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 about Autosomal dominant optic atrophy, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
107 drug discovery papers about Autosomal dominant optic atrophy, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-05-31 | Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy.
Autosomal dominant optic atrophy (ADOA) caused by mutations in the nuclear-encoded OPA1 gene result in the preferential loss of retinal ganglion cells (RGCs) and progressive optic nerve degeneration. The severity of ADOA can be highly variable. This study compared the pathophysiological consequences of the c.1034 G > A OPA1 missense mutation and the c.1305+2delGT OPA1 deletion. There was a significant correlation between the severity of visual loss and the extent of macular RGC loss as determined by optical coherence tomography imaging. In cells transfected with the c.1034 G > A mutant, the percentage of fragmented mitochondria was greater than 60% with cytochrome c (cyt c) overflow, and significantly elevated levels of reactive oxygen species (ROS) and apoptosis. In contrast, the c.1305+2delGT mutant caused mitochondrial fragmentation in ~ 20% of HeLa cells, resulting in less cyt c overflow and apoptosis. The extent of mitochondrial network fragmentation and apoptosis increased with decreasing WT OPA1 mRNA expression levels. The c.1034 G > A OPA1 missense mutation is likely to induce a dominant-negative effect compared with haploinsufficiency with the c.1305+2delGT OPA1 deletion. These contrasting pathophysiological mechanisms could influence disease severity in ADOA through their differential consequences on mitochondrial structure and function. The small drug molecule Paromomycin was able to rescue the mitochondrial fragmentation induced by the c.1034 G > A mutation, providing proof-of-concept for further therapeutic validation in ADOA.
2025-05-09 | SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy.
Autosomal dominant optic atrophy (ADOA), the most prevalent hereditary optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the optic atrophy type 1 (OPA1) gene, which encodes a conserved GTPase important for mitochondrial inner membrane dynamics. To date, the disease mechanism remains unclear, and no therapies are available. We generated a mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulated key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identified sterile alpha and TIR motif containing 1 (SARM1), a neurodegeneration switch, as a key driver of RGC degeneration in these mice. Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation. Additionally, we show that a portion of SARM1 localized within the mitochondrial intermembrane space. These findings indicated that SARM1 was activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.
2025-04-09 | Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function.
Autosomal optic atrophy (AOA) is a form of hereditary optic neuropathy characterized by the irreversible and progressive degermation of the retinal ganglion cells. Most cases of AOA are associated with a single dominant mutation in OPA1, which encodes a protein required for fusion of the inner mitochondrial membrane. It is unclear how loss of OPA1 leads to neuronal death, and despite ubiquitous expression appears to disproportionately affect the RGCs. This study introduces two novel in vivo models of OPA1-mediated AOA, including the first developmentally viable vertebrate Opa1 knockout (KO). These models allow for the study of Opa1 loss in neurons, specifically RGCs. Though survival is significantly reduced in Opa1 deficient zebrafish and Drosophila, both models permit the study of viable larvae. Moreover, zebrafish Opa1 KO larvae show impaired visual function but unchanged locomotor function, indicating that retinal neurons are particularly sensitive to Opa1 loss. Proteomic profiling of both models reveals marked disruption in protein expression associated with mitochondrial function, consistent with an observed decrease in mitochondrial respiratory function. Similarly, mitochondrial fragmentation and disordered cristae organization were observed in neuronal axons in both models highlighting Opa1's highly conserved role in regulating mitochondrial morphology and function in neuronal axons. Importantly, in Opa1 deficient zebrafish, mitochondrial disruption and visual impairment precede degeneration of RGCs. These novel models mimic key features of AOA and provide valuable tools for therapeutic screening. Our findings suggest that therapies enhancing mitochondrial function may offer a potential treatment strategy for AOA.
2025-03-23 | Targeting OPA1 protein for therapeutic intervention in autosomal dominant optic atrophy: In silico drug discovery.
Autosomal dominant hereditary optic atrophy (ADOA) is a prevalent hereditary condition characterized by the gradual and simultaneous deterioration of vision. Mutations in Optic atrophy 1 (OPA1) have been linked to ADOA, the prevailing form of inherited optic neuropathy. However, the current therapeutic options are limited. This study aimed to identify a drug-like molecule that can serve as an activator of the OPA1 GTPase domain, using in silico virtual screening and molecular dynamic simulation pipeline. A ligand-based pharmacophore model was generated to identify the important biological entities in natural compounds, followed by virtual screening pipeline. Total 55,96,00 drug-like compounds were screened and then subsequently proceed for molecular docking, molecular dynamics simulation (200ns), MM-PBSA analysis, and ADMET (Swiss ADME server) studies. Virtual screening revealed the top-ranked compound ZINC000009190697 (-8 kcal/mol). Furthermore, the stability of the top hit compound at the active site of OPA1 was demonstrated using molecular dynamics simulations and MM-PBSA calculations. ADMET analysis assisted in the identification of the top hit compound as possible activators of OPA1 with optimal drug-like properties. These results indicated that there is need of further experimental assessment of the top-hit compound ZINC000009190697 in wet lab to confirm its efficacy as a potential OPA1 activator in both in vitro and in vivo studies.
2025-02-19 | The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease
Mitochondrial dynamics, governed by fusion and fission, are crucial for maintaining cellular homeostasis, energy production, and stress adaptation. MFN2 and OPA1, key regulators of mitochondrial fusion, play essential roles beyond their structural functions, influencing bioenergetics, intracellular signalling, and quality control mechanisms such as mitophagy. Disruptions in these processes, often caused by MFN2 or OPA1 mutations, are linked to neurodegenerative diseases like Charcot-Marie-Tooth disease type 2A (CMT2A) and Autosomal Dominant Optic Atrophy (ADOA). This review explores the molecular mechanisms underlying mitochondrial fusion, the impact of MFN2 and OPA1 dysfunction on oxidative phosphorylation and autophagy, and their role in disease progression. Additionally, we discuss the divergent cellular responses to MFN2 and OPA1 mutations, particularly in terms of proliferation, senescence, and metabolic signalling. Finally, we highlight emerging therapeutic strategies to restore mitochondrial integrity, including mTOR modulation and autophagy-targeted approaches, with potential implications for neurodegenerative and metabolic disorders.
gene therapies
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.
