RARE DISEASE
Autosomal dominant optic atrophy
Autosomal dominant optic atrophy
Autosomal dominant optic atrophy
Synonyms: ADOA, DOA
Synonyms: ADOA, DOA
Synonyms: ADOA, DOA
Drug discovery
1
drug
With orphan designation
Overview
Autosomal dominant optic atrophy (ADOA) is a rare inherited mitochondrial disorder characterized by bilateral, progressive optic neuropathy, typically presenting in childhood with insidious vision loss, central scotomas, and color vision deficits. Caused primarily by OPA1 gene mutations (65-90% of cases), it leads to retinal ganglion cell degeneration through mitochondrial dysfunction [1][6][10]. Approximately 20% develop ADOA-plus syndrome with extra-ocular manifestations like sensorineural deafness and neuropathy [5][9][13].
Therapies
Supportive care: Low-vision aids, cochlear implants (for ADOA-plus), and genetic counseling [5][17][18]
Investigational agents: Idebenone (ubiquinone analogue) shows potential for neuroprotection in trials [3][7][18]
Emerging approaches: OPA1-targeted gene therapy in preclinical development [3][11][14]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare ophthalmic disorders
Research Papers
107 drug discovery papers related to Autosomal dominant optic atrophy, with 5 first-in-class and 0 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
107 drug discovery papers related to Autosomal dominant optic atrophy, with 5 first-in-class and 0 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-07 | Impact of Inner Retinal Layer Thinning on Visual Function in OPA1 Autosomal Dominant Optic Atrophy and Associations With Age and Genetic Variant Class.
Inner retinal layer thinning in autosomal dominant optic atrophy (ADOA) can affect visual acuity (VA), but impact on perimetric parameters and disease-related changes with increasing age are undefined. One hundred eight patients with ADOA harboring a disease-causing variant in OPA1 were analyzed retrospectively, including best-corrected VA, mean deviation (MD) from 30-2 threshold perimetry, MD in the papillomacular bundle (PMB) subfield, and retinal layer thickness in spectral-domain optical coherence tomography (OCT). Twenty-three of 57 detected variants in OPA1 are newly reported. In multivariable mixed-effect models, peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer (mGCL) thicknesses impacted visual function, with an average deterioration of 0.1 logMAR per 3.2 µm mGCL reduction (P < 0.001), PMB-MD loss of 0.75 dB/µm mGCL (P = 0.002), and MD loss of 0.11 dB/µm pRNFL (P = 0.048). Age impacted mGCL thickness (-0.06 µm/year; P = 0.023). In available long-term follow-ups mGCL lost 0.26 ± 0.10 µm/year. Missense variants caused worse VA (0.83 vs. 0.49 logMAR, P = 0.016), MD (-11.48 vs. -3.04 decibel [dB], P = 0.005), and PMB-MD (-16.25 vs. -4.17 dB, P = 0.001) than haploinsufficiency variants, and lower mGCL (20.12 vs. 21.97 µm, P = 0.044) and pRNFL thickness (52.41 vs. 66.41 µm, P < 0.001). VA and central scotoma severity in OPA1-related ADOA are significantly associated with inner retinal layer thickness, which is impacted by patient age. The mGCL thickness and sensitivity in the PMB subfield were the most indicative clinical parameters for disease-related changes, with worse outcomes in heterozygotes with missense variants in OPA1.
2026-02-18 | Disrupted energy metabolism is associated with retinal ganglion cell degeneration in autosomal dominant optic atrophy.
