A Natural History Study of Subjects with X-linked Retinoschisis in Anticipation of a Phase I/II Gene Therapy Trial

Transcription

1 A Natural History Study of Subjects with X-linked Retinoschisis in Anticipation of a Phase I/II Gene Therapy Trial Mark E. Pennesi, MD/PhD Associate Professor

2 X-linked Retinoschisis Background Rare X-Linked recessive Incidence: :5, to :3, Prevalence: ~35, patients in US and EU Mutations in single gene RS in all cases Retinoschisin 4 kda protein secreted by photoreceptor and bipolar cells Forms extracellular homo-octameric complexes around photoreceptor inner segments, OPL and INL Maintains retinal cellular organization and synaptic structure

3 Clinical Features of X-Linked Retinoschisis Clinical Features Family History Decreased central vision Maculoschisis (%) Peripheral schisis (%) Vitreous Hemorrhage Retinal Detachments Negative waveform ERG Spoke-wheeling in fovea Maculoschisis by SD-OCT XLRS Normal Peripheral retinoschisis Reduced b:a-wave ratio on Full Field ERG Images: Santos et al. 5 and CEI

4 Additional Testing Modalities in XLRS Kinetic Visual Fields Multifocal ERG Static Visual Fields Microperimetery

5 This is an exciting time for Patients with X-Linked Retinoschisis Two Gene Therapy Trials: NCT NIH Study of RS Ocular Gene Transfer for X-linked Retinoschisis NCT466 - AGTC Safety and Efficacy of raav-hrs in Patients With X-linked Retinoschisis (XLRS)

6 Critical Questions How progressive is this disease? What might be good endpoints for a trial? Do carbonic anhydrase inhibitors make a difference?

7 Natural History Study in XLRS Inclusion: Males, Confirmed mutation in RS, Age 6 yrs. Study Design: 3 year, Phase longitudinal study Enrollment: 55 patients Sites: Casey Eye Institute (OHSU) Kellogg Eye Center (U. Mich.) Retina Foundation of the Southwest Primary Endpoints: Change in time of: BCVA, Visual Fields, SD-OCT, ERG Secondary Endpoints: Response to Carbonic Anhydrase Inhibitors

8 Spectrum of Mutations in Natural History Study Subject# Mutation Mutation Type RFS4 c.a>t p.ml Missense mutation RFS6 c.a>t p.ml Missense mutation KEC-6 c.35t>a; c.5+5g>c p.lh Missense/Splice site CEI c.96dupc:p.trp33leufs*53 Duplication CEI c.99g>a p.w33stop Missense mutation CEI-5 c.99g>a p.w33stop Nonsense CEI c.3c>g:pp68r Missense mutation CEI3 c.8g>a p.g7s Missense mutation KEC-4 c.8g>a p.g7s Missense mutation RFS c.4g>a p.e7k Missense mutation CEI-6 c.4g>a p.e7k Missense mutation RFS4 c.3dup Duplication RFS c.66>a p.y89c Missense mutation RFS9 c.78a>g p.y93c Missense mutation KEC-7 c.86t>c p.w96r Missense mutation CEI4 c.88t>c p.w96r Missense mutation CEI c.34c>t p.rw Missense mutation CEI-4 c.34c>t p.rw Missense mutation RFS c.34c>t p.rw Missense mutation RFS8 c.35g>a p.rq Missense mutation CEI c.35g>c p.9r Missense mutation CEI-9 c.39g>a p.cy Missense mutation KEC c.39g>a p.cy Missense mutation KEC c.39g>a p.cy Missense mutation CEI6 c.464a>g p.y55c Missense mutation RFS3 c.5delc Deletion RFS9 c.535a>g p.n79d Missense mutation RFS6 c.574c>t p.p9s Missense mutation RFS5 c.574c>t p.p9s Missense mutation RFS c.574c>t p.p9s Missense mutation CEI c.579dupc Duplication KEC c.596t>c p.i99t Missense mutation CEI5 c.596t>c p.i99t Missense mutation CEI c.598c>t p.rc Missense mutation CEI-7 c.599g>a p.rh Missense mutation CEI-8 c.599g>a p.rh Missense mutation CEI8 c.599g>a p.rh Missense mutation CEI9 c.599g>a p.rh Missense mutation RFS3 c.599g>a p.rh Missense mutation RFS c.66g>c p.r9p Missense mutation KEC-5 c.637c>t p.r3w Missense mutation CEI7 Exon deletion Deletion CEI Exon deletion Deletion

