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Review
. 2024 Jan;21(1):e00311.
doi: 10.1016/j.neurot.2023.e00311. Epub 2024 Jan 19.

Challenges and opportunities to bridge translational to clinical research for personalized mitochondrial medicine

Andrea L Gropman  1 , Martine N Uittenbogaard  2 , Anne E Chiaramello  3
Affiliations
Review

Challenges and opportunities to bridge translational to clinical research for personalized mitochondrial medicine

Andrea L Gropman et al. Neurotherapeutics. 2024 Jan.

Abstract

Mitochondrial disorders are a group of rare and heterogeneous genetic diseases characterized by dysfunctional mitochondria leading to deficient adenosine triphosphate synthesis and chronic energy deficit in patients. The majority of these patients exhibit a wide range of phenotypic manifestations targeting several organ systems, making their clinical diagnosis and management challenging. Bridging translational to clinical research is crucial for improving the early diagnosis and prognosis of these intractable mitochondrial disorders and for discovering novel therapeutic drug candidates and modalities. This review provides the current state of clinical testing in mitochondrial disorders, discusses the challenges and opportunities for converting basic discoveries into clinical settings, explores the most suited patient-centric approaches to harness the extraordinary heterogeneity among patients affected by the same primary mitochondrial disorder, and describes the current outlook of clinical trials.

Keywords: Clinical trial; Energy metabolism; Mitochondrial medicine; Next generation therapeutics; Patient-centric approach.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anne Chiaramello (Corresponding author) and Andrea Gropman (co-author) reports financial support was provided by National Institutes of Health, National Center for Advancing Translational Sciences. Anne Chiaramello reports financial support was provided by U.S. Department of Defense.

Figures

Fig. 1
Fig. 1
General pipeline from translational to clinical research for primary mitochondrial disorders. The left column illustrates recruitment of family members suspected of an inherited primary mitochondrial disorder for a skin biopsy to derive dermal fibroblasts that are used for genetic testing and determination of the heteroplasmic levels for mitochondrial pathogenic variants. In the absence of animal models for mtDNA variants, patient-derived cells are used to determine: 1) mitochondrial signature via investigations of OXPHOS metabolism and mitochondrial homeostasis; 2) comprehensive omics-based investigations; 3) high-throughput drug screening to identify potential drug candidates and OXPHOS and omics-derived biomarkers; 4) Phase 1 of clinical trials to assess safety of drug candidates; 5) Phases II and III to assess efficacy of the tested drug candidate and to validate biomarkers and end-points; and 6) FDA approval of the drug product for therapeutic modality.
Fig. 2
Fig. 2
Pipeline for clinical and genetic diagnoses of patients suspected of a primary mitochondrial disease. A schematic representation of a patient harboring a mixed mitochondrial population with healthy (blue) mitochondrial and diseased (red) mitochondria, which varies among different organs giving rise to heterogeneous neurological and non-neurological symptoms. Beneath is indicated the diagnostic workflow for intertwined and comprehensive clinical and genetic investigations.
Fig. 3
Fig. 3
Various nutraceutical-based interventions and drug candidates tested in clinical trials to stimulate mitochondrial biogenesis in patients with primary mitochondrial disorders. This schematic illustration only summarizes the most relevant types of interventions. A mitochondrion is shown in blue, while the nucleus is shown in purple. The cytoplasm is indicated in orange. The electron chain transfer is illustrated in green with the five multisubunit complexes of the OXPHOS pathway (CI, CII, CIII, CIV, and CV). The supplement L-carnitine is represented by a yellow circle with its role in the translocation of long chain fatty acids into the mitochondrial matrix to promote mitochondrial bioenergetics. The three electron carriers, coenzyme Q10 (CoQ10), idebenone and EPI-743 are illustrated by colored hexagons to promote electron transport between Complex I and Complex III and between Complex II and Complex III for ATP synthesis by Complex V (ATP synthase). The taurine supplement is indicated by a yellow circle and its action on the modification of the mitochondrial tRNALeu(UUR) is illustrated in the case of MELAS due to the pathogenic mitochondrial variant shown by an x letter in mutant mtDNA in red. Wild type (WT) mtDNA is shown in black. Patients with MELAS are prescribed oral or IV arginine (yellow circle) to produce nitric oxide (NO) via the enzyme nitric oxide synthase (NOS) for increasing vasodilation of small cerebral blood vessels to diminish the severity and frequency of stroke-like episode (SLE). Citrulline (green circle) is another supplement currently tested in a clinical trial on MELAS patients based on its conversion to arginine via the intermediate argininosuccinate (light blue circle). Omaveloxolone, currently tested in phase 2 clinical trial, is illustrated by a yellow circle and its action to boost the expression levels of the nuclear factor erythroid 2-related factor 2 (NRF-2) transcription factor by preventing its degradation is shown with an arrow and a positive sign. The drug candidate REN001, indicated by a blue circle, acts as an agonist to activate the peroxisomal proliferator activated receptor delta (PPARδ), resulting in increased expression of the peroxisomal proliferator activated receptor-gamma coactivator-1α (PGC-1α) to turn on the transcriptional program of mitochondrial biogenesis and bioenergetics.
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