Effects of clofibrate and KH176 on life span and motor function in mitochondrial complex I-deficient mice

Frambach, Sanne J.C.M.; Wal, Melissa A.E. van de; Broek, P.H.H. van den; Smeitink, Jan A.M.; Rüssel, Frans G. M.; Haas, Ria de; Schirris, Tom J.J.

doi:10.1016/j.bbadis.2020.165727

Cited by 19 publications

(15 citation statements)

References 58 publications

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“…The therapeutic efficacy of KH176 was tested in preclinical models of PMD. Long-term KH176 treatment ameliorated the clinical phenotype and the brain microstructural coherence of the CI-deficient Ndufs4 ko mouse model [ 269 , 270 ]; however, no further improvement was observed with combined treatment with the PPAR agonist clofibrate [ 270 ]. A Phase 1 clinical trial in healthy adult male volunteers deemed that KH176 is well tolerated up to single doses of 800 mg and multiple doses of 400 mg b.i.d.…”

Section: “One-size-fits-all” Approachesmentioning

confidence: 99%

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

et al. 2020

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Primary mitochondrial diseases (PMD) refer to a group of severe, often inherited genetic conditions due to mutations in the mitochondrial genome or in the nuclear genes encoding for proteins involved in oxidative phosphorylation (OXPHOS). The mutations hamper the last step of aerobic metabolism, affecting the primary source of cellular ATP synthesis. Mitochondrial diseases are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. The limited information of the natural history, the limitations of currently available preclinical models, coupled with the large variability of phenotypical presentations of PMD patients, have strongly penalized the development of effective therapies. However, new therapeutic strategies have been emerging, often with promising preclinical and clinical results. Here we review the state of the art on experimental treatments for mitochondrial diseases, presenting “one-size-fits-all” approaches and precision medicine strategies. Finally, we propose novel perspective therapeutic plans, either based on preclinical studies or currently used for other genetic or metabolic diseases that could be transferred to PMD.

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Section: “One-size-fits-all” Approachesmentioning

confidence: 99%

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

et al. 2020

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“…In the Ndufs4 ‐/‐ mouse, KH176 administration improved rotarod performance and gait abnormalities with retention of the microstructural organization in some areas of the brain; KH176 treatment was neither able to reduce or prevent the severe brain pathology, nor had it tangible effects on the onset or severity of the disease, as measured by phenotypic scoring or lifespan [43]. However, recent data showed a slight, but significant, increase in the lifespan and amelioration of some gait and motor parameters in KH176‐treated Ndufs4‐/‐ mice [44].…”

Section: Generalist Strategiesmentioning

confidence: 99%

Strategies for fighting mitochondrial diseases

Viscomi

Zeviani

2020

J Intern Med

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“…Nevertheless, recent data should provide cause for optimism that in vivo models can be of benefit for preclinical drug testing. Low oxygen 55 and ppar agonists 56 have recently demonstrated efficacy on life span in the NDUFS4 KO model. Mice with defined mtDNA mutations at relevant heteroplasmic levels have been established, 57 providing excellent opportunity to test genetic approaches to heteroplasmy reduction 58,59 .…”

Section: Collaborative Need #3—target Validation/preclinical Modelingmentioning

confidence: 99%

Developing new treatments in partnership for primary mitochondrial disease: What does industry need from academics, and what do academics need from industry?

Thompson

2020

J of Inher Metab Disea

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Developing novel therapeutics for primary mitochondrial disease is likely to require significant academia-industry collaboration. Translational assessments, a tool often used in industry at target validation stage, can highlight disease specific development challenges which requires focused collaborative effort. For PMD, definition of pivotal trial populations and primary endpoints is challenging given lack of clinical precedence, high numbers of subgroups with overlapping symptoms despite common genetics. Disease pathophysiology has not been systematically assessed simultaneously with outcomes in available natural history studies, resulting in a lack of pathophysiology biomarker utilization in clinical trials. Preclinical model systems are available to assist drug development efforts, although these may require better standardization and access. Multistakeholder precompetitive efforts have been used to progress disease pathophysiology biomarker and confirmatory clinical trial endpoint readiness in neurological disease with limited treatment options, such as rare familial Parkinson's disease. This type of approach may be beneficial for PMD therapeutic development, although requires significant funding and time, supported by industry and other funding bodies. Industry expertise on chemistry, data quality and drug development know-how is available to support academic drug development efforts. A combination of industry mindset-reduction of uncertainty to provide an indication statement supportable by evidence-together with academic approach-question-based studies to understand disease mechanisms and patients-has great potential to deliver novel PMD therapeutics.

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Effects of clofibrate and KH176 on life span and motor function in mitochondrial complex I-deficient mice

Cited by 19 publications

References 58 publications

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

Strategies for fighting mitochondrial diseases

Developing new treatments in partnership for primary mitochondrial disease: What does industry need from academics, and what do academics need from industry?

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