Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective

Abstract

Mitochondrial diseases (MDs) are a group of severe genetic disorders caused by mutations in the nuclear or mitochondrial genome encoding proteins involved in the oxidative phosphorylation (OXPHOS) system. MDs have a wide range of symptoms, ranging from organ-specific to multisystemic dysfunctions, with different clinical outcomes. The lack of natural history information, the limits of currently available preclinical models, and the wide range of phenotypic presentations seen in MD patients have all hampered the development of effective therapies. The growing number of pre-clinical and clinical trials over the last decade has shown that gene therapy is a viable precision medicine option for treating MD. However, several obstacles must be overcome, including vector design, targeted tissue tropism and efficient delivery, transgene expression, and immunotoxicity. This manuscript offers a comprehensive overview of the state of the art of gene therapy in MD, addressing the main challenges, the most feasible solutions, and the future perspectives of the field.

The potential for mitochondrial therapeutics in the treatment of primary open-angle glaucoma: a review

“…As many of these mitochondria-targeted treatment modalities are in the early stages of understanding and development, administration techniques and protocols are not yet standardized to allow for consistent, effective, and specific delivery of treatment. For example, gene therapy is challenged with DNA vector design, mitotherapy is challenged with functional incorporation into target cells, stem cell therapy is challenged with induced differentiation into a specific cell line, and antioxidant therapy is challenged with subcellular delivery into mitochondria ( Tan et al, 2018 ; Zinovkin and Zamyatnin, 2019 ; Zhang et al, 2021 ; Di Donfrancesco et al, 2022 ). Therapies with more straightforward delivery methods also have concerns surrounding study design and treatment administration.…”

Mitochondrial Base Editing: Recent Advances towards Therapeutic Opportunities

“…There has been significant progress in understanding the genetics of mitochondria and the connections between gene mutations and diseases [ 2 , 83 ]. Furthermore, acquired mtDNA mutations have been linked to aging, cancer, and neurodegenerative diseases [ 15 , 84 , 85 , 86 ]. With the rapid advancement of mtDNA editing tools and related science, it is expected that this innovative technique will soon be tested in clinical settings.…”

Precision mitochondrial medicine

“…A precise genetic diagnosis enables targeted treatments such as co-enzyme Q10 and analogues in defects of ubiquinone biosynthesis (Yubero et al, 2018 ), or riboflavin supplementation in patients with SLC52A2 mutations (Cali et al, 1993 ). Several gene therapy approaches are also in development and require a precise molecular diagnosis (Di Donfrancesco et al, 2022 ). Disease gene discovery for mitochondrial disorders has also identified many molecular pathways essential for mitochondrial biogenesis and maintenance.…”