Autosomal dominant optic atrophy (ADOA) is a hereditary optic neuropathy caused by OPA1 variants, leading to retinal ganglion cell (RGC) degeneration and vision loss. The mechanisms behind RGC vulnerability to mitochondrial dysfunction remain unclear. We developed a patient-specific Opa1V291D/+ knock-in mouse model to investigate mitochondrial dysfunction and retinal metabolism in ADOA. We observed that Opa1V291D/+ mice exhibited anatomical and functional RGC abnormalities recapitulating the ADOA phenotypes. Reduced optic atrophy 1 (OPA1) protein levels were noted in Opa1V291D/+ mice, accompanied by decreased protein stability. Moreover, mitochondrial function was compromised, as indicated by reduced Complex I activity, increased oxidative stress, and diminished adenosine triphosphate production in the retinas of Opa1V291D/+ mice. Spatial metabolomics revealed energy deficits in the inner retina and heightened glycolysis in the outer retina. Immunostaining showed decreased expression of glycolytic proteins in the ganglion cell layer. Single-nucleus RNA sequencing disclosed significant down-regulation of energy-production genes in RGCs, while other retinal cell types remained unaffected. These findings emphasize the specific vulnerability of RGCs to bioenergetic crises, connecting disrupted energy homeostasis to their degeneration. By increasing the nicotinamide adenine dinucleotide (NAD+)/reduced form of NAD+ (NADH) redox ratio through the overexpression of mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) in RGCs, we demonstrated improved RGC function and survival through enhanced energy metabolism and reduced oxidative stress. These findings confirm that disrupted energy metabolism leads to RGC degeneration and emphasize the enhancement of the NAD+/NADH redox ratio as a promising treatment strategy to protect RGCs from degeneration in ADOA.
2026-01-21 | Volumetric brain analysis and associated retinal thinning in autosomal dominant optic atrophy patients.
Dominant optic atrophy (DOA) is an inherited mitochondrial disorder characterized by retinal thinning and progressive visual loss. When accompanied by additional neurological or systemic features, such as progressive external ophthalmoplegia, myopathy, or deafness, it is classified as DOA-plus (DOA+). Although central nervous system involvement has been associated with cortical and cerebellar atrophy, specific regional patterns remain unclear. This study aimed to investigate cortical lobe alterations in DOA+ patients and examine the association between retinal thinning and structural changes in the primary visual cortex (V1). Seven DOA+ patients and seven age- and sex-matched healthy controls underwent 3T brain MRI, including 3D T1-weighted imaging, and optical coherence tomography (OCT). Cortical parameters including surface area, gray matter volume, and cortical thickness were quantified using automated whole-brain analysis. Comparisons between DOA+ patients and control groups were performed using independent t-tests, and associations between OCT metrics and V1 cortical measures were assessed with Spearman's rank correlation. DOA+ patients showed a trend toward atrophy in V1 and across all cortical lobes, with statistically significant differences observed only in V1 and occipital lobe (p < 0.001). The occipital lobe demonstrated the greatest reduction in gray matter volume (25.1%, p < 0.001). A positive correlation was observed between average RNFL thickness and average V1 thickness (ρ = 0.90, p = 0.037). DOA+ patients showed significant atrophy in occipital lobe. An association between retinal thinning and average V1 thickness was observed. However, a definite causal relationship cannot be established. Further studies in larger, genetically diverse cohorts are needed to validate these findings.
2026-04-07 | Impact of Inner Retinal Layer Thinning on Visual Function in OPA1 Autosomal Dominant Optic Atrophy and Associations With Age and Genetic Variant Class.
Inner retinal layer thinning in autosomal dominant optic atrophy (ADOA) can affect visual acuity (VA), but impact on perimetric parameters and disease-related changes with increasing age are undefined. One hundred eight patients with ADOA harboring a disease-causing variant in OPA1 were analyzed retrospectively, including best-corrected VA, mean deviation (MD) from 30-2 threshold perimetry, MD in the papillomacular bundle (PMB) subfield, and retinal layer thickness in spectral-domain optical coherence tomography (OCT). Twenty-three of 57 detected variants in OPA1 are newly reported. In multivariable mixed-effect models, peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer (mGCL) thicknesses impacted visual function, with an average deterioration of 0.1 logMAR per 3.2 µm mGCL reduction (P < 0.001), PMB-MD loss of 0.75 dB/µm mGCL (P = 0.002), and MD loss of 0.11 dB/µm pRNFL (P = 0.048). Age impacted mGCL thickness (-0.06 µm/year; P = 0.023). In available long-term follow-ups mGCL lost 0.26 ± 0.10 µm/year. Missense variants caused worse VA (0.83 vs. 0.49 logMAR, P = 0.016), MD (-11.48 vs. -3.04 decibel [dB], P = 0.005), and PMB-MD (-16.25 vs. -4.17 dB, P = 0.001) than haploinsufficiency variants, and lower mGCL (20.12 vs. 21.97 µm, P = 0.044) and pRNFL thickness (52.41 vs. 66.41 µm, P < 0.001). VA and central scotoma severity in OPA1-related ADOA are significantly associated with inner retinal layer thickness, which is impacted by patient age. The mGCL thickness and sensitivity in the PMB subfield were the most indicative clinical parameters for disease-related changes, with worse outcomes in heterozygotes with missense variants in OPA1.
