bims-curels 2024-01-07 papers

Issue of 2024–01–07
eight papers selected by
Cure Mito Foundation

J Inherit Metab Dis. 2024 Jan 03.

Gene therapy for mitochondrial disorders.

Nandaki Keshavan, Michal Minczuk, Carlo Viscomi, Shamima Rahman.

In this review, we detail the current state of application of gene therapy to primary mitochondrial disorders (PMDs). Recombinant adeno-associated virus-based (rAAV) gene replacement approaches for nuclear gene disorders have been undertaken successfully in more than ten preclinical mouse models of PMDs which has been made possible by the development of novel rAAV technologies that achieve more efficient organ targeting. So far, however, the greatest progress has been made for Leber Hereditary Optic Neuropathy, for which phase 3 clinical trials of lenadogene nolparvovec demonstrated efficacy and good tolerability. Other methods of treating mitochondrial DNA (mtDNA) disorders have also had traction, including refinements to nucleases that degrade mtDNA molecules with pathogenic variants, including transcription activator-like effector nucleases, zinc-finger nucleases, and meganucleases (mitoARCUS). rAAV-based approaches have been used successfully to deliver these nucleases in vivo in mice. Exciting developments in CRISPR-Cas9 gene editing technology have achieved in vivo gene editing in mouse models of PMDs due to nuclear gene defects and new CRISPR-free gene editing approaches have shown great potential for therapeutic application in mtDNA disorders. We conclude the review by discussing the challenges of translating gene therapy in patients both from the point of view of achieving adequate organ transduction as well as clinical trial design.

Keywords: AAV; CRISPR; LHON; gene editing; gene therapy; mitochondrial disease

DOI: https://doi.org/10.1002/jimd.12699

EMBO J. 2024 Jan 02.

Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.

Zhan Yin, Ahmed-Noor A Agip, Hannah R Bridges, Judy Hirst.

Respiratory complex I (NADH:ubiquinone oxidoreductase) is essential for cellular energy production and NAD+ homeostasis. Complex I mutations cause neuromuscular, mitochondrial diseases, such as Leigh Syndrome, but their molecular-level consequences remain poorly understood. Here, we use a popular complex I-linked mitochondrial disease model, the ndufs4-/- mouse, to define the structural, biochemical, and functional consequences of the absence of subunit NDUFS4. Cryo-EM analyses of the complex I from ndufs4-/- mouse hearts revealed a loose association of the NADH-dehydrogenase module, and discrete classes containing either assembly factor NDUFAF2 or subunit NDUFS6. Subunit NDUFA12, which replaces its paralogue NDUFAF2 in mature complex I, is absent from all classes, compounding the deletion of NDUFS4 and preventing maturation of an NDUFS4-free enzyme. We propose that NDUFAF2 recruits the NADH-dehydrogenase module during assembly of the complex. Taken together, the findings provide new molecular-level understanding of the ndufs4-/- mouse model and complex I-linked mitochondrial disease.

Keywords: Complex I; Cryo-EM; Leigh Syndrome; Mitochondria; NADH:Ubiquinone Oxidoreductase

DOI: https://doi.org/10.1038/s44318-023-00001-4

Heliyon. 2024 Jan 15. 10(1): e23137

A case of Leigh syndrome presented with paroxysmal body swing.

Jia Zhang, Jing Gan, Jianjun Wang.

Background: Leigh syndrome (LS) is a heterogeneous neurodegenerative disease that is the most common manifestation of mitochondrial disease in children.
Methods: We report a case of Leigh syndrome with paroxysmal body swing in a 1-year-old boy.
Results: The boy presented with paroxysmal body swing, and the electroencephalogram showed no epileptic discharge during the paroxysmal episode. It was determined to be a nonepileptic seizure, which was the first LS phenotype described. After treatment with a vitamin cocktail, the paroxysmal body swing improved.
Conclusion: LS should be considered for children with onset of infantile and paroxysmal body swing combined with developmental regression, and early mitochondrial genetic testing can aid in diagnosis and guide early intervention.

Keywords: Leigh syndrome; MT-ND5; Paroxysmal episode; de novo

DOI: https://doi.org/10.1016/j.heliyon.2023.e23137

Res Involv Engagem. 2024 Jan 03. 10(1): 3

Recommendations for successful involvement of patient partners in complex intervention research: a collaborative learning process.

Pernille Christiansen Skovlund, Jeanette Finderup, Sanne Aabo, Flemming Jensen, Henning Søndergaard, Lotte Ørneborg Rodkjær.

