2026 — ARVO: Diffusion of AAV2-based gene therapy into contralateral optic nerve in Leber hereditary optic neuropathy
2026 — ARVO: Deep Learning Based Retinal Vessel Metrics Can Differentiate Leber Hereditary Optic Neuropathy (LHON) from Dominant Optic Atrophy (DOA)
2026 — NANOS: Does OPA1 Genotype And Visual Outcomes Predict Idebenone Treatment In Dominant Optic Atrophy (DOA)?
2026 — NANOS: Deep Learning-Based Retinal Vessel Segmentation and Analysis of Intensity and Density in Leber’s Hereditary Optic Neuropathy
2025 — AAO: New Insights on AAV2-ND4 Transfer Between Eyes: Post-Mortem Analyses in Leber Hereditary Optic Neuropathy Following Gene Therapy
2025 — ARVO: The First Report of Amyloid Beta in the Optic Nerve Head in a Rare Case of Homozygous Familial Alzheimer Disease: An Immunohistochemical Study
2025 — ARVO: New Insights on AAV2-ND4 Transfer Between Eyes: Ocular Post-Mortem Analyses in Leber Hereditary Optic Neuropathy Following AAV2 Gene Therapy
2025 — ARVO: Immunohistochemistry of Optic Nerve Head Drusen in a Rare Case of Autosomal Dominant Alzheimer Disease
2025 — ARVO: Cytokine-Mediated Proinflammation in the Optic Nerve Head of Leber Hereditary Optic Neuropathy: An Immunohistochemical Study
2024 — ARVO: Archetypal analysis on visual fields of recovered and not-recovered chronic LHON patients
2024 — NANOS: Ocular Post-Mortem Analyses with Histopathological and Molecular Assessments in LHON Following AAV2 Gene Therapy
2023 — AOS: Blindness from the LHON mtDNA mutation 3460A>G starts with ND1 trapping of COQ10 and excessive ROS
2023 — AAO: Histopathological and molecular characterizations in ocular post-mortem analyses following AAV2 gene therapy for LHON
2023 — EVER: Molecular mechanisms that cause cell death in LHON
2023 — ARVO: Histopathological and molecular characterization in ocular post-mortem analyses following AAV2 gene therapy for LHON
2023 — NANOS: Sustained Bilateral Improvement After Unilateral AAV2 Gene Therapy for LHON: Update and Bilateral Ocular Post-mortem Analyses
2015 — EVER: What pathological mechanism causes optic atrophy in LHON
Conference sections
ARVO
2026 — Diffusion of AAV2-based gene therapy into contralateral optic nerve in Leber hereditary optic neuropathy
Authors: Alfredo A. Sadun; Nancy J. Newman; Valérie Biousse; Leonardo Caporali; Fred Ross-Cisneros; Santino Blando; Elisa Boschetti; Lindreth DuBois; Henry Liu; Philippe Ancian; Magali Taiel; Valerio Carelli
Theme: Gene therapy / diffusion pathway
Summary: Purpose: To investigate how unilateral AAV2-ND4 gene therapy may produce bilateral biological effects in LHON. Methods/Results: Post-mortem retinal and optic nerve analyses after lenadogene nolparvovec treatment showed asymmetric transgene distribution in the treated eye, lower-level transgene detection in the untreated eye, and evidence of signal along optic nerve and related visual pathway structures. Conclusion: The findings support inter-eye transfer after unilateral administration and suggest that diffusion pathways beyond direct local injection may contribute to the bilateral treatment effect observed in LHON gene-therapy trials.
2026 — Deep Learning Based Retinal Vessel Metrics Can Differentiate Leber Hereditary Optic Neuropathy (LHON) from Dominant Optic Atrophy (DOA)
Authors: Maryam Golmohammadi; Amin Ramezani; Danielle A. Gauthier; Fred N. Ross-Cisneros; Michael Gilhooley; Alfredo A. Sadun
Summary: Purpose: To determine whether deep learning-derived retinal vessel biomarkers can distinguish LHON from DOA using color fundus photographs. Methods/Results: A modified BCDU-Net model segmented retinal vessels and quantified vessel density, vessel intensity, skeleton length, and curvature. LHON eyes showed significantly higher values than DOA across all four metrics, with moderate effect sizes. Conclusion: Quantitative retinal vascular profiling may provide an objective, image-based biomarker to support differential diagnosis of mitochondrial optic neuropathies and reveal disease-specific vascular remodeling.
