Taylor R W, Chinnery P F, Turnbull D M, Lightowlers R N
Department of Neurology, The Medical School, University of Newcastle upon Tyne, UK.
Hum Reprod. 2000 Jul;15 Suppl 2:79-85. doi: 10.1093/humrep/15.suppl_2.79.
Defects of mitochondrial (mt) DNA cause a diverse group of incurable, progressive diseases that often lead to severe disability and premature death. Most patients with pathogenic mtDNA defects have a mixture of mutant and wild-type mtDNA (heteroplasmy), and the clinical defect is only expressed when the percentage of mutant mtDNA exceeds a critical threshold. Since mtDNA is continually replicating and being turned over, we have proposed an approach to the treatment of these disorders that utilizes sequence-specific antigenomic peptide nucleic acids (PNAs) to hybridize and specifically inhibit the replication of mutant mtDNA under physiological conditions. By allowing the selective propagation of wild-type molecules, it may be possible to correct the cellular biochemical defect and to prevent the progression of disease. This paper summarizes the experimental progress in this area, including the cellular uptake of PNA molecules and their import into mitochondria both in vitro and in cell culture by the addition of a nuclear-encoded mitochondrial targeting sequence. The possibilities of extending this strategy to the treatment of mtDNA deletion disorders are discussed.
线粒体（mt）DNA缺陷会引发一系列无法治愈的进行性疾病，这些疾病常常导致严重残疾和过早死亡。大多数患有致病性mtDNA缺陷的患者体内突变型和野生型mtDNA混合存在（异质性），只有当突变型mtDNA的比例超过临界阈值时，临床缺陷才会表现出来。由于mtDNA不断复制和更新，我们提出了一种治疗这些疾病的方法，即利用序列特异性反基因组肽核酸（PNA）在生理条件下杂交并特异性抑制突变型mtDNA的复制。通过使野生型分子选择性增殖，有可能纠正细胞生化缺陷并阻止疾病进展。本文总结了该领域的实验进展，包括PNA分子的细胞摄取以及通过添加核编码的线粒体靶向序列在体外和细胞培养中使其导入线粒体的情况。还讨论了将该策略扩展到治疗mtDNA缺失疾病的可能性。
