1] Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany [2] DZHK (German Centre for Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
1] Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany [2] DZHK (German Centre for Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck, Hamburg, Germany [3] Hamburg Zentrum für Experimentelle Therapie Forschung (HEXT) Vector Core Unit, Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Nat Commun. 2014 Dec 2;5:5515. doi: 10.1038/ncomms6515.
Homozygous or compound heterozygous frameshift mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C) cause neonatal hypertrophic cardiomyopathy (HCM), which rapidly evolves into systolic heart failure and death within the first year of life. Here we show successful long-term Mybpc3 gene therapy in homozygous Mybpc3-targeted knock-in (KI) mice, which genetically mimic these human neonatal cardiomyopathies. A single systemic administration of adeno-associated virus (AAV9)-Mybpc3 in 1-day-old KI mice prevents the development of cardiac hypertrophy and dysfunction for the observation period of 34 weeks and increases Mybpc3 messenger RNA (mRNA) and cMyBP-C protein levels in a dose-dependent manner. Importantly, Mybpc3 gene therapy unexpectedly also suppresses accumulation of mutant mRNAs. This study reports the first successful long-term gene therapy of HCM with correction of both haploinsufficiency and production of poison peptides. In the absence of alternative treatment options except heart transplantation, gene therapy could become a realistic treatment option for severe neonatal HCM.
MYBPC3 编码心肌肌球蛋白结合蛋白 C（cMyBP-C）的纯合或复合杂合框移突变导致新生儿肥厚型心肌病（HCM），这种疾病在生命的第一年迅速发展为收缩性心力衰竭和死亡。在这里，我们展示了在基因上模拟这些人类新生儿心肌病的同源性 Mybpc3 靶向敲入（KI）小鼠中，Mybpc3 基因治疗的成功长期应用。在 1 日龄 KI 小鼠中单次系统给予腺相关病毒（AAV9）-Mybpc3 可防止心脏肥大和功能障碍的发展，观察期为 34 周，并以剂量依赖性方式增加 Mybpc3 信使 RNA（mRNA）和 cMyBP-C 蛋白水平。重要的是，Mybpc3 基因治疗出人意料地还抑制了突变 mRNA 的积累。这项研究报告了首例成功的 HCM 长期基因治疗，纠正了单倍不足和产生毒性肽。在除心脏移植之外没有其他替代治疗选择的情况下，基因治疗可能成为严重新生儿 HCM 的一种现实治疗选择。
