient visual loss (associated with induced retinal detachment)
Mild post operative inflammation
No surgical complications
No immune response to vector or RPE65
Visual acuity following subretinal injection
LogMAR(Snellen)
Baseline 2 months
post-op
4 months
post-op
6 months
post-op
12 months
post-op
#1 Study eye 1.16 (20/286) 1.06 (20/226) 0.98 (20/190) 0.86 (20/145)
Control eye 0.88 (20/150) 0.90 (20/156) 0.68 (20/95) 0.78 (20/120)
#2 Study eye 1.52 (20/662) 1.50 (20/632) 1.58 (20/760) 1.52 (20/662)
Control eye 1.62 (20/833) 1.56 (20/662) 1.52 (20/662) 1.58 (20/760)
#3 Study eye 0.76 (20/115) 0.90 (20/156) 0.80 (20/126) 0.76 (20/115)
Control eye 0.54 (20/69) 0.46 (20/58) 0.40 (20/50) 0.44 (20/55)
Microperimetry
control eye
control eye
control eye
study eye
study eye
study eye
Subject #2 Subject #3Subject #1
Microperimetry: Subject #3; 6 months following surgery
control eyestudy eye
Microperimetry: Subject #3; 6 months following surgery
control eyestudy eye
Microperimetry: Subject #3; 6 months following surgery
control eyestudy eye
Dark-adapted perimetry; change in sensitivity over 6 months
control eye
control eye
control eye
study eye
study eye
study eye
#2
#3
#1
Field of right eye
Field of left eye
Dark-adapted perimetry: Subject #3; 6 months following surgery
control (left) eye
study (right) eye
P<0.01
P<0.05
P<0.1
P>= 0.1
P >= 0.1
P<0.1
P< 0.05
P< 0.01
P< 0.001
Positive slope
Negative slope
Dark-adapted perimetry: Subject #3; 6 months following surgery
control (left) eye
study (right) eye
P<0.01
P<0.05
P<0.1
P>= 0.1
P >= 0.1
P<0.1
P< 0.05
P< 0.01
P< 0.001
Positive slope
Negative slope
Assessment of visually-guided mobility: UCL Pedestrian Accessibility & Movement Environment Laboratory
Assessment of visually-guided mobility
Subject #2 Subject #3Subject #1
4 lux4 lux 4 lux
240 lux240 lux 240 lux
Assessment of visually-guided mobilitySubject #3; 6 months following surgery
4 lux
Visually-guided mobility: Subject #3; 6 months following surgery
• Subretinal vector injection is safe
Conclusions
• Even in advanced retinal degeneration, rAAV2.hRPE65p.hRPE65 can improve vision
• These results support further studies in children with RPE65 defects
Acknowledgements
Andrew Dick and The UK RPE65 Gene Therapy Data Safety Monitoring CommitteeAlan Bird, Andrew Webster and Zdenek Gregor: Moorfields RPE65 Gene Therapy Advisory CommitteeVivien Perry and Moorfields PharmaceuticalsGraeme Black and the Manchester Regional Genetics LaboratoryDavid WongThe patients and their families
The Moorfields Eye Hospital / UCL Eye Gene Therapy Study Group; G.W. Aylward, D. Boampong, C. Broderick, P. Buch, C. Childs, Y. Duran, D. Ehlich, S. Falk, M. Feely, T. Fujiyama, F. Ikeji, V. Luong, A. Milliken, R. Maclaren, P. Moradi, F. Mowat, M. Richardson, C. Ripamonti, A.G. Robson, H. Rostron, I. Russell-Eggitt, P. Schlottmann, M. Tschernutter and N. Wasseem.
FundingUK Department of Health The British Retinitis Pigmentosa Society Special Trustees of Moorfields Eye HospitalThe Sir Jules Thorn Charitable TrustThe European Union (EVI Genoret and Clinigene programmes)
The Wellcome Trust The Medical Research CouncilFoundation Fighting Blindness USAFight for SightThe Ulverscroft FoundationFighting Blindness Ireland
Moorfields Eye Hospital and UCL Institute of Ophthalmology Biomedical Research Centre for Ophthalmology JWBB is a Wellcome Advanced Fellow; AJT is a Wellcome Senior Fellow
UCL