PROJECT SUMMARY
Optic neuropathies are common causes of blindness worldwide, affect the lives of millions, and lack effective
treatments to restore vision. Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy that
affects ~3 per 100,000 people worldwide, results in vision impairment, and has no treatment. It is primarily due
to mutations in the optic atrophy 1 (OPA1) gene, which encodes a mitochondrial dynamin-related protein critical
for mitochondrial stability and energy production. A major limitation to the development of effective therapies for
optic neuropathies is the use of animal models that poorly replicate the human condition. Particularly for optic
nerve and RGC disorders, studies would benefit from the use nonhuman primates (NHP) with optic nerve and
retinal anatomy, physiology and pathology, which closely mirrors that of humans. Consequently, well-defined
NHP models of optic neuropathy that are more predictive of human conditions are necessary to efficiently
advance new therapies. We identified rhesus macaques heterozygous and homozygous for a missense mutation
in OPA1 that demonstrate optic nerve head pallor and thinning of the retinal nerve fiber layer in comparison to
wildtype controls; these findings are consistent with ADOA in human patients. We will fully define this NHP model
of ADOA and determine its impact on RGC structure and function longitudinally over a 5-year period. Specifically,
we will assess the onset and progression of retinal dysfunction utilizing electroretinography, retinal flavoprotein
fluorescence and visual testing. Importantly, we will correlate the clinical findings with detailed transcriptomic,
histologic, and immunohistochemical data for a comprehensive characterization of this NHP model of ADOA.
The ADOA transcriptome from NHPs is highly likely to identify novel genes and pathways involved in RGC
pathology and neurodegeneration as well as validate previously implicated pathways thus revealing new
therapeutic targets. We will also perform detailed histological, immunohistochemical and ultrastructural analyses
to assess RGC soma, axons and dendrites as well as their mitochondrial size and number in the macula,
papillomacular bundle, and periphery of the retina. Finally, through selective breeding of ADOA-affected NHPs,
we will generate a supply of macaques heterozygous and homozygous for the OPA1 mutation for future study.
To make this new NHP optic neuropathy model available for therapeutic testing, we propose three Specific Aims:
1) To define the morphologic features and phenotypic spectrum of a NHP model of ADOA, 2) to determine the
impact of the OPA1 A8S mutation on RGC function in NHPs, and 3) to determine mRNA and protein expression
in RGCs of ADOA-affected NHPs. Once the most predictive endpoints of disease and sufficient animals with
ADOA are identified, we will pursue additional studies of etiopathogenesis and novel therapeutic strategies. This
comprehensive NHP model of ADOA will be a highly valuable resource for the vision science and
neurodegenerative disease communities.