IT TAKES TWO TO TANGO: Potential Novel Therapies for Autosomal Dominant Optic Atrophy (ADOA)

Ritu Sampige^1*Lyra Seaborn¹Molly Pluenneke¹Annika Jyothi¹Sophie Saland²Chisom M. Chinedu-Obi³Caroline Keehn¹Andrew Lee^{1,10,11,4,5,6,7,8,9}

• ¹Baylor College of Medicine, Houston, United States
• ²The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, United States
• ³Tulane University School of Medicine, New Orleans, United States
• ⁴Department of Ophthalmology, University of Texas Medical Branch, Galveston, United States
• ⁵Texas A&M School of Engineering Medicine, Bryan, United States
• ⁶Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston, United States
• ⁷The Houston Methodist Research Institute, Houston Methodist Hospital, Houston, United States
• ⁸Center for Space Medicine, Baylor College of Medicine, Houston, United States
• ⁹Departments of Ophthalmology, Neurology, and Neurosurgery, Weill Cornell Medicine, New York, United States
• ¹⁰The University of Texas MD Anderson Cancer Center, Houston, United States
• ¹¹The University of Iowa Hospitals and Clinics Department of Ophthalmology and Visual Sciences, Iowa City, United States

Autosomal dominant optic atrophy (ADOA) is among the most prevalent inherited optic neuropathies with hallmark symptoms of bilateral, painless, progressive, and typically permanent vision loss over time. ADOA can affect patients’ quality of life with debilitating visual symptoms, and there is a pressing need for effective therapeutics. In this paper, we review the current and future investigational therapies for ADOA, including the use of intravitreal injections of antisense oligonucleotides through Targeted Augmentation of Nuclear Gene Output (TANGO), CRISPR-based therapy, genetic editing, gene replacement approaches, and idebenone, a small-molecule mitochondrial modulator. Additionally, we review clinical trials for ADOA treatment and opportunities for future research on ADOA therapeutics, including the utilization of mitochondria-targeted peptides and antioxidants, NAD+ boosters/metabolic support, mitophagy and fission-fusion modulators, and cell-based regenerative therapy. The use of emerging technology to compensate for OPA1 protein haploinsufficiency provides new and vast avenues for the management of this otherwise vision-altering disease. Increased awareness of therapeutics for ADOA will allow for patient counseling regarding treatment access via clinical trials and for underscoring the importance of genetically testing family members, who may be incidentally identified with ADOA in a timely manner for newly available therapies. While patients with ADOA typically have poor visual prognoses, there are increasing promising therapies with the potential for preserving and improving visual function.