2025 — The First Report of Amyloid Beta in the Optic Nerve Head in a Rare Case of Homozygous Familial Alzheimer Disease: An Immunohistochemical Study
Authors: Fred N. Ross-Cisneros; Danielle A. Gauthier; Maryam Golmohammadi; Amir H. Kashani; John M. Ringman; Alfredo A. Sadun
Theme: Familial Alzheimer disease / amyloid beta in optic nerve head
Summary: Purpose: To test whether amyloid beta is present in the optic nerve head of a rare homozygous familial Alzheimer disease case. Methods/Results: Immunohistochemistry for AB42 in a post-mortem eye showed amyloid beta within the prelaminar optic nerve head, including aggregate-like deposits, plaque-like staining, and dense accumulation around medium to large blood vessels; staining was limited in the lamina cribrosa and post-laminar optic nerve head. Conclusion: The findings extend Alzheimer-related amyloid pathology into the optic nerve head and support involvement of the anterior visual pathway in neurodegenerative disease.
2025 — New Insights on AAV2-ND4 Transfer Between Eyes: Ocular Post-Mortem Analyses in Leber Hereditary Optic Neuropathy Following AAV2 Gene Therapy
Authors: Valerio Carelli; Nancy J. Newman; Valérie Biousse; Leonardo Caporali; Fred Ross-Cisneros; Santino Blando; Elisa Boschetti; Lindreth DuBois; Henry Liu; Philippe Ancian; Magali Taiel; Alfredo A. Sadun
Theme: Gene therapy / AAV2-ND4 inter-eye transfer
Summary: Purpose: To examine post-mortem ocular evidence for AAV2-ND4 transfer after unilateral lenadogene nolparvovec therapy in MT-ND4 LHON. Methods/Results: Two treated patients developed intraocular inflammation that resolved clinically. Molecular and histopathologic analyses showed different degrees of retinal ganglion cell and optic nerve preservation, asymmetric transgene distribution in treated retinal tissue, and AAV2-ND4 detection in both treated and untreated ocular and optic nerve structures. Conclusion: The results strengthen evidence that unilateral AAV2-based gene therapy can lead to bilateral transgene presence and raise important questions about the pathways of inter-eye transfer.
2025 — Immunohistochemistry of Optic Nerve Head Drusen in a Rare Case of Autosomal Dominant Alzheimer Disease
Authors: Danielle A. Gauthier; Fred N. Ross-Cisneros; Maryam Golmohammadi; Amir H. Kashani; John M. Ringman; Alfredo A. Sadun
Theme: Optic nerve head drusen / Alzheimer disease pathology
Summary: Purpose: To investigate optic nerve head drusen in a rare autosomal dominant Alzheimer disease case and assess whether the deposits contain markers of amyloid, axonal injury, and gliosis. Methods/Results: Immunostaining for AB42, neurofilament protein, and GFAP was positive within the drusen, with heterogeneous staining patterns and stronger AB42 signal around the drusen periphery. Conclusion: The findings support a model in which optic nerve head drusen may reflect axonal degeneration and astrocytic response in the prelaminar optic nerve head, with amyloid beta potentially contributing to local neurodegenerative injury.
2025 — Cytokine-Mediated Proinflammation in the Optic Nerve Head of Leber Hereditary Optic Neuropathy: An Immunohistochemical Study
Authors: Maryam Golmohammadi; Fred N. Ross-Cisneros; Danielle A. Gauthier; Alfredo A. Sadun
Theme: LHON / neuroinflammation / optic nerve head pathology
Summary: Purpose: To determine whether LHON optic nerve head tissue shows evidence of proinflammatory cytokine activity despite the disease often being considered non-inflammatory. Methods/Results: Post-mortem LHON eyes were immunostained for IL-1beta and compared with controls. Positive staining was observed in optic nerve head structures, especially the lamina choroidalis and lamina cribrosa, while a LHON carrier and most controls were largely unstained. Conclusion: IL-1beta staining suggests inflammatory signaling within LHON optic nerve head tissue, although whether this represents a primary driver of damage or a secondary response to axonal degeneration remains unresolved.
2024 — Archetypal analysis on visual fields of recovered and not-recovered chronic LHON patients
Authors: Catarina P. Coutinho; Ferdinando Zanchetta; Michele Carbonelli; Marco Battista; Alice Galzignato; Chiara La Morgia; Giulia Amore; Martina Romagnoli; Luigi Brotto; Paolo Nucci; Vincenzo Parisi; Maria Lucia Cascavilla; Leonardo Caporali; Francesco Bandello; Alfredo A. Sadun; Valerio Carelli; Rita Fioresi; Piero Barboni
Theme: Machine learning / visual fields
Summary: Purpose: To apply archetypal analysis to chronic LHON visual fields and determine whether visual field patterns differ between patients with and without visual acuity recovery. Methods/Results: Analysis of 220 visual fields from 117 patients identified seven archetypes, including total loss, normal visual field, small and large cecocentral scotomas, diffuse abnormalities, and other patterns. Total loss was more frequent in non-recovered cases, while normal fields and small cecocentral scotomas were more frequent in recovered cases. Conclusion: Visual acuity recovery and visual field recovery are related but not interchangeable, so both measures are important for evaluating LHON outcomes.
