Viral Vector-Based Gene Therapy for OPA1 Gene Mutation-Induced Dominant Optic Atrophy (UCLA Case No. 2025-004)

UCLA researchers in the Department of Ophthalmology have developed a viral vector-based gene therapy to restore OPA1 protein levels in patients with OPA1-mutated dominant optic atrophy. The optimized vectors will be delivered intravitreally to patients’ eyes, providing a minimally invasive, effective treatment with reduced side effects.

BACKGROUND: Dominant optic atrophy (DOA) is the most common hereditary disorder of the optic nerve, with the majority of cases (60-70%) caused by mutations in the optic atrophy 1 (OPA1) gene. The OPA1 protein is essential for mitochondrial function, including maintaining mitochondrial structure, dynamics, and bioenergetics. OPA1 mutations primarily impact retinal ganglion cells (RGCs), the neurons responsible for transmitting visual information from the retina to the brain via the optic nerve, leading to progressive vision loss due to mitochondrial dysfunction. There is no established cure for OPA1-mutated DOA, and treatments primarily focus on managing symptoms and slowing progression. Gene therapy, which involves modifying, replacing, or introducing genetic material within a patient’s cells, offers a promising approach to address the root cause of DOA by directly targeting and correcting the underlying genetic mutation.

INNOVATION: UCLA researchers discovered reduced OPA1 expression in OPA1 mutant pluripotent stem cells (PSCs), indicating that some cases of DOA may result from haploinsufficiency. To address this deficiency, they have developed adeno-associated virus (AAV) and lentivirus vectors to deliver and express OPA1 complementary DNA (cDNA) to restore OPA1 protein levels. Additionally, they established OPA1-DOA disease models using stem cell-derived human retinal projection neurons that exhibit disease pathology. These models exhibit measurable disease phenotypes, offering a platform to evaluate and test potential therapies. The researchers plan to use two types of promoters to drive OPA1 expression and identify optimized gene therapy vectors for intravitreal delivery to patients’ eyes as a treatment for DOA.

POTENTIAL APPLICATIONS:

• Treating OPA1 gene mutation-induced DOA
• Enhancing mitochondrial stability

ADVANTAGES:

• Directly targets the OPA1 mutation by expressing OPA1 cDNA, addressing the disease's root cause
• Multiple promoters will be used to drive OPA1 expression, improving the effectiveness of treatment and reducing off-target effects
• Intravitreal delivery is minimally invasive and provides direct access to the affected area, potentially improving gene uptake, reducing systemic side effects, and increasing treatment effectiveness

DEVELOPMENT-TO-DATE:

Currently undergoing in vitro testing of OPA1-expressing viral vectors to transduce OPA1 mutant neurons in PSC-based OPA1-DOA disease models.

Related papers (by the inventors only):

1. Pohl KA, Zhang X, Pham AH, Chan JW, Sadun AA, Yang XJ. Establishing induced pluripotent stem cell lines from two dominant optic atrophy patients with distinct OPA1 mutations and clinical pathologies. Front Genet. 2023 Sep 4;14:1251216. doi: 10.3389/fgene.2023.1251216. PMID: 37745862; PMCID: PMC10513078.
2. Xian-Jie Yang, Katherine Pohl, Xiangmei Zhang, Johnny Ji, Duc Hoang, Benjamin Smith, Steven A Barnes; Establishing isogenic pluripotent stem cell-based models for OPA1 mutation-caused dominant optic atrophy. Invest. Ophthalmol. Vis. Sci. 2024;65(7):4520.
3. Steven A Barnes, Benjamin Smith, Xiangmei Zhang, Duc Hoang, Katherine Pohl, Xian-Jie Yang; Electrophysiological properties distinguish OPA1 mutant and isogenic control pluripotent stem cell-derived human retinal ganglion cells. Invest. Ophthalmol. Vis. Sci. 2024;65(7):4533.

Keywords: Viral vector, gene therapy, dominant optic atrophy, retinal ganglion cell, mitochondrial, adeno-associated virus, lentivirus vector, pluripotent stem cell, neuron, intravitreal delivery, disease model, mutation, PSC, DOA, OPA1, RGC