A Single Intravitreal Injection of rAAV2-ND4 for the Treatment of Leber's Hereditary Optic Neuropathy

Study Overview
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Brief Summary
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This study is meant to evaluate the safety and efficacy of rAAV2-ND4 treatment for Leber hereditary optic neuropathy with the G11778A mutation in mitochondrial DNA.

Detailed Description
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Leber's Optic Hereditary Neuropathy (LHON) is a maternally inherited ocular disorder primarily associated with mutations in mitochondrial DNA. The disease is a common cause of blindness in both eyes of affected teenagers and young adults. There is currently no approved effective treatment for LHON. In 2011, the first LHON gene therapy investigator-initiated study was conducted (registered in December 2010 with ClinicalTrials.gov Identifier NCT01267422) to explore the safety and efficacy of gene therapy for LHON. The gene therapy was a recombinant adeno-associated virus serotype 2 containing human mitochondrial ND4 (MT-ND4) gene (rAAV2-ND4). By 36 months of follow-up, six out of nine patients who received the rAAV2-ND4 intravitreal injection experienced clinically significant vision improvement and no adverse events were observed. This is an open-label, single-arm, multi-center study to further evaluate the safety and efficacy of rAAV-ND4 in the treatment of LHON patients with G11778A mutation. All patients will be treated with a single intravitreal injection rAAV-ND4, with dose 1 × 10^10 vg/0.05 mL in one of the eyes.

Official Title
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A Single Intravitreal Injection of rAAV2-ND4 for the Treatment of Leber's Hereditary Optic Neuropathy

Conditions
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Leber Hereditary Optic Neuropathy

Intervention / Treatment
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* Drug: rAAV2-ND4


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients carry the mitochondrial point mutation at 11778, which is consistent with the diagnostic criteria for LHON. No apparent eye sight improvement in LHON patients or any other treatment within the past year. Eyesight of both eyes is below 0.3. Patients signed written informed consent. Patients are between the ages of 10 and 65 years old and able to tolerate the gene therapy procedure which includes local anesthesia. Patients are willing to follow the doctor's instructions and to consult the doctor at prescribed times. Patient's physical examination results are all normal, including liver function, kidney function, routine blood test, routine urine test, complete immunological test, and humoral immune response. Exclusion Criteria: Patients who are wearing a cardiac pacemaker, suffering from severe heart, lung or kidney function failure, various hemorrhagic diseases, acute infectious diseases, high fever, or convalescing after heart surgery or who are pregnant are excluded. Patients who are participating in other clinical studies are excluded. Patients who suffer from a diagnosed mental problem are excluded. Patients who suffer from chronic diseases such as diabetes and hypertension are excluded. Patients who show abnormal test results such as positive AAV2 humoral immune response (positive means that the AAV2 neutralizing antibody assay of patient was significant different when comparing free serum with 1:20 serum concentrations) and abnormal human T lymphocyte subsets CD3+, CD3+/CD4+ and CD3+/CD8+ prior to gene therapy surgery are excluded.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 65 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: rAAV2-ND4<br>A Single IVT Injection of recombinant Adeno-Associated Virus-NADH dehydrogenase, subunit 4 (complex I)（rAAV2-ND4)（0.05ml).The dose is 1 × 10^10 vg/0.05 mL for test groups. | Drug: rAAV2-ND4<br>* a Single IVT Injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BCVA | The Best Corrected Visual Acuity | Change from Baseline at 12 months . | 
| Computerized Visual Field |  | Change from Baseline at 12 months . | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VEP | visual evoked potential | Change from Baseline at 12 months . | 
| RNFL | retinal nerve fiber layer | Change from Baseline at 12 months . | 
| Liver function in plasma |  | Change from Baseline at 12 months . | 
| kidney function in plasma |  | Change from Baseline at 12 months . | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LHON,G11778A mutation, rAAV2-ND4，gene therapy