Zhang Jing, Gutierrez-Lara Erika Joana, Do Aryanne, Nguyen Lena, Nair Anju, Selvan Nithya, Fenn Tim, Adler Eric, Khanna Richie, Sheikh Farah
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
LEXEO Therapeutics Inc, New York, NY, USA.
NPJ Regen Med. 2025 Apr 3;10(1):17. doi: 10.1038/s41536-025-00401-6.
Plakophilin-2 (PKP2) mutations cause fatal genetic heart disease and arrhythmogenic cardiomyopathy (ACM) with primary effects on the right ventricle (RV). Adeno-associated virus (AAV)-PKP2 gene therapy shows promise as a therapeutic strategy but lacks long-term data and guidelines on minimal effective doses in animal studies for treating RV deficits, arrhythmia burden, and improving survival when administered during disease settings, which are most relevant to clinical trials. Using AAVrh10, known for its preferential cardiac gene expression at lower doses, we show minimal doses required for efficacy for AAVrh10.PKP2 (LX2020) to rescue cardiac (molecular and especially RV) deficits, arrhythmia burden and survival in PKP2 ACM mice, suggesting its potential to reverse late-stage pathology. Safety assessments in non-human primates revealed no adverse events. These data support LX2020 as a viable treatment for PKP2 ACM patients.
桥粒芯蛋白2（PKP2）突变会导致致命的遗传性心脏病和致心律失常性心肌病（ACM），主要影响右心室（RV）。腺相关病毒（AAV）-PKP2基因疗法显示出作为一种治疗策略的前景，但缺乏关于在动物研究中治疗RV缺陷、心律失常负担以及在疾病发生时给药以改善生存率的最小有效剂量的长期数据和指导原则，而这些与临床试验最为相关。使用以低剂量时优先在心脏表达基因而闻名的AAVrh10，我们展示了AAVrh10.PKP2（LX2020）挽救PKP2 ACM小鼠的心脏（分子水平，尤其是RV）缺陷、心律失常负担和生存率所需的最小剂量，表明其具有逆转晚期病理状况的潜力。在非人类灵长类动物中的安全性评估未发现不良事件。这些数据支持LX2020作为PKP2 ACM患者的一种可行治疗方法。