2026-01-21 | 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.
2025-11-30 | Advanced therapies for inherited optic neuropathies.
Inherited optic neuropathies (IONs), such as Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA), typically lead to irreversible severe vision loss due to mitochondrial dysfunction causing retinal ganglion cell degeneration. Although current treatment options are limited, substantial progress has been made recently in our understanding of the molecular genetic pathways that lead to retinal ganglion cell loss. Clinical trials for LHON have demonstrated the efficacy of idebenone, an oral neuroprotective agent, and gene replacement therapy using allotopic gene expression. Early phase clinical trials are underway for ADOA caused by variants in the nuclear gene OPA1 using innovative techniques to modulate gene expression in a variant-agnostic manner. In this review, we have critically appraised a range of therapeutic strategies, including gene editing and stem cell-based optic nerve regeneration, with a discussion of the barriers to translation. Future studies focussing on understanding genetic heterogeneity, disease variability and optimising patient selection for clinical trials are essential to improve patient management and fast track transformative therapies for IONs.
2025-07-25 | Technological advances in the diagnosis and management of inherited optic neuropathies
Preferential degeneration of retinal ganglion cells (RGCs) is a defining feature of the inherited optic neuropathies (IONs), a group of monogenic eye diseases predominately comprising Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). Their pathogenesis is characterised by mitochondrial dysfunction, which causes loss of RGCs leading to irreversible vision loss. Although currently incurable, there are several emerging therapeutic avenues encompassing gene therapies, precision medicine strategies and neuroprotection. These are underscored by recent technological advances such as next-generation sequencing and improved disease modelling. In this review, we discuss these advances and the impact these will have on future diagnostic and treatment capabilities. We first focus on the clinical presentation and pathogenic mechanisms of LHON and DOA, followed by a discussion of emerging technology to facilitate diagnosis and treatment. We highlight the current unmet clinical demand of IONs, and the promise of current and future research developments.
2025-07-13 | CRISPRa-Mediated Increase of OPA1 Expression in Dominant Optic Atrophy.
Dominant Optic Atrophy (DOA) is the most common inherited optic neuropathy and presents as gradual visual loss caused by the loss of retinal ganglion cells (RGCs). Over 60% of DOA cases are caused by pathogenic variants in the OPA1 gene, which encodes a mitochondrial GTPase essential in mitochondrial fusion. Currently, there are no treatments for DOA. Here, we tested the therapeutic potential of an approach to DOA using CRISPR activation (CRISPRa). Homology directed repair was used to introduce a common OPA1 pathogenic variant (c.2708_2711TTAGdel) into HEK293T cells as an in vitro model of DOA. Heterozygous c.2708_2711TTAGdel cells had reduced levels of OPA1 mRNA transcript, OPA1 protein, and mitochondrial network alterations. The effect of inactivated Cas9 fused to an activator (dCas9-VPR) was tested with a range of guide RNAs (gRNA) targeted to the promotor region of OPA1. gRNA3 and dCas9-VPR increased OPA1 expression at the RNA and protein level towards control levels. Importantly, the correct ratio of OPA1 isoform transcripts was maintained by CRISPRa. CRISPRa-treated cells showed an improvement in mitochondrial networks compared to untreated cells, indicating partial rescue of a disease-associated phenotype. Collectively, these data support the potential application of CRISPRa as a therapeutic intervention in DOA.
proteins
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.
2022-04-19 | [Bax inhibitor 1 inhibits vascular calcification in mice by activating optic atrophy 1 expression].
To investigate the effects of Bax inhibitor 1 (BI- 1) and optic atrophy protein 1 (OPA1) on vascular calcification (VC). Mouse models of VC were established in ApoE-deficient (ApoE-/-) diabetic mice by high-fat diet feeding for 12 weeks followed by intraperitoneal injections with Nε-carboxymethyl-lysine for 16 weeks. ApoE-/- mice (control group), ApoE-/- diabetic mice (VC group), ApoE-/- diabetic mice with BI-1 overexpression (VC + BI-1TG group), and ApoE-/- diabetic mice with BI-1 overexpression and OPA1 knockout (VC+BI-1TG+OPA1-/- group) were obtained for examination of the degree of aortic calcification using von Kossa staining. The changes in calcium content in the aorta were analyzed using ELISA. The expressions of Runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP-2) were detected using immunohistochemistry, and the expression of cleaved caspase-3 was determined using Western blotting. Cultured mouse aortic smooth muscle cells were treated with 10 mmol/L β-glycerophosphate for 14 days to induce calcification, and the changes in BI-1 and OPA1 protein expressions were examined using Western blotting and cell apoptosis was detected using TUNEL staining. ApoE-/- mice with VC showed significantly decreased expressions of BI-1 and OPA1 proteins in the aorta (P=0.0044) with obviously increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P= 0.0041). Overexpression of BI-1 significantly promoted OPA1 protein expression and reduced calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P=0.0006). OPA1 knockdown significantly increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 in the aorta (P=0.0007). BI-1 inhibits VC possibly by promoting the expression of OPA1, reducing calcium deposition and inhibiting osteogenic differentiation and apoptosis of the vascular smooth muscle cells. 探讨Bax抑制因子1(BI-1)和视神经萎缩蛋白1(OPA1)蛋白对血管钙化的影响。 ApoE-/-糖尿病小鼠高脂喂养12周后予以腹腔注射Nε(-1-羧甲基)-L-赖氨酸16周建立血管钙化模型, 实验将小鼠分为4组, 6只/组: 对照组(ApoE-/-小鼠普通饲料喂养)、钙化组(ApoE-/-小鼠建立钙化模型)、钙化+BI-1TG组(血管特异性过表达BI-1的ApoE-/-小鼠建立钙化模型)和钙化+ BI-1TG+OPA1-/-组(血管特异性过表达BI-1和基因敲除OPA1的ApoE-/-小鼠建立钙化模型)。另β磷酸甘油诱导血管平滑肌细胞建立细胞钙化模型。使用von Kossa染色检测血管钙化程度, 使用ELISA检测主动脉钙含量, 使用免疫组织化学方法检测Runt相关转录因子2和骨形态发生蛋白2表达、使用TUNEL检测细胞凋亡率, 使用Western blot检测BI-1、OPA1、Runt相关转录因子2、骨形态发生蛋白2和活化的半胱氨酸天冬氨酸蛋白酶3水平的表达。 血管钙化后, BI-1和OPA1蛋白表达均下降(P=0.0044), 钙沉积、Runt相关转录因子2、骨形态发生蛋白2及活化的半胱氨酸天冬氨酸蛋白酶3表达增加(P=0.0041)。过表达BI-1促进OPA1蛋白表达, 钙沉积、Runt相关转录因子2、骨形态发生蛋白2及活化的半胱氨酸天冬氨酸蛋白酶3表达均减少(P=0.0006)。基因敲除OPA1蛋白后, 钙沉积、Runt相关转录因子2、骨形态发生蛋白2及活化的半胱氨酸天冬氨酸蛋白酶3又明显增多(P=0.0007)。 BI-1可能通过促进OPA1表达, 减轻钙沉积、细胞骨型分化和细胞凋亡, 继而抑制血管钙化。
2020-04-13 | SSBP1 mutations in dominant optic atrophy with variable retinal degeneration.
Autosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a portion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explore their causality. Linkage analysis and sequencing were performed in multigeneration families and unrelated patients to identify disease-causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model. We defined a new ADOA locus on 7q33-q35 and identified 3 different missense variants in SSBP1 (NM_001256510.1; c.113G>A [p.(Arg38Gln)], c.320G>A [p.(Arg107Gln)] and c.422G>A [p.(Ser141Asn)]) in affected individuals from 2 families and 2 singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 for single-strand DNA. Antisense-mediated knockdown of endogenous ssbp1 messenger RNA (mRNA) in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point toward an essential role of ssbp1 in retinal development and the dominant-negative nature of the identified human variants, which is consistent with the segregation pattern observed in 2 multigeneration families studied. SSBP1 is an essential protein for mitochondrial DNA replication and maintenance. Our data have established pathogenic variants in SSBP1 as a cause of ADOA and variable retinal degeneration. ANN NEUROL 2019;86:368-383.
2016-01-07 | Modeling autosomal dominant optic atrophy using induced pluripotent stem cells and identifying potential therapeutic targets
Abstract Background Many retinal degenerative diseases are caused by the loss of retinal ganglion cells (RGCs). Autosomal dominant optic atrophy is the most common hereditary optic atrophy disease and is characterized by central vision loss and degeneration of RGCs. Currently, there is no effective treatment for this group of diseases. However, stem cell therapy holds great potential for replacing lost RGCs of patients. Compared with embryonic stem cells, induced pluripotent stem cells (iPSCs) can be derived from adult somatic cells, and they are associated with fewer ethical concerns and are less prone to immune rejection. In addition, patient-derived iPSCs may provide us with a cellular model for studying the pathogenesis and potential therapeutic agents for optic atrophy. Methods In this study, iPSCs were obtained from patients carrying an OPA1 mutation ( OPA1 +/− - iPSC) that were diagnosed with optic atrophy. These iPSCs were differentiated into putative RGCs, which were subsequently characterized by using RGC-specific expression markers BRN3a and ISLET-1. Results Mutant OPA1 +/− -iPSCs exhibited significantly more apoptosis and were unable to efficiently differentiate into RGCs. However, with the addition of neural induction medium, Noggin, or estrogen, OPA1 +/− -iPSC differentiation into RGCs was promoted. Conclusions Our results suggest that apoptosis mediated by OPA1 mutations plays an important role in the pathogenesis of optic atrophy, and both noggin and β-estrogen may represent potential therapeutic agents for OPA1- related optic atrophy.
2007-01-25 | Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology.
Many muscular and neurological disorders are associated with mitochondrial dysfunction and are often accompanied by changes in mitochondrial morphology. Mutations in the gene encoding OPA1, a protein required for fusion of mitochondria, are associated with hereditary autosomal dominant optic atrophy type I. Here we show that mitochondrial fragmentation correlates with processing of large isoforms of OPA1 in cybrid cells from a patient with myoclonus epilepsy and ragged-red fibers syndrome and in mouse embryonic fibroblasts harboring an error-prone mitochondrial mtDNA polymerase gamma. Furthermore, processed OPA1 was observed in heart tissue derived from heart-specific TFAM knock-out mice suffering from mitochondrial cardiomyopathy and in skeletal muscles from patients suffering from mitochondrial myopathies such as myopathy encephalopathy lactic acidosis and stroke-like episodes. Dissipation of the mitochondrial membrane potential leads to fast induction of proteolytic processing of OPA1 and concomitant fragmentation of mitochondria. Recovery of mitochondrial fusion depended on protein synthesis and was accompanied by resynthesis of large isoforms of OPA1. Fragmentation of mitochondria was prevented by overexpressing OPA1. Taken together, our data indicate that proteolytic processing of OPA1 has a key role in inducing fragmentation of energetically compromised mitochondria. We present the hypothesis that this pathway regulates mitochondrial morphology and serves as an early response to prevent fusion of dysfunctional mitochondria with the functional mitochondrial network.
cell therapies
2024-07-13 | Creation of an Isogenic Human iPSC-Based RGC Model of Dominant Optic Atrophy Harboring the Pathogenic Variant c.1861C>T (p.Gln621Ter) in the OPA1 Gene.
