Treatment for mitochondrial diseases

Liufu, Tongling; Wang, Zhao-xia

doi:10.1515/revneuro-2020-0034

Cited by 15 publications

(10 citation statements)

References 42 publications

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“…A number of case-studies have described mitochondrial diseases, however, consensus on the diagnosis and treatment of mitochondrial disease continues to be elusive. The Mitochondrial Medicine Society published guidelines in 2015 [31], but importantly, no FDA approved therapies are available for the treatment of mitochondrial disease [46]. Current treatment recommendations are supportive in nature.…”

Section: Modeling Mitochondrial Diseasementioning

confidence: 99%

Gaining Insight into Mitochondrial Genetic Variation and Downstream Pathophysiology: What Can i(PSCs) Do?

Moreira

Gopal

Kotton

et al. 2021

Genes

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Mitochondria are specialized organelles involved in energy production that have retained their own genome throughout evolutionary history. The mitochondrial genome (mtDNA) is maternally inherited and requires coordinated regulation with nuclear genes to produce functional enzyme complexes that drive energy production. Each mitochondrion contains 5-10 copies of mtDNA and consequently, each cell has several hundreds to thousands of mtDNAs. Due to the presence of multiple copies of mtDNA in a mitochondrion, mtDNAs with different variants may co-exist, a condition called heteroplasmy. Heteroplasmic variants can be clonally expanded, even in post-mitotic cells, as replication of mtDNA is not tied to the cell-division cycle. Heteroplasmic variants can also segregate during germ cell formation, underlying the inheritance of some mitochondrial mutations. Moreover, the uneven segregation of heteroplasmic variants is thought to underlie the heterogeneity of mitochondrial variation across adult tissues and resultant differences in the clinical presentation of mitochondrial disease. Until recently, however, the mechanisms mediating the relation between mitochondrial genetic variation and disease remained a mystery, largely due to difficulties in modeling human mitochondrial genetic variation and diseases. The advent of induced pluripotent stem cells (iPSCs) and targeted gene editing of the nuclear, and more recently mitochondrial, genomes now provides the ability to dissect how genetic variation in mitochondrial genes alter cellular function across a variety of human tissue types. This review will examine the origins of mitochondrial heteroplasmic variation and propagation, and the tools used to model mitochondrial genetic diseases. Additionally, we discuss how iPSC technologies represent an opportunity to advance our understanding of human mitochondrial genetics in disease.

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Section: Modeling Mitochondrial Diseasementioning

confidence: 99%

Gaining Insight into Mitochondrial Genetic Variation and Downstream Pathophysiology: What Can i(PSCs) Do?

Moreira

Gopal

Kotton

et al. 2021

Genes

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“…The lack of mtDNA quality control and repair systems leads to the assumption that "allotopic expression" of mtDNA can be an approach in treating mitochondrial dysfunction [110]. The term "allotopic" means that mtDNA-encoded genes are either transiently expressed in the nucleus or permanently inserted in the non-coding regions of the nuclear genome [111]. In general, the allotopic expression strategy was developed to treat pri-mary mitochondrial diseases caused by mtDNA mutations.…”

Section: Allotopic Expression Of Mtdna-encoded Mitochondrial Genesmentioning

confidence: 99%

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

Prasuhn

Brüggemann

2021

Genes

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Background: Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches. Methods: This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome. Results: Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future. Conclusions: Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies.

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“…Furthermore, there is no evidence of an approved gene therapy or ASO aimed at restoring the functionality of mitochondrial proteins. Up-to-date details on conducted or ongoing clinical trials are reported in the recent reviews of Liufu et al [ 309 ], Almannai et al [ 254 ], Tinker et al [ 310 ], and Pitceathly et al [ 311 ]. Many innovative therapeutic treatments are being developed in order to have targeted therapies for each type of NMD that take into account the history and progression of the disease.…”

Section: Diagnosis and Treatmentsmentioning

confidence: 99%

An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases

et al. 2021

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Neuromuscular diseases (NMDs) are dysfunctions that involve skeletal muscle and cause incorrect communication between the nerves and muscles. The specific causes of NMDs are not well known, but most of them are caused by genetic mutations. NMDs are generally progressive and entail muscle weakness and fatigue. Muscular impairments can differ in onset, severity, prognosis, and phenotype. A multitude of possible injury sites can make diagnosis of NMDs difficult. Mitochondria are crucial for cellular homeostasis and are involved in various metabolic pathways; for this reason, their dysfunction can lead to the development of different pathologies, including NMDs. Most NMDs due to mitochondrial dysfunction have been associated with mutations of genes involved in mitochondrial biogenesis and metabolism. This review is focused on some mitochondrial routes such as the TCA cycle, OXPHOS, and β-oxidation, recently found to be altered in NMDs. Particular attention is given to the alterations found in some genes encoding mitochondrial carriers, proteins of the inner mitochondrial membrane able to exchange metabolites between mitochondria and the cytosol. Briefly, we discuss possible strategies used to diagnose NMDs and therapies able to promote patient outcome.

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Treatment for mitochondrial diseases

Cited by 15 publications

References 42 publications

Gaining Insight into Mitochondrial Genetic Variation and Downstream Pathophysiology: What Can i(PSCs) Do?

Gaining Insight into Mitochondrial Genetic Variation and Downstream Pathophysiology: What Can i(PSCs) Do?

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases

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