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An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model
Published on: March 9, 2022
Moving towards clinical trials for mitochondrial diseases
Robert D S Pitceathly1, Nandaki Keshavan2,3, Joyeeta Rahman2
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
Abstract:
Primary mitochondrial diseases represent some of the most common and severe inherited metabolic disorders, affecting ~1 in 4,300 live births. The clinical and molecular diversity typified by mitochondrial diseases has contributed to the lack of licensed disease-modifying therapies available. Management for the majority of patients is primarily supportive. The failure of clinical trials in mitochondrial diseases partly relates to the inefficacy of the compounds studied. However, it is also likely to be a consequence of the significant challenges faced by clinicians and researchers when designing trials for these disorders, which have historically been hampered by a lack of natural history data, biomarkers and outcome measures to detect a treatment effect. Encouragingly, over the past decade there have been significant advances in therapy development for mitochondrial diseases, with many small molecules now transitioning from preclinical to early phase human interventional studies. In this review, we present the treatments and management strategies currently available to people with mitochondrial disease. We evaluate the challenges and potential solutions to trial design and highlight the emerging pharmacological and genetic strategies that are moving from the laboratory to clinical trials for this group of disorders.
Insights
Primary mitochondrial diseases are severe inherited metabolic disorders lacking approved therapies. Recent advances show promise with new drug and genetic strategies moving into clinical trials for better treatment options.
Area of Science:
- Biochemistry
- Genetics
- Clinical Medicine
Background:
- Primary mitochondrial diseases are common, severe inherited metabolic disorders affecting ~1 in 4,300 live births.
- Current management is largely supportive due to clinical and molecular diversity and a lack of disease-modifying therapies.
- Clinical trials have faced challenges including ineffective compounds, limited natural history data, and a lack of biomarkers and outcome measures.
Purpose of the Study:
- To review current treatments and management strategies for mitochondrial diseases.
- To evaluate challenges and propose solutions for clinical trial design in mitochondrial diseases.
- To highlight emerging pharmacological and genetic therapies progressing to clinical trials.
Main Methods:
- Literature review of current treatments and management strategies.
- Analysis of challenges and potential solutions for clinical trial design.
- Overview of preclinical and early-phase human interventional studies for novel therapies.
Main Results:
- Significant advances in therapy development over the past decade.
- Numerous small molecules are transitioning from preclinical to early-phase human studies.
- Emerging pharmacological and genetic strategies show potential for treating mitochondrial diseases.
Conclusions:
- Despite challenges, progress in therapy development for mitochondrial diseases is encouraging.
- Novel pharmacological and genetic approaches are advancing towards clinical application.
- Improved trial design, supported by better data and biomarkers, is crucial for future success.
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