bims-curels 2024-12-22 papers

Issue of 2024–12–22
ten papers selected by
Cure Mito Foundation

Curr Opin Pediatr. 2025 Feb 01. 37(1): 107-111

Updates on neurologic manifestations of mitochondrial disease.

PURPOSE OF REVIEW: Primary mitochondrial disease (PMD) is diverse both genetically and phenotypically. Neurologic manifestations are present at a high rate and often pose complications for providers. The review will discuss common manifestations and how advances in genetic testing have broadened understanding of PMDs.
RECENT FINDINGS: Across all areas of PMD research, genetic advancements are notable both for mitochondrial and nuclear DNA.
SUMMARY: Global understanding of PMDs is driving deeper and broader research. Neurologic manifestations primarily include neuromuscular disease, epilepsy, stroke-like episodes and neurodegeneration, and advances in all areas have benefitted from global reporting of genetic studies.

DOI: https://doi.org/10.1097/MOP.0000000000001418

Curr Opin Neurol. 2024 Dec 23.

Clinical trials in Leber hereditary optic neuropathy: outcomes and opportunities.

Benson S Chen, Nancy J Newman.

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

DOI: https://doi.org/10.1097/WCO.0000000000001343

Neurochem Res. 2024 Dec 14. 50(1): 61

Mechanism and Clinical Application Prospects of Mitochondrial DNA Single Nucleotide Polymorphism in Neurodegenerative Diseases.

Mengying Xu, Tianjiao Li, Xuan Liu, Binish Islam, Yuyue Xiang, Xiyan Zou, Jianwu Wang.

Mitochondrial dysfunction is well recognized as a critical component of the complicated pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. This review investigates the influence of mitochondrial DNA single nucleotide polymorphisms on mitochondrial function, as well as their role in the onset and progression of these neurodegenerative diseases. Furthermore, the contemporary approaches to mitochondrial regulation in these disorders are discussed. Our objective is to uncover early diagnostic targets and formulate precision medicine strategies for neurodegenerative diseases, thereby offering new paths for preventing and treating these conditions.

Keywords: Mitochondrial dysfunction; Mitochondrial regulation technologies; Neurodegenerative diseases; SNPs; mtDNA

DOI: https://doi.org/10.1007/s11064-024-04311-9

Res Involv Engagem. 2024 Dec 18. 10(1): 129

Establishing patient partners' roles on research teams: a scoping review.

Georgia Tobiano, Brigid M Gillespie, Joan Carlini, Rachel Muir, Jananee Rasiah, Ching Shan Wan, Tamara L McCarron, Karen Moffat, Sepideh Jahandideh, Wendy Chaboyer.

BACKGROUND: There are a myriad of ways patient partners can enact their roles on research teams. International guidelines emphasize the need for a collaborative approach to determining these roles to try to improve research impact and positive patient partner experience. The aims of this review were to: (1) describe how patient partners' roles as co-researchers in health research are determined; and (2) identify factors that influence how these decisions are made.
METHODS: A scoping review was conducted. Four databases were searched plus citation searching occurred. Descriptions of English language studies of any design and commentaries of studies that report on patient partners' or researchers' reflections on their decision-making processes for engagement were included. Two reviewers completed screening and data extraction, with a third to resolve disagreements. Results were summarized and then content analysis was undertaken to synthesize the findings. Two patient partners contributed to the protocol development, screening, data interpretation, and manuscript writing at varying times during the process.
RESULTS: A total of 45 papers (25 commentaries, 19 studies and 1 both a study and commentary) were included in this review. Most papers were from the United Kingdom (n = 15) and Canada (n = 12). Most patient partners had experiences related to chronic conditions rather than acute or time-limited illnesses. The synthesis yielded two categories. The first category, the research and research team attributes shape patient partner roles, encompassed patient partner, researcher and activity related factors that influenced patient partner engagement in activities. The second category, shared and ongoing decision-making, described the decision-making process to determine patient partner engagement, timing of these decisions, and tools to support these decisions.
CONCLUSION: A dynamic, systematic and shared decision-making approach to determining patient partners' roles in the research process has the potential to support meaningful engagement and maximize benefits. Because the research process may evolve over time and patient partners situations can change, there may be a need to renegotiate the patient partner's role.

