The pursuit of precision mitochondrial medicine: Harnessing preclinical cellular and animal models to optimize mitochondrial disease therapeutic discovery.
The pursuit of precision mitochondrial medicine: Harnessing preclinical cellular and animal models to optimize mitochondrial disease therapeutic discovery.
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追求精确的线粒体医学：利用临床前细胞和动物模型优化线粒体疾病的治疗发现。
DOI：
10.1002/jimd.12319
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发表时间：
2021-03
影响因子：
4.2
通讯作者：
Falk MJ
中科院分区：
文献类型：
--
作者：
Falk MJ
Mitochondria share extensive evolutionary conservation across nearly all living species. This homology allows robust insights to be gained into pathophysiologic mechanisms and therapeutic targets for the heterogeneous class of primary mitochondrial diseases through the study of diverse in vitro cellular and in vivo animal models. Dramatic advances in genetic technologies, ranging from RNA interference to achieve graded knock-down of gene expression to CRISPR/Cas-based gene editing that yields a stable gene knock-out or targeted mutation knock-in, have enabled the ready establishment of mitochondrial disease models for a plethora of individual nuclear gene disorders. These models are complemented and extended by the use of pharmacologic inhibitor-based stressors to characterize variable degrees, onset, duration, and combinations of acute on chronic mitochondrial dysfunction in individual respiratory chain enzyme complexes or distinct biochemical pathways in mitochondria. Herein is described the rationale for, and progress made in, “therapeutic cross-training”, a novel approach meant to improve the validity and rigor of experimental conclusions when testing therapies by studying treatment effects in multiple, evolutionarily-distinct species, including C. elegans (invertebrate, worm), D. rerio (vertebrate, zebrafish), M. musculus (mammal, mouse), and/or human patient primary fibroblast cell line models of primary mitochondrial disease. The goal of these pre-clinical studies is to identify lead therapies from candidate molecules or library screens that consistently demonstrate efficacy, with minimal toxicity, in specific subtypes of mitochondrial disease. Conservation of in vitro and in vivo therapeutic effects of lead molecules across species has proven extensive, where molar concentrations found to be toxic or efficacious in one species are often consistent with therapeutic effects at similar doses seen in other mitochondrial disease models. Phenotypic outcome studies in all models are prioritized at the level of survival and function, to reflect the ultimate goal of developing highly potent therapies for human mitochondrial disease. Lead compounds that demonstrate significant benefit on gross phenotypes may be further scrutinized in these same models to decipher their cellular targets, mechanism(s), and detailed biochemical effects. High-throughput, automated technologic advances will be discussed that enable efficient, parallel screening in a diverse mitochondrial disease disorders and overarching subclasses of compounds, concentrations, libraries, and combinations. Overall, this therapeutic cross-training approach has proven valuable to identify compounds with optimal potency and safety profiles among major biochemical subtypes or specific genetic etiologies of mitochondrial disease. This approach further supports rational prioritization of lead compounds, target concentrations, and specific disease phenotypes, outcomes, and subgroups to optimally inform the design of clinical trials that test their efficacy in human mitochondrial disease subjects.
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DOI：
10.1007/978-1-61779-504-6_16
发表时间：
2012
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Dingley, Stephen;Chapman, Kimberly A;Falk, Marni J
通讯作者：
Falk, Marni J
影响因子：
11.1
作者：
Falk, Marni J.;Polyak, Erzsebet;Zhang, Zhe;Peng, Min;King, Rhonda;Maltzman, Jonathan S.;Okwuego, Ezinne;Horyn, Oksana;Nakamaru-Ogiso, Eiko;Ostrovsky, Julian;Xie, Letian X.;Chen, Jia Yan;Marbois, Beth;Nissim, Itzhak;Clarke, Catherine F.;Gasser, David L.
通讯作者：
Gasser, David L.
影响因子：
9.8
作者：
Gai, Xiaowu;Ghezzi, Daniele;Zeviani, Massimo
通讯作者：
Zeviani, Massimo
影响因子：
9.2
作者：
Falk, Marni J.;Kayser, Ernst-Bernhard;Sedensky, Margaret M.
通讯作者：
Sedensky, Margaret M.
影响因子：
12.4
作者：
Connolly NMC;Theurey P;Adam-Vizi V;Bazan NG;Bernardi P;Bolaños JP;Culmsee C;Dawson VL;Deshmukh M;Duchen MR;Düssmann H;Fiskum G;Galindo MF;Hardingham GE;Hardwick JM;Jekabsons MB;Jonas EA;Jordán J;Lipton SA;Manfredi G;Mattson MP;McLaughlin B;Methner A;Murphy AN;Murphy MP;Nicholls DG;Polster BM;Pozzan T;Rizzuto R;Satrústegui J;Slack RS;Swanson RA;Swerdlow RH;Will Y;Ying Z;Joselin A;Gioran A;Moreira Pinho C;Watters O;Salvucci M;Llorente-Folch I;Park DS;Bano D;Ankarcrona M;Pizzo P;Prehn JHM
通讯作者：
Prehn JHM