Patient-derived lymphoblastoid cell lines harboring mitochondrial DNA mutations as tool for small molecule drug discovery

被引：6

作者：

Chin R.M. ^{[1
]}

Panavas T. ^{[2
]}

Brown J.M. ^{[3
]}

Johnson K.K. ^{[1
]}

机构：

[1] Alexion Pharmaceuticals Inc., 100 College Street, New Haven, 06510, CT

[2] Biotherapeutic Molecule Discovery, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, 06877, CT

[3] Wave Life Sciences, 733 Concord Ave., Cambridge, 02138, MA

来源：

BMC Research Notes | / 11卷 / 1期

关键词：

ATP6; High-throughput screening; Idebenone; Lymphoblastoid cell lines; Mitochondria; Mitochondrial disease; ND1; ND4; Respiration;

D O I：

10.1186/s13104-018-3297-6

中图分类号：

学科分类号：

摘要：

Objective: Mitochondrial diseases are a group of devastating disorders for which there is no transformative cure. The majority of therapies for mitochondrial disease - approved, previously tested, or currently in development - are small molecules. The implementation of better cell-based models of mitochondrial disease can accelerate and improve the accuracy of small molecule drug discovery. The objective of this study is to evaluate the use of patient-derived lymphoblastoid cell lines for small molecule research in mitochondrial disease. Results: Five lymphoblastoid cell lines derived from mitochondrial disease patients harboring point mutations in mtND1, mtND4, or mtATP6 were characterized in two high throughput assays assessing mitochondrial function. In a pilot "clinical trial in a dish" experiment, the efficacy of idebenone - an approved therapy for mitochondrial disease - on the lymphoblastoid cell lines was tested. Idebenone increased the basal respiration of all lymphoblastoid cell lines except those harboring the 8993T>G point mutation in mtATP6. Our results posit lymphoblastoid cell lines as a strong model for mitochondrial disease research with small molecules and have implications for the clinical efficacy of idebenone. © 2018 The Author(s).

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