Phase I Trial of Gene Vector to Patients With Retinal Disease Due to RPE65 Mutations

Study Overview
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Brief Summary
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A recombinant adeno-associated virus serotype 2 (rAAV2) vector has been altered to carry the human RPE65 (hRPE65) gene. This vector has been shown to restore vision in animal models that resemble human RPE65-associated Leber congenital amaurosis (LCA), an incurable retinal degeneration that causes severe vision loss. The proposed study is an open label, Phase I clinical trial of subretinal rAAV2-CBSB-hRPE65 administration to individuals with RPE65-associated retinal disease. Five cohorts will be included in this trial. Cohorts 1, 2 and 4 will consist of individuals 18 years of age and older. Cohorts 3 and 5 will consist of individuals between the ages of 8 and 17, inclusive. Enrollment in Cohorts 3 and 5 will begin only after confirming the safety of rAAV2-CBSB-hRPE65 administration in the older groups of participants. This trial will lead to a greater understanding of the safety and thereby potential value of gene transfer in RPE65-associated retinal disease and will have implications for other forms of retinal degenerative disease amenable to this type of intervention. The goal of this clinical trial is to determine the safety of uniocular subretinal administration of rAAV2-CBSB-hRPE65 in individuals with RPE65-associated retinal disease. Ocular and systemic toxicity will be assessed prior to and following vector administration to determine if there are adverse changes that may be associated with vector administration.

Official Title
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Phase I Trial of Ocular Subretinal Injection of a Recombinant Adeno-Associated Virus (rAAV2-CBSB-hRPE65) Gene Vector to Patients With Retinal Disease Due to RPE65 Mutations (Clinical Trials of Gene Therapy for Leber Congenital Amaurosis)

Conditions
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Amaurosis of Leber, Retinal Diseases

Intervention / Treatment
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* Genetic: rAAV2-CBSB-hRPE65


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RPE65-associated retinal disease (two disease-causing RPE65 mutations); Clinical diagnosis of Leber congenital amaurosis (LCA)/early-onset retinal degeneration (EORD) and of severely impaired visual and retinal function, and best corrected visual acuity of 20/40 or worse in the study eye; Ability to perform tests of visual and retinal function; Visible photoreceptor layer on a standard OCT scan; Good general health; Ability to comply with research procedures; Specific for Cohorts 1, 2 and 4: 18 years of age and older; Specific for Cohorts 3 and 5: Between 8 and 17 years of age, inclusive. Exclusion Criteria: AAV antibody titers greater than two standard deviations above normal at baseline; Humoral immune deficiency as evidenced by low tetanus toxoid IgG antibody titers; Pre-existing eye conditions that would preclude the planned surgery or interfere with the interpretation of study endpoints or surgical complications; Complicating systemic diseases; Use of anti-platelet agents that may alter coagulation within 7 days prior to study agent administration; Use of immunosuppressive medications; Pregnancy or breastfeeding; Individuals (males and females) of childbearing potential who are unwilling to use effective contraception; Any condition that would prevent a subject from completing follow-up examinations during the course of the study; Any condition that makes the subject unsuitable for the study; Current, or recent participation, in any other research protocol involving investigational agents or therapies; Recent receipt of an investigational biologic therapeutic agent.

Ages Eligible for Study
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Minimum Age: 8 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>All clinical trial subjects received the same vector. | Genetic: rAAV2-CBSB-hRPE65<br>* One or two, uniocular, subretinal injections; relative doses: 0.3X (Cohort 1), 0.6X (Cohort 2), 0.45X (Cohort 3), 0.9X (Cohorts 4 and 5)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary safety endpoint in this trial is the standard ocular examination. Toxicity will also be assessed by measurement of vision, hematology and serum chemistries, assays for vector genomes, reported subject history of symptoms and adverse events. |  | 15 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual function will be quantified prior to and after vector administration in order to determine whether vector administration affects visual function. |  | 15 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leber congenital amaurosis, LCA, RPE65, Retinal disease due to RPE65 mutations, RPE65-associated Leber congenital amaurosis