Clinical trials in Leber hereditary optic neuropathy: outcomes and opportunities DOI
Benson Chen, Nancy J. Newman

Current Opinion in Neurology, Journal Year: 2024, Volume and Issue: 38(1), P. 79 - 86

Published: Dec. 20, 2024

Purpose of review Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA disease characterised by sequential bilateral vision loss due to retinal ganglion cells. The purpose this provide an update on the results recent clinical trials for LHON, focusing studies idebenone and lenadogene nolparvovec gene therapy. Recent findings Evidence from three (RHODOS, RHODOS-OFU, LEROS) suggest that should be started early continued at least 24 months. Treatment effect varies according stage LHON underlying mutation. Favourable outcomes are associated with m.11778G>A mutation chronic eyes m.14484T>C Caution taken in subacute/dynamic m.3460G>A mutation, possible worsening idebenone. Compared external natural history cohort, pooled data four (RESCUE, REVERSE, RESTORE REFLECT) show single intravitreal injection can result sustained visual improvement patients aged ≥15 years when treated within 1 year onset. Although treatment modest, final acuity (∼1.2 logMAR) significantly differs published benefit more pronounced than alone Summary There increasing evidence potential therapeutic

Language: Английский

Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial DOI Creative Commons
Patrick Yu‐Wai‐Man, Valério Carelli, Nancy J. Newman

et al.

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(3), P. 101437 - 101437

Published: Feb. 29, 2024

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown be effective in stabilizing restoring patients treated within 1 year of onset The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy safety idebenone treatment (900 mg/day) with LHON up 5 years after symptom (N = 199) over period 24 months, compared an external history control cohort 372), matched by time since onset. meets its primary endpoint confirms long-term subacute/dynamic chronic phases; effect varies depending on phase causative mtDNA mutation. findings will help guide clinical management LHON.

Language: Английский

Citations

17
Mitochondrial diseases: from molecular mechanisms to therapeutic advances DOI Creative Commons
Hu Wen,

Hui Deng,

Bingyan Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 9, 2025

Abstract Mitochondria are essential for cellular function and viability, serving as central hubs of metabolism signaling. They possess various metabolic quality control mechanisms crucial maintaining normal activities. Mitochondrial genetic disorders can arise from a wide range mutations in either mitochondrial or nuclear DNA, which encode proteins other contents. These defects lead to breakdown metabolism, such the collapse oxidative phosphorylation, one mitochondria’s most critical functions. diseases, common group disorders, characterized by significant phenotypic heterogeneity. Clinical symptoms manifest systems organs throughout body, with differing degrees forms severity. The complexity relationship between mitochondria diseases results an inadequate understanding genotype-phenotype correlation these historically making diagnosis treatment challenging often leading unsatisfactory clinical outcomes. However, recent advancements research technology have significantly improved our management conditions. translations mitochondria-related therapies actively progressing. This review focuses on physiological mitochondria, pathogenesis potential diagnostic therapeutic applications. Additionally, this discusses future perspectives diseases.

Language: Английский

Citations

4
Leber’s hereditary optic neuropathy – current status of idebenone and gene replacement therapies DOI Creative Commons
Thomas Klopstock,

Li Zeng,

Claudia Priglinger

et al.

Medizinische Genetik, Journal Year: 2025, Volume and Issue: 37(1), P. 57 - 63

Published: Feb. 6, 2025

Language: Английский

Citations

1
Mitochondrial endogenous substance transport-inspired nanomaterials for mitochondria-targeted gene delivery DOI
Yi Wang, Jingsong Yang, Min Zhao

et al.

Advanced Drug Delivery Reviews, Journal Year: 2024, Volume and Issue: 211, P. 115355 - 115355

Published: June 5, 2024

Language: Английский

Citations

4
Retinal light damage: From mechanisms to protective strategies DOI Creative Commons

Zhao Zhang,

Xiaoqian Shan,

Shujiao Li

et al.

Survey of Ophthalmology, Journal Year: 2024, Volume and Issue: 69(6), P. 905 - 915

Published: July 23, 2024

Highlights•Light damage is considered to be an important pathogenic factor leading retinal degenerative diseases.•The mechanisms of light include the disruption REDOX balance and Ca2+ homeostasis, pyroptosis, endoplasmic reticulum stress, cell autophagy inflammatory release.•The strategy protection promising.AbstractVisible serves as a crucial medium for vision formation.;however, prolonged or excessive exposure recognized significant etiological contributing diseases. The retina, with its unique structure adaptability, relies on homeostasis cellular functions maintain visual health. Under normal conditions, retina can mount adaptive responses various insults, including light-induced damage. Unfortunately, intense triggers cascade pathological alterations in photoreceptor cells, pigment epithelial ganglion glial cells. These encompass intracellular Ca²⁺ autophagy, release cytokines, culminating irreversible We first delineate through 4 main avenues: mitochondria function, inflammation. Subsequently, we discuss protective strategies against damage, aiming guide research toward prevention treatment conditions.

Language: Английский

Citations

4
Idebenone Protects Photoreceptors Impaired by Oxidative Phosphorylation Disorder in Retinal Detachment DOI Creative Commons
Li‐Song Wang,

Gaocheng Zou,

Yuanye Yan

et al.

