The special considerations of gene therapy for mitochondrial diseases

Slone, Jesse; Huang, Taosheng

doi:10.1038/s41525-020-0116-5

Cited by 46 publications

(36 citation statements)

References 76 publications

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“…Mitochondrial disorders are largely treated symptomatically [80]. Gene therapy represents a promising treatment option for mitochondrial disease; however, a number of challenges are faced including multi-organ involvement, crossing the blood brain barrier, import of proteins into the matrix and the ethical justification of mitochondrial replacement therapy [81]. Here we discuss the consequence of mutation in genes involved in mitochondrial import (summarised in Table 1).…”

Section: Mitochondrial Disease As a Consequence Of Dysfunctional Protmentioning

confidence: 99%

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

2021

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The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction in this fundamental cellular process is linked to a variety of pathologies including neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancer, demonstrating the importance of mitochondrial protein import machinery for cellular function. Correct import of proteins into mitochondria requires the co‐ordinated activity of multimeric protein translocation and sorting machineries located in both the outer and inner mitochondrial membranes, directing the imported proteins to the destined mitochondrial compartment. This dynamic process maintains cellular homeostasis, and its dysregulation significantly affects cellular signalling pathways and metabolism. This review summarises current knowledge of the mammalian mitochondrial import machinery and the pathological consequences of mutation of its components. In addition, we will discuss the role of mitochondrial import in cancer, and our current understanding of the role of mitochondrial import in neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease.

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Section: Mitochondrial Disease As a Consequence Of Dysfunctional Protmentioning

confidence: 99%

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

2021

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“…Currently, old (e.g., antioxidants) and new molecules (e.g., sirtuin activators) are being tested (see discussion below). Finally, and importantly, gene therapy as the ultimate tool to manage primary mitochondrial genetic diseases is actively pursued, albeit encountering great difficulties due to specific biological properties of the mitochondria that complicate genetic manipulation and the methods needed for targeted mitochondrial delivery 107 …”

Section: Targeting the Mitochondriamentioning

confidence: 99%

Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications

Manolis¹,

Manolis

et al. 2020

Medicinal Research Reviews

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Mitochondria provide energy to the cell during aerobic respiration by supplying ~95% of the adenosine triphosphate (ATP) molecules via oxidative phosphorylation. These organelles have various other functions, all carried out by numerous proteins, with the majority of them being encoded by nuclear DNA (nDNA). Mitochondria occupy ~1/3 of the volume of myocardial cells in adults, and function at levels of high‐efficiency to promptly meet the energy requirements of the myocardial contractile units. Mitochondria have their own DNA (mtDNA), which contains 37 genes and is maternally inherited. Over the last several years, a variety of functions of these organelles have been discovered and this has led to a growing interest in their involvement in various diseases, including cardiovascular (CV) diseases. Mitochondrial dysfunction relates to the status where mitochondria cannot meet the demands of a cell for ATP and there is an enhanced formation of reactive‐oxygen species. This dysfunction may occur as a result of mtDNA and/or nDNA mutations, but also as a response to aging and various disease and environmental stresses, leading to the development of cardiomyopathies and other CV diseases. Designing mitochondria‐targeted therapeutic strategies aiming to maintain or restore mitochondrial function has been a great challenge as a result of variable responses according to the etiology of the disorder. There have been several preclinical data on such therapies, but clinical studies are scarce. A major challenge relates to the techniques needed to eclectically deliver the therapeutic agents to cardiac tissues and to damaged mitochondria for successful clinical outcomes. All these issues and progress made over the last several years are herein reviewed.

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“…Recently, besides recent trials which evaluated the potential therapeutic effects of idebenone in LHON [ 9 , 10 ], there is also a great interest in the new possibilities offered by mitochondrial biogenesis [ 77 ]. Gene therapy is mainly focused on the prevention of mtDNA related syndromes through the elimination of mutated mtDNA from oocytes [ 78 ], and the systemic or local administration of vectors to restore mitochondrial functionality [ 79 ].…”

Section: Resultsmentioning

confidence: 99%

Therapeutical Management and Drug Safety in Mitochondrial Diseases—Update 2020

Gruosso

Montano

Simoncini

et al. 2020

JCM

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Mitochondrial diseases (MDs) are a group of genetic disorders that may manifest with vast clinical heterogeneity in childhood or adulthood. These diseases are characterized by dysfunctional mitochondria and oxidative phosphorylation deficiency. Patients are usually treated with supportive and symptomatic therapies due to the absence of a specific disease-modifying therapy. Management of patients with MDs is based on different therapeutical strategies, particularly the early treatment of organ-specific complications and the avoidance of catabolic stressors or toxic medication. In this review, we discuss the therapeutic management of MDs, supported by a revision of the literature, and provide an overview of the drugs that should be either avoided or carefully used both for the specific treatment of MDs and for the management of comorbidities these subjects may manifest. We finally discuss the latest therapies approved for the management of MDs and some ongoing clinical trials.

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The special considerations of gene therapy for mitochondrial diseases

Cited by 46 publications

References 76 publications

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications

Therapeutical Management and Drug Safety in Mitochondrial Diseases—Update 2020

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