2023 — Histopathological and molecular characterization in ocular post-mortem analyses following AAV2 gene therapy for LHON
Authors: Valerio Carelli; Leonardo Caporali; Fred Ross-Cisneros; Elisa Boschetti; Nancy J. Newman; Valérie Biousse; Lindreth DuBois; Henry Liu; Philippe Ancian; Magali Taiel; Alfredo A. Sadun
Summary: Purpose: To present post-mortem histopathologic and molecular findings from a RESCUE-study participant after unilateral lenadogene nolparvovec treatment. Methods/Results: The treated eye developed inflammation that resolved clinically, while post-mortem tissue showed optic nerve head inflammatory infiltration, asymmetric retinal AAV2-ND4 distribution, and lower-level transgene detection in the fellow eye. Conclusion: These findings represent an early public version of the post-mortem AAV2-ND4 series and support evolving evidence for contralateral transgene detection after unilateral therapy.
Summary: Purpose: To place LHON within the broader category of mitochondrial optic neuropathies and summarize clinical features, mechanisms, and treatment directions. Methods/Results: The overview describes bilateral central visual loss, early color vision loss, papillomacular bundle vulnerability, temporal optic disc pallor, and emerging therapies including idebenone, EPI-743, mitochondrial-targeted strategies, and AAV2 gene-therapy trials. Conclusion: Mitochondrial optic neuropathies share a recognizable clinical and mechanistic pattern and continue to serve as a key model for developing targeted neuroprotective and gene-based therapies.
NANOS
2026 — Does OPA1 Genotype And Visual Outcomes Predict Idebenone Treatment In Dominant Optic Atrophy (DOA)?
Authors: Danielle A. Gauthier; Maryam Golmohammadi; Ananya Srivastava; Alfredo A. Sadun; Michael J. Gilhooley
Theme: Dominant optic atrophy / idebenone use
Summary: Purpose: To evaluate whether idebenone use in DOA is associated with molecular diagnosis, OPA1 status, or worse baseline visual severity. Methods/Results: In a retrospective cohort of 39 DOA patients, idebenone use was compared with genetic testing status, OPA1 mutation status, visual acuity, visual field mean deviation, and RNFL thickness. Idebenone use was common but was not significantly associated with genetic diagnosis, OPA1 mutation, visual acuity, visual field loss, or RNFL thickness. Conclusion: Current off-label idebenone use in DOA does not appear to be guided by measured genotype or structural/functional severity, supporting the need for larger prospective treatment studies.
2026 — Deep Learning-Based Retinal Vessel Segmentation and Analysis of Intensity and Density in Leber’s Hereditary Optic Neuropathy
Authors: Maryam Golmohammadi; Amin Ramezani; Danielle A. Gauthier; Shenoda Abd Elmaseh; Michael J. Gilhooly; Alfredo A. Sadun
Summary: Purpose: To use deep learning to identify retinal vascular changes in LHON compared with normal controls and to examine vessel features by mutation, age, and gender. Methods/Results: Convolutional neural networks segmented vessels from 1,084 fundus images and quantified vessel area, segmentation regions, vessel density, vessel intensity, and variability. LHON eyes showed larger vessel area, greater segmentation regions, increased intensity variability, mutation-specific vessel-intensity differences, and a weak age-related association with vessel brightness; gender-related differences were not significant. Conclusion: Deep learning can detect LHON-associated vascular remodeling and may help characterize mitochondrial optic neuropathy for early detection and future monitoring.
2024 — Ocular Post-Mortem Analyses with Histopathological and Molecular Assessments in LHON Following AAV2 Gene Therapy
Authors: Alfredo A. Sadun; Nancy J. Newman; Leonardo Caporali; Fred Ross-Cisneros; Elisa Boschetti; Valérie Biousse; Lindreth DuBois; Henry Liu; Philippe Ancian; Magali Taiel; Valerio Carelli
Theme: Gene therapy / ocular post-mortem analysis
Summary: Purpose: To describe ocular post-mortem findings after unilateral AAV2-ND4 gene therapy for LHON. Methods/Results: Treated eyes showed intraocular inflammation that resolved clinically, and one case showed chronic inflammatory infiltration around the optic nerve head and temporal retina. Molecular testing demonstrated asymmetric AAV2-ND4 retinal transfection in the injected eye and lower-level signal in the fellow eye. Conclusion: These findings support the biological plausibility of contralateral transgene detection after unilateral treatment and contribute to understanding both tissue distribution and safety/pathology findings after AAV2-ND4 therapy.