Autosomal dominant optic atrophy (ADOA) is a rare progressive disease mainly caused by mutations in OPA1, a nuclear gene encoding for a mitochondrial protein that plays an essential role in mitochondrial dynamics, cell survival, oxidative phosphorylation, and mtDNA maintenance. ADOA is characterized by the degeneration of retinal ganglion cells (RGCs). This causes visual loss, which can lead to legal blindness in many cases. Nowadays, there is no effective treatment for ADOA. In this article, we have established an isogenic human RGC model for ADOA using iPSC technology and the genome editing tool CRISPR/Cas9 from a previously generated iPSC line of an ADOA plus patient harboring the pathogenic variant NM_015560.3: c.1861C>T (p.Gln621Ter) in heterozygosis in OPA1. To this end, a protocol based on supplementing the iPSC culture media with several small molecules and defined factors trying to mimic embryonic development has been employed. Subsequently, the created model was validated, confirming the presence of a defect of intergenomic communication, impaired mitochondrial respiration, and an increase in apoptosis and ROS generation. Finally, we propose the analysis of OPA1 expression by qPCR as an easy read-out method to carry out future drug screening studies using the created RGC model. In summary, this model provides a useful platform for further investigation of the underlying pathophysiological mechanisms of ADOA plus and for testing compounds with potential pharmacological action.
2022-05-04 | Induced Pluripotent Stem Cells for Inherited Optic Neuropathies-Disease Modeling and Therapeutic Development.
Inherited optic neuropathies (IONs) cause progressive irreversible visual loss in children and young adults. There are limited disease-modifying treatments, and most patients progress to become severely visually impaired, fulfilling the legal criteria for blind registration. The seminal discovery of the technique for reprogramming somatic nondividing cells into induced pluripotent stem cells (iPSCs) has opened several exciting opportunities in the field of ION research and treatment. A systematic review of the literature was conducted with PubMed using the following search terms: autosomal dominant optic atrophy, ADOA, dominant optic atrophy, DOA, Leber hereditary optic neuropathy, LHON, optic atrophy, induced pluripotent stem cell, iPSC, iPSC derived, iPS, stem cell, retinal ganglion cell, and RGC. Clinical trials were identified on the ClinicalTrials.gov website. This review article is focused on disease modeling and the therapeutic strategies being explored with iPSC technologies for the 2 most common IONs, namely, dominant optic atrophy and Leber hereditary optic neuropathy. The rationale and translational advances for cell-based and gene-based therapies are explored, as well as opportunities for neuroprotection and drug screening. iPSCs offer an elegant, patient-focused solution to the investigation of the genetic defects and disease mechanisms underpinning IONs. Furthermore, this group of disorders is uniquely amenable to both the disease modeling capability and the therapeutic potential that iPSCs offer. This fast-moving area will remain at the forefront of both basic and translational ION research in the coming years, with the potential to accelerate the development of effective therapies for patients affected with these blinding diseases.
2020-06-15 | Bioenergetic Crosstalk between Mesenchymal Stem Cells and various Ocular Cells through the intercellular trafficking of Mitochondria
Rationale: Mitochondrial disorders preferentially affect tissues with high energy requirements, such as the retina and corneal endothelium, in human eyes. Mesenchymal stem cell (MSC)-based treatment has been demonstrated to be beneficial for ocular degeneration. However, aside from neuroprotective paracrine actions, the mechanisms underlying the beneficial effect of MSCs on retinal and corneal tissues are largely unknown. In this study, we investigated the fate and associated characteristics of mitochondria subjected to intercellular transfer from MSCs to ocular cells. Methods: MSCs were cocultured with corneal endothelial cells (CECs), 661W cells (a photoreceptor cell line) and ARPE-19 cells (a retinal pigment epithelium cell line). Immunofluorescence, fluorescence activated cell sorting and confocal microscopy imaging were employed to investigate the traits of intercellular mitochondrial transfer and the fate of transferred mitochondria. The oxygen consumption rate of recipient cells was measured to investigate the effect of intercellular mitochondrial transfer. Transcriptome analysis was performed to investigate the expression of metabolic genes in recipient cells with donated mitochondria. Results: Mitochondrial transport is a ubiquitous intercellular mechanism between MSCs and various ocular cells, including the corneal endothelium, retinal pigmented epithelium, and photoreceptors. Additionally, our results indicate that the donation process depends on F-actin-based tunneling nanotubes. Rotenone-pretreated cells that received mitochondria from MSCs displayed increased aerobic capacity and upregulation of mitochondrial genes. Furthermore, living imaging determined the ultimate fate of transferred mitochondria through either degradation by lysosomes or exocytosis as extracellular vesicles. Conclusions: For the first time, we determined the characteristics and fate of mitochondria undergoing intercellular transfer from MSCs to various ocular cells through F-actin-based tunneling nanotubes, helping to characterize MSC-based treatment for ocular tissue regeneration.
2019-12-01 | Stem Cell Ophthalmology Treatment Study (SCOTS): bone marrow derived stem cells in the treatment of Dominant Optic Atrophy
Background: We report the results of 6 patients with Dominant Optic Atrophy (DOA) who met inclusion criteria and were treated in the Stem Cell Ophthalmology Treatment Study (SCOTS). SCOTS/SCOTS 2 is an Institutional Review Board approved and NIH registered (NCT 03011541) clinical study that uses autologous bone marrow derived stem cells (BMSC) in the treatment of optic nerve and retinal disease. Methods: This is an open label, non-randomized clinical study using natural history of the disease as the comparator. BMSC were separated from aspirated autologous bone marrow with minimal manipulation using an FDA cleared Class II medical device. Patients were treated with combinations of retrobulbar, subtenons, intravitreal or subretinal placement of BMSC followed by intravenous injection of BMSC depending on the arm of the study chosen. There were no surgical complications. Results: Of the patients treated, 83.3% (5 of 6 patients) experienced visual improvements and in all of these cases both eyes improved. Ten eyes or 83.3% experienced gains in visual acuity with a median improvement of 2.125 Snellen lines, or approximately 10.63 letters. Two eyes were considered unchanged compared to longstanding measurements. Using LogMAR, the average improvement in vision for all eyes was 29.5%. The averagevisual acuity increasein eyes that improved was 33.3%. Findings were statistically significant with P<0.001. Conclusions: Using autologous BMSC per protocols developed in the SCOTS/SCOTS 2 clinical studies resulted in statistically significant visual acuity improvements in patients with DOA or Kjers Optic Neuropathy. Improvements occurred in 83.3% of eyes and averaged 29.5%. Mitochondrial transfer and neuroprotective exosome secretions from the BMSC may have been key to the improvements observed in this mitochondrial disease.
small molecules
2025-05-31 | Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy.