Investigative Ophthalmology & Visual Science, Journal Year: 2025, Volume and Issue: 66(1), P. 17 - 17

Published: Jan. 8, 2025

Purpose: Oxidative phosphorylation (OXPHOS) is an aerobic metabolic mechanism, and its dysfunction plays important role in the pathological changes of ischemic diseases. However, systematic studies on occurrence retinal detachment (RD) are lacking. Methods: Single-cell RNA sequencing (scRNA-seq) human retina was performed to detect various cells after RD. In this study, animal experiments were conducted explore OXPHOS activity addition, idebenone, a coenzyme Q10 (CoQ10) analog currently used treat Leber hereditary optic neuropathy (LHON), improve disorder experimental RD model. Results: ScRNA-seq revealed abnormal energy metabolism pathways Adenosine triphosphate (ATP) reactive oxygen species (ROS) main products OXPHOS, mouse model indicated that rise ROS levels may have greater impact photoreceptors early stage, whereas decreased ATP synthesis observed later stage; these threaten function morphology retina. Idebenone administered mice intragastrically, leading reduced stage post-RD improved which closely related maintenance mitochondrial morphology. Conclusions: leads photoreceptor degeneration RD, can be alleviated by improving function.

Language: Английский

Citations

0
Idebenone improves mitochondrial respiratory activity and attenuates oxidative damage via the SIRT3-SOD2 pathway in a prion disease cell model DOI

Zhixin Sun,

Pei Wen,

Dongming Yang

et al.

Life Sciences, Journal Year: 2025, Volume and Issue: 366-367, P. 123481 - 123481

Published: Feb. 19, 2025

Language: Английский

Citations

0
Primary mitochondrial diseases: The intertwined pathophysiology of bioenergetic dysregulation, oxidative stress and neuroinflammation DOI
Kevin Aguilar, Patrycja Jakubek, António Zorzano

et al.

European Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 54(7)

Published: April 21, 2024

Abstract Objectives and scope Primary mitochondrial diseases (PMDs) are rare genetic disorders resulting from mutations in genes crucial for effective oxidative phosphorylation (OXPHOS) that can affect function. In this review, we examine the bioenergetic alterations stress observed cellular models of primary (PMDs), shedding light on intricate complexity between dysfunction pathology. We explore diverse utilized to study PMDs, including patient‐derived fibroblasts, induced pluripotent stem cells (iPSCs) cybrids. Moreover, also emphasize connection neuroinflammation. Insights The central nervous system (CNS) is particularly vulnerable due its dependence aerobic metabolism correct functioning OXPHOS. Similar other neurodegenerative affecting CNS, individuals with PMDs exhibit several neuroinflammatory hallmarks alongside neurodegeneration, a pattern extensively mouse diseases. Based histopathological analysis postmortem human brain tissue findings posit neuroinflammation not merely consequence neurodegeneration but potential pathogenic mechanism disease progression deserves further investigation. This recognition may pave way novel therapeutic strategies group devastating currently lack treatments. Summary summary, review provides comprehensive overview redox imbalance while underscoring significance as driver progression.

Language: Английский

Citations

2
Hereditary Optic Neuropathies: An Updated Review DOI Open Access
Samuel Lee,

Caroline Mura,

Nicolas J. Abreu

et al.

Journal of Clinical & Translational Ophthalmology, Journal Year: 2024, Volume and Issue: 2(3), P. 64 - 78

Published: June 26, 2024

Hereditary optic neuropathies (HONs) are a class of genetic disorders that may lead to vision loss due either acute or progressive injury the nerve. Although HONs commonly manifest as isolated atrophy, these can also have variety characteristic clinical features and time courses narrow differential diagnosis. While two most prevalent Leber Optic Neuropathy (LHON) Dominant Atrophy (DOA), phenotypic spectrum conditions, well landscape less common neuropathies, been better characterized through advances in molecular diagnostic testing. Treatment targeting various pathogenic mechanisms has investigated, although studies applicability remain nascent. Present management largely remains supportive. In this review, we discuss features, diagnosis, current treatment, future directions for HONs.

Language: Английский

Citations

2
Gene therapy for Leber hereditary optic neuropathy DOI
Marco Battista, Valério Carelli,

Leonardo Bottazzi

et al.

Expert Opinion on Biological Therapy, Journal Year: 2024, Volume and Issue: 24(6), P. 521 - 528

Published: June 2, 2024

Introduction Leber hereditary optic neuropathy (LHON) is among the most frequent inherited mitochondrial disease, causing a severe visual impairment, mostly in young-adult males. The causative mtDNA variants (the three common are m.11778 G>A/MT-ND4, m.3460 G>A/MT-ND1, and m.14484T>C/MT-ND6) by affecting complex I impair oxidative phosphorylation retinal ganglion cells, ultimately leading to irreversible cell death consequent functional loss. gene therapy based on allotopic expression of wild-type transgene carried adeno-associated viral vectors (AVV-based) appears promising approach disease its efficacy has been explored several large clinical trials.

Language: Английский

Citations

2