Dominant Optic Atrophy (DOA)

Dominant optic atrophy (DOA) is more frequently called OPA1-related optic atrophy (OMIM 165500); it is the most common type of inherited optic nerve damage. At Protheragen, we strive to mitigate the impact of this insidious disease by offering a full range of services focused on the creation of both diagnostic and therapeutic solutions for DOA.

Overview of Dominant Optic Atrophy (DOA)

Dominant Optic Atrophy (DOA) is the most common form of inherited optic neuropathy. It involves progressive bilateral visual loss, which usually presents in early childhood. This form of optic atrophy predominantly arises due to OPA1 gene mutations, which encode a cell dynamin-like GTPase protein crucial for mitochondrial fusion and function. Unlike other forms of optic neuropathies like Leber Hereditary Optic Neuropathy (LHON), DOA has clinically significant variability in the severity of vision loss. Severity can range from having normal vision to being profoundly visually impaired. Multisystemic features are present in approximately 20% of DOA cases, including but not limited to sensorineural hearing loss and peripheral neuropathy.

Fig. 1 Schematic figure of the four animal models used to study OPA1. (Del Dotto V., et al., 2021)

Pathogenesis of Dominant Optic Atrophy (DOA)

Mitochondrial dysfunction that stems from OPA1 gene mutations directly underlies the pathogenesis of DOA. OPA1 is responsible for mitochondrial fusion, bioenergetics, and stabilizing the mitochondrial respiratory chain complexes. Its mutation gives rise to cell energy blockade, an increase in cell death, and fragmentation of the mitochondria.. Retinal ganglion cells (RGCs) possess long axons and have a high metabolism, translating to significantly high energy requirements for maintaining ionic gradients, completing transport, and powering the system. Thus, they are especially vulnerable. The RGCs' papillomacular bundle is also highly vulnerable because of the low supply of blood, light-induced oxidative stress, and limited mitochondrial transport. Additionally, some OPA1 variants exert dominant-negative effects, further complicating the disease mechanism.

Therapeutics Development for Dominant Optic Atrophy (DOA)

• Pharmacological Neuroprotection
  Using antioxidants and mitigating oxidative damage and mitochondrial dysfunction aims to protect against neurodegenerative processes pharmacologically. In treating cases with Dominantly Inherited Atrophy (DOA), Idebenone, which is a synthetic form of coenzyme Q10, appears to improve or at least preserve visual acuity based on clinical trials. Its effectiveness in stabilizing vision in patients with Leber Hereditary Optic Neuropathy (LHON) also indicates possible neuroprotective capacity for DOA.
• Gene Therapies
  The goal of gene therapy for DOA is to address the OPA1 genetic defects using multiple approaches. There is some evidence of efficacy in mice using some functional OPA1 gene delivery via AAV vectors. OPA1 genes delivered by intravitreal injections seem to slow retinal ganglion cell (RGC) degeneration. Additionally, artificial transcription factors (ATFs) and RNA-based approaches are being explored to enhance normal OPA1 expression.
• Cell-Based Regenerative Therapies
  Cell-based regenerative therapies are focused on trying to replace damaged retinal ganglion cells (RGCs) using the patient's stem cells that have been converted to induced pluripotent stem cells (iPSCs). These iPSCs may be differentiated into RGCs and implanted in the retina to bring back visual perception. This method offers a lot of possibilities; however, many issues, such as long-term cell survival, proper axon routing, and viable integration within the retinal circuitry, still need to be worked on.

Table 1. Clinical trials for DOA. (Wong D. C., et al., 2023)

Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.

Our Services

Protheragen provides full-service support for the development of diagnostic and therapeutic solutions for Dominant Optic Atrophy (DOA). We specialize in in silico modeling and bioinformatics, as well as undertake experimental validation at both in vitro and in vivo levels. We utilize state-of-the-art technologies to hypothesize the pathogenic effect of new variants, validate cellular model impact, and evaluate postulated therapeutic effects in preliminary animal experiments.

At Protheragen, we comprehensively comprehend how every research project comes with its own distinct needs. The services we provide are tailored to fit all these needs specifically. For the crafting of diagnostics and therapeutics for DOA, our professional team works precisely with the clients so that every single project is approached with the care and meticulous attention that it merits. If you are interested in our services, please feel free to contact us.

References

• Del Dotto, Valentina, and Valerio Carelli. "Dominant optic atrophy (DOA): modeling the kaleidoscopic roles of OPA1 in mitochondrial homeostasis." Frontiers in Neurology 12 (2021): 681326.
• Wong, David CS, et al. "OPA1 dominant optic atrophy: pathogenesis and therapeutic targets." Journal of Neuro-Ophthalmology 43.4 (2023): 464-474.