Rhesus macaques with an OPA1 mutation demonstrate features of autosomal dominant optic atrophy

Area of Science:

• Ophthalmology
• Genetics
• Neuroscience

Background:

• Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy.
• Mutations in the OPA1 gene are the primary cause of ADOA.
• Existing models do not fully recapitulate the human disease's complexity.

Purpose of the Study:

• To establish and characterize a novel nonhuman primate (NHP) model of ADOA.
• To investigate the pathogenesis of ADOA using this NHP model.
• To provide a translational platform for testing therapeutic interventions.

Main Methods:

• Genetic sequencing to identify OPA1 mutation in rhesus macaques.
• Ocular examinations, spectral-domain optical coherence tomography, and fundus photography.
• Electroretinography, histopathology, immunohistochemistry, and transmission electron microscopy (TEM).

Main Results:

• Established a rhesus macaque model heterozygous for the OPA1A8S missense mutation.
• Documented retinal nerve fiber layer thinning, retinal ganglion cell loss, and dysfunction.
• Observed OPA1 mislocalization, reduced mitochondrial density, and ultrastructural changes in affected macaques.

Conclusions:

• The NHP model exhibits key pathological features of human ADOA.
• Phenotypic variability in the model mirrors clinical heterogeneity in patients.
• This model offers a valuable preclinical tool for ADOA therapeutic development.