BACKGROUND: Patient and public involvement in health-related research is a new discipline in Denmark. In 2021, a national conference titled 'Patient and Public Involvement in Complex Intervention Research' provided a forum for discussion between patient partners, researchers and clinicians on involving patients as partners in complex intervention research.
METHODS: We aimed to describe specific challenges to and initiatives for patient partner involvement in order to develop recommendations for creating successful partnerships in complex intervention research. Through a collaborative learning process, 140 researchers identified the most important challenges for them in patient partner involvement and potential initiatives to improve such involvement. At a subsequent workshop, four patient partners identified the challenges and initiatives from their perspective as patient partners. They also gave feedback on the challenges and initiatives suggested by the researchers and helped shape three recommendations for practice. Three of the patient partners were involved in writing this paper.
RESULTS: The five most important challenges identified by researchers were time, recruitment, ethics, power and inequality. Between four and seven initiatives to overcome these challenges were suggested. The three most important challenges identified by patient partners were communication, when you get information that is hard to handle and recruitment. They suggested three to four initiatives for improvement. Patient partners confirmed the importance of all the researcher identified challenges when presented with them, they also provided additional comments on the researchers' initiatives. This led to the formation of recommendations for involving patient partners.
CONCLUSIONS: A collaborative learning process was shown to be a suitable method for patient partner involvement. Consistency was seen between the challenges and initiatives identified by researchers and patient partners. Based on these observations, three recommendations were developed: (1) create specific programmes that aim to involve all kind of patients (including but limited to vulnerable patients) as patient partners, (2) produce ethical guidelines for the involvement of patient partners, and (3) develop a national strategy for patient partner involvement. To build on these recommendations, a joint workshop with both researchers and patient partners is needed.

Keywords: Challenges; Collaborative learning process; Initiatives; Patient partners; Recommendations; Workshops

DOI: https://doi.org/10.1186/s40900-023-00533-3

Res Involv Engagem. 2024 Jan 02. 10(1): 1

Patient engagement in clinical trial design for rare neuromuscular disorders: impact on the DELIVER and ACHIEVE clinical trials.

Patricia Furlong, Ashish Dugar, Molly White.

BACKGROUND: Engaging individuals living with disease in drug development and regulatory processes leads to more thoughtful and sensitive trial designs, drives more informative and meaningful outcomes from clinical studies, and builds trust between the public, government, and industry stakeholders. This engagement is especially important in the case of rare diseases, where affected individuals and their families face many difficulties getting information, treatment, and support. Dyne Therapeutics is developing therapeutics for people with genetically-driven muscle diseases. During the development of potential treatments for Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1), Dyne sought the opinions of individuals living with these diseases to inform its clinical trial design and to decrease the difficulties that participants and families might experience participating in them.
METHODS: Dyne engaged individuals and families living with DMD and DM1 as expert partners in its clinical development programs. Dyne convened panels of affected individuals and care partners/parents of individuals living with DMD (n = 8) or DM1 (n = 18). Workshops focused on how affected individuals and their families evaluate and select clinical trials for participation, the importance, quality, and burden associated with individual trial design elements, participation considerations such as site location and the study visit design, patient privacy, the suitability and scope of travel and participant support programs, and the accessibility of content in the informed consent (or assent) forms. Dyne also engaged the DMD Community Advisory Board (CAB) to collect feedback and advice on designing optimal and meaningful clinical trials and measuring relevant outcomes.
RESULTS: The issues most important to individuals living with DM1 and DMD regarding clinical trials were the ability to participate/access to the trial, perceptions of benefit and risk of trials and potential treatments, the flexibility of participation, clear communication from the sponsor, availability of information from trusted sources, and patient enrollment. In response to the patient advisory workshops and CAB feedback, Dyne refined clinical trial inclusion/exclusion criteria and clinic visit design, developed a travel service program to address the burden of clinical trial travel and enable long-distance and cross-border participation, planned for home visits when feasible, and allowed for adequate rest before clinic visit initiation and between assessments. Additionally, Dyne developed and implemented a transparent and consistent communications plan (including age-appropriate content) for trial participants and community members, and assessed and adjusted procedures to provide maximum participant comfort and lower anxiety, particularly with younger participants.
CONCLUSIONS: Ongoing communication with the Duchenne CAB and with DMD and DM1 patient advisory committee members allows Dyne to stay current with disease community perspectives and feedback on the needs and preferences of those affected and has provided valuable insights into the participant experience thereby helping Dyne initiate clinical trials that better meet the needs of affected individuals and their families.

Keywords: Duchenne muscular dystrophy; Myotonic dystrophy; Patient and public involvement; Patient-focused drug development

DOI: https://doi.org/10.1186/s40900-023-00535-1

Neurology. 2024 Jan 09. 102(1): e207958

FDA Patient-Focused Drug Development Guidances.

