Efficacy Study of Gene Therapy for The Treatment of Acute Leber's Hereditary Optic Neuropathy (LHON) onset within three months

Leber's Hereditary Optic Neuropathy (LHON) is a maternally inherited ocular disorder associated with a mutation in mtDNA .The disease is a common cause of teenaged blindness in both eyes for which there is currently no effective treatment.

In 2008, the investigators recognized that gene therapy for LHON could be performed not only theoretically but technically. The investigators have been carring out a series of basic and clinical studies from constructing the vectors to identifying and mitigating safety issues . After performing several animal experiments, the investigators had moved into clinical trials. In 2011, the investigators performed the first LHON gene therapy trial in the world, which was registered in December 2010 at ClinicalTrials.gov (Registration number: CT01267422) and was a preliminary study to verify the safety and efficacy of gene therapy for LHON . In the 36-month follow-up, the investigators found that six out of nine patients have vision improvement obviously and no adverse events were observed.

This is a multi - center , prospective study of 120 patients with the G11778A mutation in Mt-DNA.This clinical trial recruited 20 patients with the 11778 mutation of MT-DNA onset within three months,20 between 3 to 6 months,20 between 6 to 12 months,20 between 12 to 24 months,20 between 24 to 60 months,and 20 over 60 months.. All patients will be treated with a Single vitreous cavity injection of recombinant Adeno-Associated Virus-NADH dehydrogenase, subunit 4 (complex I)（rAAV2-ND4)（0.05ml), with dose 1 × 10^10 vg/0.05 mL .The eye of treatment is up to the time of onset.

The visual acuity, visual field,visual evoked potential （VEP）,optical coherence tomography（ OCT）, electroretinograms(ERG), retinal nerve fiber layer(RNFL)and Liver and kidney function in plasma were compared after treatment at 1,2,3,6and 12 months interval.

Inclusion Criteria:

1. Patients carry the mitochondrial point mutation at 11778, which is consistent with the diagnostic criteria for LHON.
2. The vision falls within 3 months,onset between 3 to 6 months,onset between 6 to 12 months,onset between 12 to 24 months,onset between 24 to 60 months,and onset over 60 months.
3. Patients signed written informed consent.
4. Patients are between the ages of 8 and 60 years old and able to tolerate the gene therapy procedure which includes local anesthesia.
5. Patients are willing to follow the doctor's instructions and to consult the doctor at prescribed times.
6. 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:

1. 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.
2. Patients who are participating in other clinical studies are excluded.
3. Patients who suffer from a diagnosed mental problem are excluded.
4. Patients who suffer from chronic diseases such as diabetes and hypertension are excluded.
5. 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.