# Lebers Hereditary Optic Neuropathy: Gene Therapy

> **NIH NIH UG1** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $1

## Abstract

We have made major strides towards determining the pathogenesis and testing a treatment for
Leber Hereditary Optic Neuropathy (LHON). We successfully expressed the wild-type human
NADH ubiquinone oxidoreductase subunit 4 (ND4) of complex I in the nuclear genetic code. The
protein was imported into the mitochondria by agency of a mitochondrial targeting sequence. The
gene was packaged into next generation tyrosine to phenylalanine modified self-complementary
adenoassociated virus (AAV) then injected into rodent eyes. FLAG-tagged wild-type human ND4
was detected quickly in 90% of retinal ganglion cells by 1 week post injection and it integrated
into Complex I. Furthermore, in rodent eyes also injected with a mutant G11778A ND4 homologue
responsible for most cases of LHON, wild-type ND4 restored defective ATP synthesis,
suppressed visual loss, reduced apoptosis of retinal ganglion cells and prevented demise of
axons in the optic nerve that persisted long-term. The self-complementary wild-type ND4 injected
at the relevant titer into the ex vivo human eye expressed in most retinal ganglion cells, suggesting
that it will do so in our LHON patients. Unlike Leber Congenital Amaurosis (RPE65 mutation),
there is no FDA approved treatment for the visual loss of LHON. Over the past 4 years we have
enrolled 19 LHON patients with genetic confirmation of the G11778A mutation in the ND4 subunit
of complex I into a phase I clinical trial designed to test the safety of our gene therapy vector
(IND# 15941). Nine patients were vitreally injected with low dose self-complementary scAAV2-
P1ND4v2, nine injected with medium doses and one injected with high dose. Our goal in this
competing renewal application is to test the safety and tolerability of higher doses of AAV
mediated delivery of the human ND4 gene in our phase I clinical trial of patients with mutated
G11778A mtDNA in order to move to prove efficacy in the later years of this program.

## Key facts

- **NIH application ID:** 9921407
- **Project number:** 5UG1EY023558-07
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Byron L Lam
- **Activity code:** UG1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2014-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921407

## Citation

> US National Institutes of Health, RePORTER application 9921407, Lebers Hereditary Optic Neuropathy: Gene Therapy (5UG1EY023558-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9921407. Licensed CC0.

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