Autosomal dominant optic atrophy (ADOA) caused by mutations in the nuclear-encoded OPA1 gene result in the preferential loss of retinal ganglion cells (RGCs) and progressive optic nerve degeneration. The severity of ADOA can be highly variable. This study compared the pathophysiological consequences of the c.1034 G > A OPA1 missense mutation and the c.1305+2delGT OPA1 deletion. There was a significant correlation between the severity of visual loss and the extent of macular RGC loss as determined by optical coherence tomography imaging. In cells transfected with the c.1034 G > A mutant, the percentage of fragmented mitochondria was greater than 60% with cytochrome c (cyt c) overflow, and significantly elevated levels of reactive oxygen species (ROS) and apoptosis. In contrast, the c.1305+2delGT mutant caused mitochondrial fragmentation in ~ 20% of HeLa cells, resulting in less cyt c overflow and apoptosis. The extent of mitochondrial network fragmentation and apoptosis increased with decreasing WT OPA1 mRNA expression levels. The c.1034 G > A OPA1 missense mutation is likely to induce a dominant-negative effect compared with haploinsufficiency with the c.1305+2delGT OPA1 deletion. These contrasting pathophysiological mechanisms could influence disease severity in ADOA through their differential consequences on mitochondrial structure and function. The small drug molecule Paromomycin was able to rescue the mitochondrial fragmentation induced by the c.1034 G > A mutation, providing proof-of-concept for further therapeutic validation in ADOA.
2025-05-09 | SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy.
Autosomal dominant optic atrophy (ADOA), the most prevalent hereditary optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the optic atrophy type 1 (OPA1) gene, which encodes a conserved GTPase important for mitochondrial inner membrane dynamics. To date, the disease mechanism remains unclear, and no therapies are available. We generated a mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulated key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identified sterile alpha and TIR motif containing 1 (SARM1), a neurodegeneration switch, as a key driver of RGC degeneration in these mice. Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation. Additionally, we show that a portion of SARM1 localized within the mitochondrial intermembrane space. These findings indicated that SARM1 was activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.
2025-04-09 | Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function.
Autosomal optic atrophy (AOA) is a form of hereditary optic neuropathy characterized by the irreversible and progressive degermation of the retinal ganglion cells. Most cases of AOA are associated with a single dominant mutation in OPA1, which encodes a protein required for fusion of the inner mitochondrial membrane. It is unclear how loss of OPA1 leads to neuronal death, and despite ubiquitous expression appears to disproportionately affect the RGCs. This study introduces two novel in vivo models of OPA1-mediated AOA, including the first developmentally viable vertebrate Opa1 knockout (KO). These models allow for the study of Opa1 loss in neurons, specifically RGCs. Though survival is significantly reduced in Opa1 deficient zebrafish and Drosophila, both models permit the study of viable larvae. Moreover, zebrafish Opa1 KO larvae show impaired visual function but unchanged locomotor function, indicating that retinal neurons are particularly sensitive to Opa1 loss. Proteomic profiling of both models reveals marked disruption in protein expression associated with mitochondrial function, consistent with an observed decrease in mitochondrial respiratory function. Similarly, mitochondrial fragmentation and disordered cristae organization were observed in neuronal axons in both models highlighting Opa1's highly conserved role in regulating mitochondrial morphology and function in neuronal axons. Importantly, in Opa1 deficient zebrafish, mitochondrial disruption and visual impairment precede degeneration of RGCs. These novel models mimic key features of AOA and provide valuable tools for therapeutic screening. Our findings suggest that therapies enhancing mitochondrial function may offer a potential treatment strategy for AOA.
2025-03-23 | Targeting OPA1 protein for therapeutic intervention in autosomal dominant optic atrophy: In silico drug discovery.
Autosomal dominant hereditary optic atrophy (ADOA) is a prevalent hereditary condition characterized by the gradual and simultaneous deterioration of vision. Mutations in Optic atrophy 1 (OPA1) have been linked to ADOA, the prevailing form of inherited optic neuropathy. However, the current therapeutic options are limited. This study aimed to identify a drug-like molecule that can serve as an activator of the OPA1 GTPase domain, using in silico virtual screening and molecular dynamic simulation pipeline. A ligand-based pharmacophore model was generated to identify the important biological entities in natural compounds, followed by virtual screening pipeline. Total 55,96,00 drug-like compounds were screened and then subsequently proceed for molecular docking, molecular dynamics simulation (200ns), MM-PBSA analysis, and ADMET (Swiss ADME server) studies. Virtual screening revealed the top-ranked compound ZINC000009190697 (-8 kcal/mol). Furthermore, the stability of the top hit compound at the active site of OPA1 was demonstrated using molecular dynamics simulations and MM-PBSA calculations. ADMET analysis assisted in the identification of the top hit compound as possible activators of OPA1 with optimal drug-like properties. These results indicated that there is need of further experimental assessment of the top-hit compound ZINC000009190697 in wet lab to confirm its efficacy as a potential OPA1 activator in both in vitro and in vivo studies.
2025-02-19 | The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease
Mitochondrial dynamics, governed by fusion and fission, are crucial for maintaining cellular homeostasis, energy production, and stress adaptation. MFN2 and OPA1, key regulators of mitochondrial fusion, play essential roles beyond their structural functions, influencing bioenergetics, intracellular signalling, and quality control mechanisms such as mitophagy. Disruptions in these processes, often caused by MFN2 or OPA1 mutations, are linked to neurodegenerative diseases like Charcot-Marie-Tooth disease type 2A (CMT2A) and Autosomal Dominant Optic Atrophy (ADOA). This review explores the molecular mechanisms underlying mitochondrial fusion, the impact of MFN2 and OPA1 dysfunction on oxidative phosphorylation and autophagy, and their role in disease progression. Additionally, we discuss the divergent cellular responses to MFN2 and OPA1 mutations, particularly in terms of proliferation, senescence, and metabolic signalling. Finally, we highlight emerging therapeutic strategies to restore mitochondrial integrity, including mTOR modulation and autophagy-targeted approaches, with potential implications for neurodegenerative and metabolic disorders.
gene therapies
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.