2026-02-18 | Disrupted energy metabolism is associated with retinal ganglion cell degeneration in autosomal dominant optic atrophy.
Autosomal dominant optic atrophy (ADOA) is a hereditary optic neuropathy caused by OPA1 variants, leading to retinal ganglion cell (RGC) degeneration and vision loss. The mechanisms behind RGC vulnerability to mitochondrial dysfunction remain unclear. We developed a patient-specific Opa1V291D/+ knock-in mouse model to investigate mitochondrial dysfunction and retinal metabolism in ADOA. We observed that Opa1V291D/+ mice exhibited anatomical and functional RGC abnormalities recapitulating the ADOA phenotypes. Reduced optic atrophy 1 (OPA1) protein levels were noted in Opa1V291D/+ mice, accompanied by decreased protein stability. Moreover, mitochondrial function was compromised, as indicated by reduced Complex I activity, increased oxidative stress, and diminished adenosine triphosphate production in the retinas of Opa1V291D/+ mice. Spatial metabolomics revealed energy deficits in the inner retina and heightened glycolysis in the outer retina. Immunostaining showed decreased expression of glycolytic proteins in the ganglion cell layer. Single-nucleus RNA sequencing disclosed significant down-regulation of energy-production genes in RGCs, while other retinal cell types remained unaffected. These findings emphasize the specific vulnerability of RGCs to bioenergetic crises, connecting disrupted energy homeostasis to their degeneration. By increasing the nicotinamide adenine dinucleotide (NAD+)/reduced form of NAD+ (NADH) redox ratio through the overexpression of mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) in RGCs, we demonstrated improved RGC function and survival through enhanced energy metabolism and reduced oxidative stress. These findings confirm that disrupted energy metabolism leads to RGC degeneration and emphasize the enhancement of the NAD+/NADH redox ratio as a promising treatment strategy to protect RGCs from degeneration in ADOA.
2026-01-21 | Volumetric brain analysis and associated retinal thinning in autosomal dominant optic atrophy patients.
Dominant optic atrophy (DOA) is an inherited mitochondrial disorder characterized by retinal thinning and progressive visual loss. When accompanied by additional neurological or systemic features, such as progressive external ophthalmoplegia, myopathy, or deafness, it is classified as DOA-plus (DOA+). Although central nervous system involvement has been associated with cortical and cerebellar atrophy, specific regional patterns remain unclear. This study aimed to investigate cortical lobe alterations in DOA+ patients and examine the association between retinal thinning and structural changes in the primary visual cortex (V1). Seven DOA+ patients and seven age- and sex-matched healthy controls underwent 3T brain MRI, including 3D T1-weighted imaging, and optical coherence tomography (OCT). Cortical parameters including surface area, gray matter volume, and cortical thickness were quantified using automated whole-brain analysis. Comparisons between DOA+ patients and control groups were performed using independent t-tests, and associations between OCT metrics and V1 cortical measures were assessed with Spearman's rank correlation. DOA+ patients showed a trend toward atrophy in V1 and across all cortical lobes, with statistically significant differences observed only in V1 and occipital lobe (p < 0.001). The occipital lobe demonstrated the greatest reduction in gray matter volume (25.1%, p < 0.001). A positive correlation was observed between average RNFL thickness and average V1 thickness (ρ = 0.90, p = 0.037). DOA+ patients showed significant atrophy in occipital lobe. An association between retinal thinning and average V1 thickness was observed. However, a definite causal relationship cannot be established. Further studies in larger, genetically diverse cohorts are needed to validate these findings.
Access all drug discovery articles and probability of success in trials forecasts:
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Drug Discovery Landscape
1 orphan drug designation for Autosomal dominant optic atrophy.
1 orphan drug designation for Autosomal dominant optic atrophy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
18?mer antisense oligonucleotide complementary to OPA1 pre-mRNA | oligonucleotides | FDA | 2022-07-29 | — | Stoke Therapeutics, Inc. |
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