2023 — Sustained Bilateral Improvement After Unilateral AAV2 Gene Therapy for LHON: Update and Bilateral Ocular Post-mortem Analyses
Authors: Alfredo A. Sadun; Leonardo Caporali; Fred Ross-Cisneros; Elisa Boschetti; Nancy J. Newman; Valérie Biousse; Lindreth DuBois; Henry Liu; Philippe Ancian; Magali Taiel; Valerio Carelli
Theme: Gene therapy / post-mortem evidence
Summary: Purpose: To connect sustained bilateral visual improvement after unilateral AAV2-ND4 gene therapy with post-mortem ocular evidence. Methods/Results: Clinical trial observations from RESCUE, REVERSE, RESTORE, and REFLECT showed bilateral improvement beyond expected natural history, while post-mortem analyses identified inflammatory changes and low-level AAV2-ND4 detection in the fellow eye. Conclusion: The combined clinical and tissue findings support continued investigation of inter-eye transfer and the biological basis for bilateral response after unilateral lenadogene nolparvovec treatment.
2022 — The Phase III REFLECT Trial: Efficacy and Safety of Bilateral Gene Therapy for Leber Hereditary Optic Neuropathy (LHON)
Authors: Newman NJ; Yu-Wai-Man P; Carelli V; Subramanian P; Moster ML; Wang AG; Leroy B; Donahue S; Biousse V; Vignal-Clermont C; Sadun AA; Rebolleda Fernández G; Fortin E; Banik R; Blouin L; Roux M; Taiel M; Sahel JA; for the REFLECT LHON Study Group
Theme: Gene therapy / clinical trial
Summary: Purpose: To evaluate efficacy and safety of bilateral versus unilateral lenadogene nolparvovec therapy in ND4-LHON. Methods/Results: In the Phase III REFLECT trial, subjects received gene therapy in the first-affected eye and either gene therapy or placebo in the second-affected eye. Treated eyes improved from nadir, bilateral treatment showed favorable visual outcomes, placebo-treated eyes also demonstrated a contralateral effect, and the safety profile remained favorable. Conclusion: REFLECT supports meaningful visual improvement and reinforces evidence that AAV2-ND4 therapy can produce bilateral benefit, even when only one eye receives active injection.
2018 — Asynchronous onset in Leber's Hereditary Optic Neuropathy
Authors: Rustum Karanjia; Henry Liu; Chiara La Morgia; Samir Nazarali; Lidia Di Vito; Michele Carbonelli; Piero Barboni; Anna Maria De Negri; Patrick Yu-Wai-Man; Alfredo Sadun; Valerio Carelli
Theme: Clinical natural history / onset pattern
Summary: Purpose: To characterize asynchronous onset patterns in LHON and better define the interval between first-eye and second-eye involvement. Methods/Results: A multicenter registry cohort was analyzed for timing of bilateral involvement, age at onset, sex distribution, and mutation subtype. Conclusion: Understanding asynchronous onset helps clarify LHON natural history, improves patient counseling about fellow-eye risk, and informs treatment timing and clinical trial design.
AAO
2025 — New Insights on AAV2-ND4 Transfer Between Eyes: Post-Mortem Analyses in Leber Hereditary Optic Neuropathy Following Gene Therapy
Authors: Alfredo A. Sadun; Nancy J. Newman; Leonardo Caporali; Fred Ross-Cisneros; Valérie Biousse; Santino Blando; Elisa Boschetti; Lindreth DuBois; Henry Liu; Philippe Ancian; Magali Taiel; Valerio Carelli
Theme: Gene therapy / inter-eye transfer
Summary: Purpose: To characterize post-mortem ocular findings in LHON patients who received unilateral AAV2-ND4 gene therapy with sham treatment in the fellow eye. Methods/Results: Histopathologic and molecular analyses showed treated-eye inflammation that resolved clinically, variable preservation of retinal ganglion cells and optic nerve axons, and detection of AAV2-ND4 in retinal and optic nerve tissues, including lower-level signal in the untreated eye. Conclusion: Transgene detection in both eyes despite unilateral administration supports inter-eye transfer and provides biological context for bilateral effects observed in clinical trials.
