Safety and Efficacy Study in Patients With Retinitis Pigmentosa Due to Mutations in PDE6B Gene

Study Overview
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Brief Summary
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The study is a Phase I/II, monocentric, open-label, dose-ranging safety and efficacy gene therapy intervention by subretinal administration of AAV2/5-hPDE6B. At least twelve patients 18 years of age or older, within four consecutive cohorts of patients, will be recruited. Then at least four patients 13 years of age or older, within a fifth cohort, will be recruited.

Detailed Description
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Retinitis pigmentosa (RP) is a disease where part of the eye (the retina) is degenerating over time. Patients initially present with night blindness, and later in life experience loss of central vision which leads to blindness. RP is a highly variable disorder with some patients developing symptomatic visual loss in childhood whereas others remain asymptomatic until mid-adulthood. There are no treatments available. This study focuses on the form of RP caused by mutations (modifications) in the genetic information necessary to make the protein called rod cGMP phosphodiesterase 6 β subunit (or PDE6β). Clinical diagnosis is made by function tests of the eye and confirmed using a specific method called molecular testing to verify that the PDE6B gene is not correct. This study uses a gene therapy vector inspired from an adeno-associated virus (AAV) called AAV2/5-hPDE6B. This vector intends to supply to the target cells the PDE6B therapeutic gene that is not functioning properly in the cell. The AAV parts of the gene therapy vector work as a vehicle to deliver the normal human PDE6B gene into the cells of the retina.

Official Title
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Safety and Efficacy of a Unilateral Subretinal Administration of HORA-PDE6B in Patients With Retinitis Pigmentosa Harbouring Mutations in the PDE6B Gene Leading to a Defect in PDE6ß Expression

Conditions
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Retinitis Pigmentosa

Intervention / Treatment
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* Biological: AAV2/5-hPDE6B


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Clinical and molecular diagnosis of retinitis pigmentosa caused by defect in PDE6B gene without other syndromic manifestations Aged above 13 years Ability to give informed consent Key Exclusion Criteria: Previous ocular surgery or thermal laser within 6 months before the surgery Lens opacities or obscured ocular media upon recruitment such reliable evaluation or grading of the posterior segment cannot be performed Known serious allergies to the fluorescein dye used in angiography, to the mydriatic, steroidal and non-steroidal eye drops Participation in another clinical trial with an investigational agent Enrolled or being enrolled in another gene therapy clinical trial Active, extraocular infection requiring the prolonged or chronic use of antimicrobial agents Chronic medical conditions, cancer Abnormal laboratory values On immunosuppressive therapy

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Five successive cohorts separated by DSMC assessments
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - Low Dose<br>Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the lowest dose. Dose-escalation will be performed after DSMC assessment. | Biological: AAV2/5-hPDE6B<br>* Subretinal administration in one eye<br>|
| Experimental: Cohort 2a - Medium Dose<br>Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the medium dose. Confirmatory dose will be determined after DSMC assessment. | Biological: AAV2/5-hPDE6B<br>* Subretinal administration in one eye<br>|
| Experimental: Cohort 2b - High Dose<br>Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the highest dose. Confirmatory dose will be determined after DSMC assessment. | Biological: AAV2/5-hPDE6B<br>* Subretinal administration in one eye<br>|
| Experimental: Cohort 3 - High Dose (confirmatory cohort)<br>Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the confirmatory dose. | Biological: AAV2/5-hPDE6B<br>* Subretinal administration in one eye<br>|
| Experimental: Cohort 4 - High Dose - 13 years old or older population<br>Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the confirmatory dose. | Biological: AAV2/5-hPDE6B<br>* Subretinal administration in one eye<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of ocular and non-ocular adverse events |  | 1 year + 4 years follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in visual function | Improvement in visual function as assessed by mobility test | 1 year + 4 years follow-up | 
| Improvement in visual fields | Improvement in visual fields as assessed by visual fields measurements | 1 year + 4 years follow-up | 
| Improvement in visual function | Improvement in visual function as assessed by reading speed | 1 year + 4 years follow-up | 
| Improvement in Quality of Life | Quality of life will be measured by Quality of Life questionnaire National Eye Institute Visual Function Questionnaire (NEI VFQ-25) | 1 year + 4 years follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adeno-associated virus, AAV, Retinitis Pigmentosa, PDE6B, Gene Therapy, Gene Transfer, Retinal Dystrophy, Eye Diseases, Vision Disorders, Eye Diseases, Hereditary, Retinal Diseases, Retinal Degeneration