Keywords: Decision making; Patient engagement; Patient participation; Research methods; Review; Stakeholder participation

DOI: https://doi.org/10.1186/s40900-024-00664-1

Ther Adv Rare Dis. 2024 Jan-Dec;5:5 26330040241307962

Advancing rare disease measurement through the Rare Disease Clinical Outcome Assessment Consortium.

Naomi Knoble, Lindsey T Murray.

There is a significant unmet need to develop and evaluate new treatments for people living with one of approximately 8000 rare diseases. Well-known difficulties in conducting clinical trials (e.g., small samples, wide geographic distribution, heterogeneous symptoms) and developing products for these rare indications persist. Identifying outcomes in rare disease clinical trials remains a hurdle that contributes to the challenges for drug and gene therapy development due to uncertainty about what aspects of a condition to measure for safety and efficacy and often with no regulatory approval precedent. To accelerate rare disease treatments by advancing outcomes measurement, the US Food and Drug Administration (FDA) funded a cooperative agreement to establish the Rare Disease COA Consortium (RD-COAC) in 2019. The RD-COAC officially launched on January 1, 2022, with the mission to enable pre-competitive, multi-stakeholder collaboration aimed at identifying scientifically sound tools and methodologies for collecting clinically meaningful and patient-centric outcomes data in treatment trials for rare diseases. The RD-COAC has four complementary workstreams to advance COA measurement for rare disease clinical trials: (1) Rare Disease COA Resource; (2) Advancing COA Measurement Topic-Focused Working Groups; (3) Rare Disease Discussion Sessions for pre-competitive collaboration and shared learnings among RD-COAC members; and (4) Dissemination. This review provides an overview of the RD-COAC's activities to date, as well as future directions and opportunities to collaborate.

Keywords: COAs; Rare Disease COA Resource; clinical outcome assessments; pre-competitive multi-stakeholder consortium; rare disease

DOI: https://doi.org/10.1177/26330040241307962

JAMA Ophthalmol. 2024 Dec 19.

Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy.

LHON Study Group

Importance: Limited studies have assessed the long-term benefit/risk of gene therapy for Leber hereditary optic neuropathy (LHON).
Objective: To determine the safety and efficacy of lenadogene nolparvovec in patients with LHON due to the MT-ND4 gene variant for up to 5 years after administration.
Design, Setting, and Participants: The RESCUE and REVERSE Long-Term Follow-up Study (RESTORE), conducted from 2018 to 2022, is the 5-year follow-up study of the 2 phase 3 clinical studies RESCUE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss Up to 6 Months From Onset in LHON Due to the MT-ND4 Mutation) and REVERSE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the MT-ND4 Mutation). At the end of each study, ie, 2 years after gene therapy administration, patients were offered enrollment in the RESTORE trial, a multinational, multicenter, prospective study, for an additional 3 years of follow-up. Patients with LHON due to the MT-ND4 gene variant received lenadogene nolparvovec in 1 eye and a sham injection in the other eye.
Intervention: Lenadogene nolparvovec was administered as a single intravitreal injection in the RESCUE/REVERSE studies.
Main Outcomes and Measures: Measures included best-corrected visual acuity (BCVA), quality of life using the National Eye Institute visual functioning questionnaire 25 (NEI VFQ-25), and adverse events.
Results: Among the 76 patients who received gene therapy in the RESCUE (n = 39) and REVERSE (n = 37) studies, 72 (94.7%) completed these studies; 62 patients (81.6%) participated in the RESTORE trial, and 55 patients (72.4%) completed the 5-year follow-up. Participants were mostly male (49 [79.0%]) with a mean (SD) age of 35.9 (15.3) years at treatment. At baseline, the mean (SD) BCVA was 1.5 (0.5) logMAR (20/600 Snellen) in eyes to be treated with lenadogene nolparvovec and 1.4 (0.5) logMAR (20/500) in sham eyes. At the end of the RESCUE/REVERSE trials, ie, 2 years after treatment, eyes treated with lenadogene nolparvovec and eyes treated with sham reached a mean BCVA value of 1.4 (0.6) logMAR (20/500). The mean (SD) change from baseline to year 2 was -0.05 (0.6) logMAR (+1 line) and 0.01 (0.6) logMAR (-0 line) in gene therapy-treated and sham eyes, respectively (difference, -0.03; 95% CI, -0.16 to 0.09; P = .60). Five years after treatment, the bilateral improvement from nadir was similar to that observed at 2 years, with a mean (SD) change in BCVA of -0.4 (0.5) logMAR (more than +4 lines) for eyes treated with lenadogene nolparvovec and -0.4 (0.4) logMAR (+4 lines) for eyes treated with sham (difference, -0.05; 95% CI, -0.15 to 0.04; P = .27). An improvement of at least -0.3 logMAR (+3 lines) from the nadir in at least 1 eye was observed in 66.1% of participants (41 of 62). Between 2 and 5 years, intraocular inflammation was noted in 4 participants with 8 events in eyes treated with lenadogene nolparvovec and 1 event in an eye treated with sham.
Conclusions and Relevance: In this analysis of the RESTORE trial, follow-up of patients with LHON due to the MT-ND4 gene variant unilaterally treated with lenadogene nolparvovec demonstrated a sustained bilateral improvement in BCVA and a good safety profile up to 5 years after treatment. This evidence of persistent benefit over time is promising for the use of gene therapy in these patients.
Trial Registration: ClinicalTrials.gov Identifier: NCT03406104.