Anne T Berg, Natasha N Ludwig, Mary Wojnaroski, Chere A T Chapman, Rebecca Hommer, Gabrielle Conecker, JayEtta Z Hecker, Jenny Downs.

Developmental and epileptic encephalopathies (DEE) are rare, often monogenic neurodevelopmental conditions. Most affected individuals have refractory seizures. All have multiple severe impairments which can be as life-limiting as or more limiting than the seizures themselves. Mechanism- and gene-targeted therapies for these individually rare, genetic conditions hold hope for treatment, amelioration of disease expression, and even cure. The near absence of fit-for-purpose (FFP) clinical outcome assessments (COA) to establish the benefits for nonseizure outcomes of these new therapies in clinical trials poses significant challenges to drug development. The Food and Drug Administration Patient-Focused Drug Development guidance series provides direction for how to overcome these challenges and to ensure FFP measures are available for trials. The goal is to have measures that address outcomes of importance to patients and caregivers, reliably and accurately measure the outcome in the spectrum of abilities for the target disease, and are sensitive to meaningful change over time. The guidances identify 3 primary strategies: (1) directly adopting and implementing available outcome measures; (2) creating measures de novo; and (3) a middle path of adapting or modifying existing measures. Emphasized throughout the guidances is the indispensable and extensive role of the patient or caregiver to assuring the goal of having fit measures is achieved. This review specifically considers the difficulties of adopting available COAs in severely impaired patient groups and ways to adapt or modify existing COAs to be FFP as encouraged in the guidances. Adaptations include alternative scoring, use of assessments in out-of-intended age ranges, and modifications for individuals with sensory or motor impairments. Some additional considerations that may facilitate achieving adequate clinical outcome measures, especially for rare diseases, include use of personalized endpoints, merging of existing COAs, and developing a consortium of rare DEE advocates and researchers to ensure fitness of adapted COAs across multiple rare disease groups. The FDA guidances help ensure that clinical trials targeting nonseizure outcomes, especially in severely impaired populations, will have adequately valid and sensitive outcome measures. This in turn will strengthen the ability of trials to provide informative tests of whether treatments provide meaningful therapeutic efficacy.

DOI: https://doi.org/10.1212/WNL.0000000000207958

BMB Rep. 2024 Jan 05. pii: 6125. [Epub ahead of print]

Mitochondrial genome editing: strategies, challenges, and applications.

Kayeong Lim.

Mitochondrial DNA (mtDNA), a multicopy genome found in mitochondria, is crucial for oxidative phosphorylation. Mutations in mtDNA can lead to severe mitochondrial dysfunction in tissues and organs with high energy demand. MtDNA mutations are closely associated with mitochondrial and age-related disease. To better understand the functional role of mtDNA and work toward developing therapeutics, it is essential to advance technology that is capable of manipulating the mitochondrial genome. This review discusses ongoing efforts in mitochondrial genome editing with mtDNA nucleases and base editors, including the tools, delivery strategies, and applications. Future advances in mitochondrial genome editing to address challenges regarding their efficiency and specificity can achieve the promise of therapeutic genome editing.

Neurol India. 2023 Nov-Dec;71(6):71(6): 1192-1196

Clinical Spectrum of Biopsy Proven Mitochondrial Myopathy.

Deepak Menon, Sruthi S Nair, Neelima Radhakrishnan, Udit Umesh Saraf, Muralidharan Nair.

Objectives: Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant, clinical data on predominant myopathic presentation of mitochondrial disorders are lacking.
Materials and Methods: Clinical, electrophysiological, biochemical, and follow-up data of patients with predominant myopathic presentation and muscle biopsy confirmed primary mitochondrial myopathy was obtained. We excluded known syndromes of mitochondrial cytopathies and encephalomyopathies.
Results: Among 16 patients, 7 had CPEO, 4 had CPEO with limb-girdle muscle weakness (LGMW), and 5 had isolated LGMW. Systemic features included seizures with photosensitivity (n = 3), diabetes (n = 1), cardiomyopathy (n = 1), and sensorineural hearing loss (n = 1) and were more common in isolated LGMW. Elevated serum creatine kinase (CK) and lactate levels and electromyography (EMG) myopathic potentials were more frequent with LGMW. During follow-up, LGMW had more severe progression of weakness.
Conclusion: We identified three subsets of mitochondrial myopathy with distinct clinical features and evolutionary patterns. Isolated LGMW was seen in 30% of patients and would represent severe end of the spectrum.

Keywords: Chronic progressive external ophthalmoplegia; limb-girdle muscle weakness; mitochondrial myopathy; muscle biopsy; photosensitive epilepsy

DOI: https://doi.org/10.4103/0028-3886.391399