9 ETDRS Letter Score ETDRS Letter Score R² =.939 Cross Sectional Visual Acuity vs. Age Age (years) Longitudinal Visual Acuity 5 5 Months Average change from baseline: +/-.4 letters Standard deviation: 4. letters Weak correlation of decreased visual acuity with age Need greater than line change for significance

10 Cross Sectional Analysis of Kinetic Visual Fields Size V4e Size III4e Size I4e Larger targets useful for safety, but probably not as useful for efficacy

11 HOV TOT GATE III (decibel steradians) HOV TOT GATE V (decibel steradians) Cross-sectional Baseline Hill of Vision Volume vs. Age Octopus 9 Static Perimetry 4 Hill of Vision (Static Perimetry, V4e Target) R² = Age (years) VFMA Hill of Vision Volume 4 Hill of Vision (Static Perimetry, III4e Target) R² = Age (years)

12 OCT Assessment Problem: Total Retinal thickness is a combination of schisis and atrophy

13 Automatic Segmentation Cysts ILM RPE After Manual Correction Developed by Tomy Tan, PhD, David Huang MD/PhD

14 Cyst Thickness Map Cyst Volume=.864 mm 3

15 Spectrum of Baseline Cyst Volume

16 How Does Treatment with Carbonic Anhydrase Inhibitors influence XLRS?

17 Right Eye BCVA=5 CAI subgroup Cyst Volume Change over time BCVA=56 BCVA=55 BCVA= Volume.7 mm 3 Left Eye BCVA= Volume.58 mm 3 Volume.6mm 3 Volume.8 mm 3 BCVA=59 BCVA=56 BCVA= Volume.946 mm 3 Volume.93 mm 3 Volume.9 mm 3 Volume.7 mm 3 Screening month 3 month 6 month

18 Right Eye T BCVA=69 BCVA=73 BCVA=73 S N I mm mm mm 3.84 mm 3 Left Eye BCVA=56 CAI subgroup Cyst Volume Change over time BCVA= BCVA= BCVA= mm 3.74 mm mm 3.98 mm BCVA= Screening month 3 month 6 month

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23 Natural History Study Conclusions Cross-sectional and natural history of XLRS demonstrates slow progression To demonstrate efficacy of a clinical trial improvement of structure of function will be needed Treatment with CAIs in XLRS Minimal effect on cyst volume and visual acuity Occasional patient has a good response

24 Acknowledgements Co-Authors Casey Eye Institute Paul Yang, MD/PhD Richard G. Weleber, MD David J. Wilson, MD Retina Foundation of the SW David G. Birch, PhD Kellogg Eye Institute U. Mich. Thiran Jayasundera, MD John Heckenlively, MD AGTC Jeffery D. Chulay, MD Clinical Trial Staff Catie Beattie, MS Joycelin Niimi, OD Chris Whitebirch, BS Lea Bennett, PhD Naheed Khan, PhD Lindsey Godsey, MS Technicians Darius Liseckas Paula Rauch, BS Melissa Kramer, MS Gareth Harman, BS Casey Reading Center Maria Parker, MD Laura Erker, PhD Ambar Faridi, MD Peter Steinkemp Ellie Chergarnov Tomy Tan, PhD Travis Smith, PhD Edye Parker, MA Statistician Dawn Peters, PhD