Safety Study of an Adeno-associated Virus Vector for Gene Therapy of Leber's Hereditary Optic Neuropathy

Study Overview
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Brief Summary
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Hypotheses: The primary hypothesis being tested is that there will be no toxicity resulting in loss of vision to no light perception in injected eyes.

Official Title
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An Open-label Dose Escalation Study of an Adeno-associated Virus Vector (scAAV2-P1ND4v2) for Gene Therapy of Leber's Hereditary Optic Neuropathy (LHON) Caused by the G11778A Mutation in Mitochondrial DNA

Conditions
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Leber's Hereditary Optic Neuropathy

Intervention / Treatment
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* Drug: injection of scAAV2-P1ND4v2 1.18x10e9 vg (Low),
* Drug: injection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med)
* Drug: injection of scAAV2-P1ND4v2 2.4 X10e10vg (High)
* Drug: injection of scAAV2-P1ND4v2 1.0 X10e11vg (Higher)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 15 or older; Patients with LHON and the G11778A mitochondrial DNA mutation. A previous CLIA certified genetic lab result showing the LHON G11778A mutation will be accepted for inclusion; Ability to perform tests of visual and retinal function; Ability to comply with research procedures; Able and willing to provide informed consent before undergoing any study related procedures. Good general health as based on the investigator's assessment of the history, physical examination and laboratory testing performed at the baseline examination. Exclusion Criteria: Unwilling or unable to give consent, Unable or unlikely to return for scheduled protocol visits Pregnant or nursing women or unwillingness for subject with childbearing potential to use contraception during the first year of the study. Optic disc drusen on exam or in previous history. Ocular diseases or visual dysfunction conditions other than refractive error (e.g. amblyopia, glaucoma, etc.) in the eye selected for the injection. Previous eye surgery in the eye selected for injection. Aspartate transaminase (AST)/alanine transaminase (ALT) >5.0 x upper limit of normal (ULN); Total bilirubin >3 x ULN; Hemoglobin < 8 g/dL; neutrophil count <1.0 x 109/L; or platelet count < 50 x 109/L a) Any laboratory screening test that meets the abnormality criteria stated above can be repeated once between Baseline one to Baseline 2. Type I diabetes or the presence of diabetic retinopathy History of neurodegenerative conditions (e.g. multiple sclerosis, neuromyelitis optica, Parkinson disease) History of autoimmune conditions (e.g. systemic lupus erythematosus) History of systemic diseases having ocular manifestations likely to confound assessment of study results. History of cancer within five years other than localized basal or squamous cell carcinoma not near the orbital area. Patients with a prior history of cancer will need documentation from their cancer specialist that the cancer was cured at least 5 years before study entry. Allergy to pupil dilating drops or narrow angles precluding safe dilation. No Light Perception (NLP) vision in either eye.

Ages Eligible for Study
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Minimum Age: 15 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 Chronic Bilateral Severe Vision Loss<br>injection of scAAV2-P1ND4v2 | Drug: injection of scAAV2-P1ND4v2 1.18x10e9 vg (Low),<br>* injection of Total Volume of each intravitreal injection is 200 µL<br>Drug: injection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med)<br>* injection of Total Volume of each intravitreal injection is 200 µL<br>Drug: injection of scAAV2-P1ND4v2 2.4 X10e10vg (High)<br>* injection of Total Volume of each intravitreal injection is 100 µL<br>Drug: injection of scAAV2-P1ND4v2 1.0 X10e11vg (Higher)<br>* injection of Total Volume of each intravitreal injection is 100 µL<br>|
| Experimental: 2 Acute Bilateral Severe Vision Loss<br>injection of scAAV2-P1ND4v2 | Drug: injection of scAAV2-P1ND4v2 1.18x10e9 vg (Low),<br>* injection of Total Volume of each intravitreal injection is 200 µL<br>Drug: injection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med)<br>* injection of Total Volume of each intravitreal injection is 200 µL<br>Drug: injection of scAAV2-P1ND4v2 1.0 X10e11vg (Higher)<br>* injection of Total Volume of each intravitreal injection is 100 µL<br>|
| Experimental: 3 Acute Unilateral Severe Vision Loss<br>injection of scAAV2-P1ND4v2 | Drug: injection of scAAV2-P1ND4v2 1.18x10e9 vg (Low),<br>* injection of Total Volume of each intravitreal injection is 200 µL<br>Drug: injection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med)<br>* injection of Total Volume of each intravitreal injection is 200 µL<br>Drug: injection of scAAV2-P1ND4v2 1.0 X10e11vg (Higher)<br>* injection of Total Volume of each intravitreal injection is 100 µL<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Primary Endpoint - Toxicity | Incidence of local and general adverse events and Serious Adverse Events | 3 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Secondary Endpoint - Safety & Efficacy | visual acuity change from baseline 2 | 3 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene therapy, Mitochondrial Genes, Leber's, AAV2 Viral vectors