Trends in Mitochondrial Therapeutics for Neurological Disease
Autor(a) principal: | |
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Data de Publicação: | 2015 |
Outros Autores: | , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/10216/105022 |
Resumo: | Neuronal homeostasis is critically dependent on healthy mitochondria. Mutations in mitochondrial DNA (mtDNA), in nuclear-encoded mitochondrial components, and age-dependent mitochondrial damage, have all been connected with neurological disorders. These in clude not only typical mitochondrial syndromes with neurological features such as encephalomyopathy, myoclonic epilepsy, neuropathy and ataxia; but also secondary mitochondrial involvement in neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. Unravelling the molecular aetiology of mitochondrial dysfunction opens new therapeutic prospects for diseases thus far lacking effective treatments. In this review we address recent advances on preventive strategies, such as pronuclear, spindle-chromosome complex, or polar body genome transfer to replace mtDNA and avoid disease transmission to newborns; we also address experimental mitochondrial therapeutics aiming to benefit symptomatic patients and prevent disease manifestation in those at risk. Specifically, we focus on: (1) gene therapy to reduce mutant mtDNA, such as anti-replicative therapies and mitochondria-targeted nucleases allowing favourable heteroplasmic shifts; (2) allotopic expression of recoded wild-type mitochondrial genes, including targeted tRNAs and xenotopic expression of cognate genes to compensate for pathogenic mutations; (3) mitochondria targeted-peptides and lipophilic cations for in vivo delivery of antioxidants or other putative therapeutics; and (4) modulation of mitochondrial dynamics at the level of biogenesis, fission, fusion, movement and mitophagy. Further advances in therapeutic development are hindered by scarce in vivo models for mitochondrial disease, with the bulk of available data coming from cellular models. Nevertheless, wherever available, we also address data from in vivo experiments and clinical trials, focusing on neurological disease models. |
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Trends in Mitochondrial Therapeutics for Neurological DiseaseMedicina básicaBasic medicineNeuronal homeostasis is critically dependent on healthy mitochondria. Mutations in mitochondrial DNA (mtDNA), in nuclear-encoded mitochondrial components, and age-dependent mitochondrial damage, have all been connected with neurological disorders. These in clude not only typical mitochondrial syndromes with neurological features such as encephalomyopathy, myoclonic epilepsy, neuropathy and ataxia; but also secondary mitochondrial involvement in neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. Unravelling the molecular aetiology of mitochondrial dysfunction opens new therapeutic prospects for diseases thus far lacking effective treatments. In this review we address recent advances on preventive strategies, such as pronuclear, spindle-chromosome complex, or polar body genome transfer to replace mtDNA and avoid disease transmission to newborns; we also address experimental mitochondrial therapeutics aiming to benefit symptomatic patients and prevent disease manifestation in those at risk. Specifically, we focus on: (1) gene therapy to reduce mutant mtDNA, such as anti-replicative therapies and mitochondria-targeted nucleases allowing favourable heteroplasmic shifts; (2) allotopic expression of recoded wild-type mitochondrial genes, including targeted tRNAs and xenotopic expression of cognate genes to compensate for pathogenic mutations; (3) mitochondria targeted-peptides and lipophilic cations for in vivo delivery of antioxidants or other putative therapeutics; and (4) modulation of mitochondrial dynamics at the level of biogenesis, fission, fusion, movement and mitophagy. Further advances in therapeutic development are hindered by scarce in vivo models for mitochondrial disease, with the bulk of available data coming from cellular models. Nevertheless, wherever available, we also address data from in vivo experiments and clinical trials, focusing on neurological disease models.20152015-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10216/105022eng0929-8673Ana Leitao RochaPedro Guedes DiasBrigida R PinhoJorge M A Oliveirainfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-29T13:08:22Zoai:repositorio-aberto.up.pt:10216/105022Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T23:34:20.901637Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Trends in Mitochondrial Therapeutics for Neurological Disease |
title |
Trends in Mitochondrial Therapeutics for Neurological Disease |
spellingShingle |
Trends in Mitochondrial Therapeutics for Neurological Disease Ana Leitao Rocha Medicina básica Basic medicine |
title_short |
Trends in Mitochondrial Therapeutics for Neurological Disease |
title_full |
Trends in Mitochondrial Therapeutics for Neurological Disease |
title_fullStr |
Trends in Mitochondrial Therapeutics for Neurological Disease |
title_full_unstemmed |
Trends in Mitochondrial Therapeutics for Neurological Disease |
title_sort |
Trends in Mitochondrial Therapeutics for Neurological Disease |
author |
Ana Leitao Rocha |
author_facet |
Ana Leitao Rocha Pedro Guedes Dias Brigida R Pinho Jorge M A Oliveira |
author_role |
author |
author2 |
Pedro Guedes Dias Brigida R Pinho Jorge M A Oliveira |
author2_role |
author author author |
dc.contributor.author.fl_str_mv |
Ana Leitao Rocha Pedro Guedes Dias Brigida R Pinho Jorge M A Oliveira |
dc.subject.por.fl_str_mv |
Medicina básica Basic medicine |
topic |
Medicina básica Basic medicine |
description |
Neuronal homeostasis is critically dependent on healthy mitochondria. Mutations in mitochondrial DNA (mtDNA), in nuclear-encoded mitochondrial components, and age-dependent mitochondrial damage, have all been connected with neurological disorders. These in clude not only typical mitochondrial syndromes with neurological features such as encephalomyopathy, myoclonic epilepsy, neuropathy and ataxia; but also secondary mitochondrial involvement in neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. Unravelling the molecular aetiology of mitochondrial dysfunction opens new therapeutic prospects for diseases thus far lacking effective treatments. In this review we address recent advances on preventive strategies, such as pronuclear, spindle-chromosome complex, or polar body genome transfer to replace mtDNA and avoid disease transmission to newborns; we also address experimental mitochondrial therapeutics aiming to benefit symptomatic patients and prevent disease manifestation in those at risk. Specifically, we focus on: (1) gene therapy to reduce mutant mtDNA, such as anti-replicative therapies and mitochondria-targeted nucleases allowing favourable heteroplasmic shifts; (2) allotopic expression of recoded wild-type mitochondrial genes, including targeted tRNAs and xenotopic expression of cognate genes to compensate for pathogenic mutations; (3) mitochondria targeted-peptides and lipophilic cations for in vivo delivery of antioxidants or other putative therapeutics; and (4) modulation of mitochondrial dynamics at the level of biogenesis, fission, fusion, movement and mitophagy. Further advances in therapeutic development are hindered by scarce in vivo models for mitochondrial disease, with the bulk of available data coming from cellular models. Nevertheless, wherever available, we also address data from in vivo experiments and clinical trials, focusing on neurological disease models. |
publishDate |
2015 |
dc.date.none.fl_str_mv |
2015 2015-01-01T00:00:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
dc.identifier.uri.fl_str_mv |
https://hdl.handle.net/10216/105022 |
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https://hdl.handle.net/10216/105022 |
dc.language.iso.fl_str_mv |
eng |
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eng |
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0929-8673 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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