2026-01-21 | 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.
2025-11-30 | Advanced therapies for inherited optic neuropathies.
Inherited optic neuropathies (IONs), such as Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA), typically lead to irreversible severe vision loss due to mitochondrial dysfunction causing retinal ganglion cell degeneration. Although current treatment options are limited, substantial progress has been made recently in our understanding of the molecular genetic pathways that lead to retinal ganglion cell loss. Clinical trials for LHON have demonstrated the efficacy of idebenone, an oral neuroprotective agent, and gene replacement therapy using allotopic gene expression. Early phase clinical trials are underway for ADOA caused by variants in the nuclear gene OPA1 using innovative techniques to modulate gene expression in a variant-agnostic manner. In this review, we have critically appraised a range of therapeutic strategies, including gene editing and stem cell-based optic nerve regeneration, with a discussion of the barriers to translation. Future studies focussing on understanding genetic heterogeneity, disease variability and optimising patient selection for clinical trials are essential to improve patient management and fast track transformative therapies for IONs.
2025-07-25 | Technological advances in the diagnosis and management of inherited optic neuropathies
Preferential degeneration of retinal ganglion cells (RGCs) is a defining feature of the inherited optic neuropathies (IONs), a group of monogenic eye diseases predominately comprising Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). Their pathogenesis is characterised by mitochondrial dysfunction, which causes loss of RGCs leading to irreversible vision loss. Although currently incurable, there are several emerging therapeutic avenues encompassing gene therapies, precision medicine strategies and neuroprotection. These are underscored by recent technological advances such as next-generation sequencing and improved disease modelling. In this review, we discuss these advances and the impact these will have on future diagnostic and treatment capabilities. We first focus on the clinical presentation and pathogenic mechanisms of LHON and DOA, followed by a discussion of emerging technology to facilitate diagnosis and treatment. We highlight the current unmet clinical demand of IONs, and the promise of current and future research developments.
2025-07-13 | CRISPRa-Mediated Increase of OPA1 Expression in Dominant Optic Atrophy.
Dominant Optic Atrophy (DOA) is the most common inherited optic neuropathy and presents as gradual visual loss caused by the loss of retinal ganglion cells (RGCs). Over 60% of DOA cases are caused by pathogenic variants in the OPA1 gene, which encodes a mitochondrial GTPase essential in mitochondrial fusion. Currently, there are no treatments for DOA. Here, we tested the therapeutic potential of an approach to DOA using CRISPR activation (CRISPRa). Homology directed repair was used to introduce a common OPA1 pathogenic variant (c.2708_2711TTAGdel) into HEK293T cells as an in vitro model of DOA. Heterozygous c.2708_2711TTAGdel cells had reduced levels of OPA1 mRNA transcript, OPA1 protein, and mitochondrial network alterations. The effect of inactivated Cas9 fused to an activator (dCas9-VPR) was tested with a range of guide RNAs (gRNA) targeted to the promotor region of OPA1. gRNA3 and dCas9-VPR increased OPA1 expression at the RNA and protein level towards control levels. Importantly, the correct ratio of OPA1 isoform transcripts was maintained by CRISPRa. CRISPRa-treated cells showed an improvement in mitochondrial networks compared to untreated cells, indicating partial rescue of a disease-associated phenotype. Collectively, these data support the potential application of CRISPRa as a therapeutic intervention in DOA.
proteins
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.
2022-04-19 | [Bax inhibitor 1 inhibits vascular calcification in mice by activating optic atrophy 1 expression].
To investigate the effects of Bax inhibitor 1 (BI- 1) and optic atrophy protein 1 (OPA1) on vascular calcification (VC). Mouse models of VC were established in ApoE-deficient (ApoE-/-) diabetic mice by high-fat diet feeding for 12 weeks followed by intraperitoneal injections with Nε-carboxymethyl-lysine for 16 weeks. ApoE-/- mice (control group), ApoE-/- diabetic mice (VC group), ApoE-/- diabetic mice with BI-1 overexpression (VC + BI-1TG group), and ApoE-/- diabetic mice with BI-1 overexpression and OPA1 knockout (VC+BI-1TG+OPA1-/- group) were obtained for examination of the degree of aortic calcification using von Kossa staining. The changes in calcium content in the aorta were analyzed using ELISA. The expressions of Runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP-2) were detected using immunohistochemistry, and the expression of cleaved caspase-3 was determined using Western blotting. Cultured mouse aortic smooth muscle cells were treated with 10 mmol/L β-glycerophosphate for 14 days to induce calcification, and the changes in BI-1 and OPA1 protein expressions were examined using Western blotting and cell apoptosis was detected using TUNEL staining. ApoE-/- mice with VC showed significantly decreased expressions of BI-1 and OPA1 proteins in the aorta (P=0.0044) with obviously increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P= 0.0041). Overexpression of BI-1 significantly promoted OPA1 protein expression and reduced calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P=0.0006). OPA1 knockdown significantly increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 in the aorta (P=0.0007). BI-1 inhibits VC possibly by promoting the expression of OPA1, reducing calcium deposition and inhibiting osteogenic differentiation and apoptosis of the vascular smooth muscle cells. 探讨Bax抑制因子1(BI-1)和视神经萎缩蛋白1(OPA1)蛋白对血管钙化的影响。 ApoE-/-糖尿病小鼠高脂喂养12周后予以腹腔注射Nε(-1-羧甲基)-L-赖氨酸16周建立血管钙化模型, 实验将小鼠分为4组, 6只/组: 对照组(ApoE-/-小鼠普通饲料喂养)、钙化组(ApoE-/-小鼠建立钙化模型)、钙化+BI-1TG组(血管特异性过表达BI-1的ApoE-/-小鼠建立钙化模型)和钙化+ BI-1TG+OPA1-/-组(血管特异性过表达BI-1和基因敲除OPA1的ApoE-/-小鼠建立钙化模型)。另β磷酸甘油诱导血管平滑肌细胞建立细胞钙化模型。使用von Kossa染色检测血管钙化程度, 使用ELISA检测主动脉钙含量, 使用免疫组织化学方法检测Runt相关转录因子2和骨形态发生蛋白2表达、使用TUNEL检测细胞凋亡率, 使用Western blot检测BI-1、OPA1、Runt相关转录因子2、骨形态发生蛋白2和活化的半胱氨酸天冬氨酸蛋白酶3水平的表达。 血管钙化后, BI-1和OPA1蛋白表达均下降(P=0.0044), 钙沉积、Runt相关转录因子2、骨形态发生蛋白2及活化的半胱氨酸天冬氨酸蛋白酶3表达增加(P=0.0041)。过表达BI-1促进OPA1蛋白表达, 钙沉积、Runt相关转录因子2、骨形态发生蛋白2及活化的半胱氨酸天冬氨酸蛋白酶3表达均减少(P=0.0006)。基因敲除OPA1蛋白后, 钙沉积、Runt相关转录因子2、骨形态发生蛋白2及活化的半胱氨酸天冬氨酸蛋白酶3又明显增多(P=0.0007)。 BI-1可能通过促进OPA1表达, 减轻钙沉积、细胞骨型分化和细胞凋亡, 继而抑制血管钙化。
2020-04-13 | SSBP1 mutations in dominant optic atrophy with variable retinal degeneration.
Autosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a portion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explore their causality. Linkage analysis and sequencing were performed in multigeneration families and unrelated patients to identify disease-causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model. We defined a new ADOA locus on 7q33-q35 and identified 3 different missense variants in SSBP1 (NM_001256510.1; c.113G>A [p.(Arg38Gln)], c.320G>A [p.(Arg107Gln)] and c.422G>A [p.(Ser141Asn)]) in affected individuals from 2 families and 2 singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 for single-strand DNA. Antisense-mediated knockdown of endogenous ssbp1 messenger RNA (mRNA) in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point toward an essential role of ssbp1 in retinal development and the dominant-negative nature of the identified human variants, which is consistent with the segregation pattern observed in 2 multigeneration families studied. SSBP1 is an essential protein for mitochondrial DNA replication and maintenance. Our data have established pathogenic variants in SSBP1 as a cause of ADOA and variable retinal degeneration. ANN NEUROL 2019;86:368-383.
2016-01-07 | Modeling autosomal dominant optic atrophy using induced pluripotent stem cells and identifying potential therapeutic targets
Abstract Background Many retinal degenerative diseases are caused by the loss of retinal ganglion cells (RGCs). Autosomal dominant optic atrophy is the most common hereditary optic atrophy disease and is characterized by central vision loss and degeneration of RGCs. Currently, there is no effective treatment for this group of diseases. However, stem cell therapy holds great potential for replacing lost RGCs of patients. Compared with embryonic stem cells, induced pluripotent stem cells (iPSCs) can be derived from adult somatic cells, and they are associated with fewer ethical concerns and are less prone to immune rejection. In addition, patient-derived iPSCs may provide us with a cellular model for studying the pathogenesis and potential therapeutic agents for optic atrophy. Methods In this study, iPSCs were obtained from patients carrying an OPA1 mutation ( OPA1 +/− - iPSC) that were diagnosed with optic atrophy. These iPSCs were differentiated into putative RGCs, which were subsequently characterized by using RGC-specific expression markers BRN3a and ISLET-1. Results Mutant OPA1 +/− -iPSCs exhibited significantly more apoptosis and were unable to efficiently differentiate into RGCs. However, with the addition of neural induction medium, Noggin, or estrogen, OPA1 +/− -iPSC differentiation into RGCs was promoted. Conclusions Our results suggest that apoptosis mediated by OPA1 mutations plays an important role in the pathogenesis of optic atrophy, and both noggin and β-estrogen may represent potential therapeutic agents for OPA1- related optic atrophy.
2007-01-25 | Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology.
Many muscular and neurological disorders are associated with mitochondrial dysfunction and are often accompanied by changes in mitochondrial morphology. Mutations in the gene encoding OPA1, a protein required for fusion of mitochondria, are associated with hereditary autosomal dominant optic atrophy type I. Here we show that mitochondrial fragmentation correlates with processing of large isoforms of OPA1 in cybrid cells from a patient with myoclonus epilepsy and ragged-red fibers syndrome and in mouse embryonic fibroblasts harboring an error-prone mitochondrial mtDNA polymerase gamma. Furthermore, processed OPA1 was observed in heart tissue derived from heart-specific TFAM knock-out mice suffering from mitochondrial cardiomyopathy and in skeletal muscles from patients suffering from mitochondrial myopathies such as myopathy encephalopathy lactic acidosis and stroke-like episodes. Dissipation of the mitochondrial membrane potential leads to fast induction of proteolytic processing of OPA1 and concomitant fragmentation of mitochondria. Recovery of mitochondrial fusion depended on protein synthesis and was accompanied by resynthesis of large isoforms of OPA1. Fragmentation of mitochondria was prevented by overexpressing OPA1. Taken together, our data indicate that proteolytic processing of OPA1 has a key role in inducing fragmentation of energetically compromised mitochondria. We present the hypothesis that this pathway regulates mitochondrial morphology and serves as an early response to prevent fusion of dysfunctional mitochondria with the functional mitochondrial network.
cell therapies
2024-07-13 | Creation of an Isogenic Human iPSC-Based RGC Model of Dominant Optic Atrophy Harboring the Pathogenic Variant c.1861C>T (p.Gln621Ter) in the OPA1 Gene.
Autosomal dominant optic atrophy (ADOA) is a rare progressive disease mainly caused by mutations in OPA1, a nuclear gene encoding for a mitochondrial protein that plays an essential role in mitochondrial dynamics, cell survival, oxidative phosphorylation, and mtDNA maintenance. ADOA is characterized by the degeneration of retinal ganglion cells (RGCs). This causes visual loss, which can lead to legal blindness in many cases. Nowadays, there is no effective treatment for ADOA. In this article, we have established an isogenic human RGC model for ADOA using iPSC technology and the genome editing tool CRISPR/Cas9 from a previously generated iPSC line of an ADOA plus patient harboring the pathogenic variant NM_015560.3: c.1861C>T (p.Gln621Ter) in heterozygosis in OPA1. To this end, a protocol based on supplementing the iPSC culture media with several small molecules and defined factors trying to mimic embryonic development has been employed. Subsequently, the created model was validated, confirming the presence of a defect of intergenomic communication, impaired mitochondrial respiration, and an increase in apoptosis and ROS generation. Finally, we propose the analysis of OPA1 expression by qPCR as an easy read-out method to carry out future drug screening studies using the created RGC model. In summary, this model provides a useful platform for further investigation of the underlying pathophysiological mechanisms of ADOA plus and for testing compounds with potential pharmacological action.