2023 — Histopathological and molecular characterizations in ocular post-mortem analyses following AAV2 gene therapy for LHON
Authors: Alfredo A. Sadun; Nancy J. Newman; Leonardo Caporali; Fred Ross-Cisneros; Elisa Boschetti; Valérie Biousse; Lindreth DuBois; Henry Liu; Philippe Ancian; Magali Taiel; Valerio Carelli
Theme: Gene therapy / post-mortem case report
Summary: Purpose: To summarize post-mortem ocular findings after unilateral AAV2-ND4 gene therapy in LHON. Methods/Results: Two RESCUE-study patients developed treated-eye inflammation that resolved, and molecular analyses showed asymmetric AAV2-ND4 distribution in the injected eye with lower-level detection in the untreated eye. Conclusion: The findings provide early clinical-conference evidence that AAV2-ND4 transfection can persist in ocular tissue after unilateral injection and may be detectable in the contralateral eye, supporting further study of inter-eye transfer.
AOS
2023 — Blindness from the LHON mtDNA mutation 3460A>G starts with ND1 trapping of COQ10 and excessive ROS
Authors: Alfredo A. Sadun; Jack Fuller; Steven Barnes; Lorenzo Sadun; Pujan Ajmera; Anastassia Alexandrova
Theme: Computational mechanism / ND1-ROS model
Summary: Purpose: To explain how the 3460A>G LHON mutation may trigger retinal ganglion cell injury through Complex I dysfunction. Methods/Results: Molecular dynamics and free-energy perturbation simulations showed that the ND1 mutation can alter CoQ10 movement, slow exit of reduced ubiquinol from the binding channel, and favor abnormal electron transfer. Conclusion: The proposed mechanism links a specific mitochondrial DNA mutation to excessive reactive oxygen species production, supporting a model of LHON optic neuropathy driven by oxidative stress rather than ATP deficiency alone.
EVER
2023 — Molecular mechanisms that cause cell death in LHON
Summary: Purpose: To explain LHON retinal ganglion cell death through molecular mechanisms involving Complex I and reactive oxygen species. Methods/Results: Computational modeling of ND1-related changes near the CoQ10 binding channel suggests that impaired ubiquinol exit and altered electron movement through iron-sulfur clusters can increase ROS generation. Conclusion: This mechanism connects mitochondrial mutation, excessive oxidative stress, and selective vulnerability of small retinal ganglion cell axons, helping explain the papillomacular bundle pattern of injury in LHON.
Summary: Purpose: To present mitochondrial optic neuropathies as a unified group of hereditary, toxic, and nutritional optic nerve disorders. Methods/Results: The framework emphasizes shared clinical features including bilateral symmetric central or cecocentral visual loss, color vision impairment, papillomacular bundle damage, and temporal optic disc pallor. Conclusion: These disorders converge on mitochondrial oxidative phosphorylation injury and reactive oxygen species generation, explaining the vulnerability of small unmyelinated axons and the interaction between genetic predisposition and environmental or nutritional stressors.
2017 — LHON: A look into nuclear and environmental factors; What is “sufficient”?
Authors: Alfredo A. Sadun; Fred Ross-Cisneros; Jack Tian; Kirsten Anderson; Anne Irvine; Rustum Karanjia; Chiara La Morgia; Meagan McManus; Doug Wallace; Valerio Carelli
Theme: Nuclear modifiers / environmental risk
Summary: Purpose: To examine why LHON mtDNA mutations are necessary but not sufficient for visual loss. Methods/Results: Patient pedigree observations and Wallace LHON mouse-model experiments were used to evaluate nuclear modifiers, environmental exposures, smoking-related patterns, and selective loss of small optic nerve fibers. Conclusion: LHON expression is best understood as a threshold phenomenon shaped by mitochondrial mutation, nuclear background, and environmental stress, helping explain incomplete penetrance, variable onset, and differences in severity.
2015 — What pathological mechanism causes optic atrophy in LHON
Authors: A. Sadun; V. Carelli; C. La Morgia; R. Karanjia
Theme: Mitochondrial mechanisms / ROS
Summary: Purpose: To explain the mechanism of optic atrophy in LHON through Complex I dysfunction and oxidative injury. Methods/Results: The abstract emphasizes that LHON mutations can produce excessive reactive oxygen species through altered electron transfer around iron-sulfur clusters, with quantum electron tunneling contributing to free-electron and ROS formation. Conclusion: Retinal ganglion cell death in LHON is likely driven substantially by ROS-mediated injury, explaining selective optic nerve fiber vulnerability beyond simple ATP reduction.
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