DOI: https://doi.org/10.1001/jamaophthalmol.2024.5375

Annu Rev Physiol. 2024 Dec 10.

Exercise as Mitochondrial Medicine: How Does the Exercise Prescription Affect Mitochondrial Adaptations to Training?

David J Bishop, Matthew J-C Lee, Martin Picard.

Mitochondria are multifaceted organelles with several life-sustaining functions beyond energy transformation, including cell signaling, calcium homeostasis, hormone synthesis, programmed cell death (apoptosis), and others. A defining aspect of these dynamic organelles is their remarkable plasticity, which allows them to sense, respond, and adapt to various stressors. In particular, it is well-established that the stress of exercise provides a powerful stimulus that can trigger transient or enduring changes to mitochondrial molecular features, activities, integrated functions, behaviors, and cell-dependent mitochondrial phenotypes. Evidence documenting the many beneficial mitochondrial adaptations to exercise has led to the notion of exercise as a mitochondrial medicine. However, as with other medicines, it is important to understand the optimal prescription (i.e., type, dose, frequency, duration). In this review, we build on a systematic biological framework that distinguishes between domains of mitochondrial biology to critically evaluate how different exercise prescription variables influence mitochondrial adaptations to training.

DOI: https://doi.org/10.1146/annurev-physiol-022724-104836

Orphanet J Rare Dis. 2024 Dec 19. 19(1): 467

Multi-stakeholder sessions on major innovation topics in rare disease clinical trials.

Daniel Bodden, Stefanie Schoenen, Stephanie Wied, Johan Verbeeck, Maya Dirani, Hiba Abou Daya, Nicole Heussen, Geert Molenberghs, Ralf-Dieter Hilgers, Rima Nabbout.

BACKGROUND: The European Joint Programme on Rare Diseases aims to enhance the rare diseases research ecosystem by bringing together stakeholders such as research funders, institutions and patient organizations. Work Package 20 focuses on the validation, use and development of innovative methodologies for rare disease clinical trials. This paper reports on the outcomes of a retreat held in April 2023, where areas for innovation and educational needs in rare disease clinical trials were discussed in multi-stakeholder sessions.
METHODS: Multi-stakeholder sessions covered the topics: Future Educational System, Randomization in Rare Disease Clinical Trials, Endpoints in Rare Disease Clinical Trials and Using History Course Data. The sessions began with expert presentations to set the scene, followed by guided discussions facilitated by questions on a collaborative digital whiteboard. Participants wrote responses, which were then discussed live with the experts.
RESULTS: Training is needed for diverse stakeholders in rare disease clinical trials to enhance understanding and drive innovation. Challenges include a lack of standardized terminology for multiple endpoints, inadequate understanding of randomization in small sample studies and various obstacles in effectively using natural history data.
CONCLUSION: Creating a comprehensive and sustainable educational program for rare diseases clinical trial methodology requires strategic collaboration and adherence to FAIR principles. The workshop highlighted the need for innovations for topics in areas such as handling missing data, optimizing the extraction of information from small samples, remote endpoint measurement and new randomized inference techniques. Additionally, integrating innovations into tailored training programs is crucial for advancing the field.

Keywords: Educational system; Finite populations; Multiple endpoints; Natural history; Randomization

DOI: https://doi.org/10.1186/s13023-024-03482-6