2022-05-04 | Induced Pluripotent Stem Cells for Inherited Optic Neuropathies-Disease Modeling and Therapeutic Development.
Inherited optic neuropathies (IONs) cause progressive irreversible visual loss in children and young adults. There are limited disease-modifying treatments, and most patients progress to become severely visually impaired, fulfilling the legal criteria for blind registration. The seminal discovery of the technique for reprogramming somatic nondividing cells into induced pluripotent stem cells (iPSCs) has opened several exciting opportunities in the field of ION research and treatment. A systematic review of the literature was conducted with PubMed using the following search terms: autosomal dominant optic atrophy, ADOA, dominant optic atrophy, DOA, Leber hereditary optic neuropathy, LHON, optic atrophy, induced pluripotent stem cell, iPSC, iPSC derived, iPS, stem cell, retinal ganglion cell, and RGC. Clinical trials were identified on the ClinicalTrials.gov website. This review article is focused on disease modeling and the therapeutic strategies being explored with iPSC technologies for the 2 most common IONs, namely, dominant optic atrophy and Leber hereditary optic neuropathy. The rationale and translational advances for cell-based and gene-based therapies are explored, as well as opportunities for neuroprotection and drug screening. iPSCs offer an elegant, patient-focused solution to the investigation of the genetic defects and disease mechanisms underpinning IONs. Furthermore, this group of disorders is uniquely amenable to both the disease modeling capability and the therapeutic potential that iPSCs offer. This fast-moving area will remain at the forefront of both basic and translational ION research in the coming years, with the potential to accelerate the development of effective therapies for patients affected with these blinding diseases.
2020-06-15 | Bioenergetic Crosstalk between Mesenchymal Stem Cells and various Ocular Cells through the intercellular trafficking of Mitochondria
Rationale: Mitochondrial disorders preferentially affect tissues with high energy requirements, such as the retina and corneal endothelium, in human eyes. Mesenchymal stem cell (MSC)-based treatment has been demonstrated to be beneficial for ocular degeneration. However, aside from neuroprotective paracrine actions, the mechanisms underlying the beneficial effect of MSCs on retinal and corneal tissues are largely unknown. In this study, we investigated the fate and associated characteristics of mitochondria subjected to intercellular transfer from MSCs to ocular cells. Methods: MSCs were cocultured with corneal endothelial cells (CECs), 661W cells (a photoreceptor cell line) and ARPE-19 cells (a retinal pigment epithelium cell line). Immunofluorescence, fluorescence activated cell sorting and confocal microscopy imaging were employed to investigate the traits of intercellular mitochondrial transfer and the fate of transferred mitochondria. The oxygen consumption rate of recipient cells was measured to investigate the effect of intercellular mitochondrial transfer. Transcriptome analysis was performed to investigate the expression of metabolic genes in recipient cells with donated mitochondria. Results: Mitochondrial transport is a ubiquitous intercellular mechanism between MSCs and various ocular cells, including the corneal endothelium, retinal pigmented epithelium, and photoreceptors. Additionally, our results indicate that the donation process depends on F-actin-based tunneling nanotubes. Rotenone-pretreated cells that received mitochondria from MSCs displayed increased aerobic capacity and upregulation of mitochondrial genes. Furthermore, living imaging determined the ultimate fate of transferred mitochondria through either degradation by lysosomes or exocytosis as extracellular vesicles. Conclusions: For the first time, we determined the characteristics and fate of mitochondria undergoing intercellular transfer from MSCs to various ocular cells through F-actin-based tunneling nanotubes, helping to characterize MSC-based treatment for ocular tissue regeneration.
2019-12-01 | Stem Cell Ophthalmology Treatment Study (SCOTS): bone marrow derived stem cells in the treatment of Dominant Optic Atrophy
Background: We report the results of 6 patients with Dominant Optic Atrophy (DOA) who met inclusion criteria and were treated in the Stem Cell Ophthalmology Treatment Study (SCOTS). SCOTS/SCOTS 2 is an Institutional Review Board approved and NIH registered (NCT 03011541) clinical study that uses autologous bone marrow derived stem cells (BMSC) in the treatment of optic nerve and retinal disease. Methods: This is an open label, non-randomized clinical study using natural history of the disease as the comparator. BMSC were separated from aspirated autologous bone marrow with minimal manipulation using an FDA cleared Class II medical device. Patients were treated with combinations of retrobulbar, subtenons, intravitreal or subretinal placement of BMSC followed by intravenous injection of BMSC depending on the arm of the study chosen. There were no surgical complications. Results: Of the patients treated, 83.3% (5 of 6 patients) experienced visual improvements and in all of these cases both eyes improved. Ten eyes or 83.3% experienced gains in visual acuity with a median improvement of 2.125 Snellen lines, or approximately 10.63 letters. Two eyes were considered unchanged compared to longstanding measurements. Using LogMAR, the average improvement in vision for all eyes was 29.5%. The averagevisual acuity increasein eyes that improved was 33.3%. Findings were statistically significant with P<0.001. Conclusions: Using autologous BMSC per protocols developed in the SCOTS/SCOTS 2 clinical studies resulted in statistically significant visual acuity improvements in patients with DOA or Kjers Optic Neuropathy. Improvements occurred in 83.3% of eyes and averaged 29.5%. Mitochondrial transfer and neuroprotective exosome secretions from the BMSC may have been key to the improvements observed in this mitochondrial disease.
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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 | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
18?mer antisense oligonucleotide complementary to OPA1 pre-mRNA | oligonucleotides | FDA | Stoke Therapeutics, Inc. |
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