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

The study is a dose-escalation study, phase 1. The objective of this proposed clinical trial is to evaluate the safety of mitochondrially targeted ND4 gene therapy with the adeno-associated viral vector in appropriate LHON patients.

The purpose of this dose-escalation study is to assess the safety and tolerability of scAAV2-P1ND4v2 (abbreviated as AAV-ND4) gene replacement therapy in subjects confirmed with the G11778A mutation in mtDNA responsible for Leber's Hereditary Optic Neuropathy. Ocular and systemic toxicity will be assessed following vector administration to determine if there are adverse changes that may be associated with vector administration.

This first-in-man (FIM) clinical trial will assess the safety, tolerability, and potential efficacy of a single intravitreal injection in patient groups reflecting the acute, pre-symptomatic, and chronic stages and manifestation of the LHON disease.

Eligibility Criteria:
Inclusion Criteria:

1. Age 15 or older;
2. 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;
3. Ability to perform tests of visual and retinal function;
4. Ability to comply with research procedures;
5. Able and willing to provide informed consent before undergoing any study-related procedures.
6. 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:

1. Unwilling or unable to give consent,
2. Unable or unlikely to return for scheduled protocol visits
3. Pregnant or nursing women or unwillingness for subject with childbearing potential to use contraception during the first year of the study.
4. Optic disc drusen on exam or in previous history.
5. Ocular diseases or visual dysfunction conditions other than refractive error (e.g. amblyopia, glaucoma, etc.) in the eye selected for the injection.
6. Previous eye surgery in the eye selected for injection.
7. 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.
8. Type I diabetes or the presence of diabetic retinopathy
9. History of neurodegenerative conditions (e.g. multiple sclerosis, neuromyelitis optica, Parkinson's disease)
10. History of autoimmune conditions (e.g. systemic lupus erythematosus)
11. 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.
12. Allergy to pupil dilating drops or narrow angles precluding safe dilation.
13. No Light Perception (NLP) vision in either eye.