GEREMY_Gene Therapy for treatment of rare inherited Arrhythmogenic Cardiomyopathy

罕见心脏病的治疗是一个危险、昂贵和耗时的过程，对疾病的病理生理机制的认识不足和缺乏相关的疾病模型阻碍了这一过程。GEREMY联盟建议通过针对致病的PLN（非桥粒）和PKP2（心脏桥粒）突变，开发遗传性心律失常性心肌病（ACM）的基因治疗（GT）来克服这一挑战。GEREMY联盟将采用一种独特的平行方法，研究各种有前途的GT方法（寡核苷酸化学、基因编辑和基因传递）。此外，该联盟将设计疾病模型，以适当评估治疗干预措施，并旨在为GT提供体外和体内临床前概念验证。与当前技术相比，GT的一个显著优势是，它有可能成为罕见心脏病的根治性治疗方法。基于之前的成功，GEREMY将把PLN和PKP2作为技术路线图。修复导致疾病的PLN和PKP2基因的主要缺陷将导致保留甚至恢复心肌收缩力。通过这种方法，GEREMY将致力于遗传性ACM和其他可能的心肌病的根治性治疗，从而显着减轻医疗负担。该项目的临床前研究和心脏遗传学专家将为突变纠正提供临床前疗效和安全性数据。具有监管和临床试验专业知识的合作伙伴（EXOM， EUF， NLHI）将在项目完成后准备立即开始临床试验，并申请孤儿药指定。EUPATI是一个患者组织和KUL伦理合作伙伴，将确保该项目始终与患者需求和伦理观点保持一致。整个联盟将有助于交流和传播结果，以确保最大限度地利用这一突破性技术。

Development of a cure for rare cardiac diseases is a risky, costly and time-consuming process, which is hampered by insufficient insight into pathophysiological mechanisms of the diseases and lack of relevant disease models. The GEREMY consortium proposes to overcome this challenge by developing a gene therapy (GT) for inherited arrhythmogenic cardiomyopathy (ACM), by targeting the disease-causing PLN (non-desmosomes) and PKP2 (cardiac desmosomes) mutations. The GEREMY consortium will apply a unique parallel approach and investigate various promising GT approaches (oligonucleotide chemistries, gene editing and gene delivery). Also, the consortium will engineer disease models for proper assessment of therapeutic interventions and aims to provide in vitro & in vivo preclinical proof of-concept for the GT. A significant benefit compared to current technologies is that the GT has the potential to be a curative treatment for rare cardiac diseases. Based on previous successes, GEREMY will target PLN & PKP2 as a roadmap of the technology. Restoring the primary defect in the PLN & PKP2 genesthat cause the disease will lead to preserving or even restoring myocardial contractility. Through this approach, GEREMY will work towards a curative treatment of inherited ACM and likely other cardiomyopathies, which significantly reduces the healthcare burden. The project’s experts in preclinical research and cardiac genetics will deliver preclinical efficacy and safety data for the mutation correction. The partners with regulatory and clinical trial expertise (EXOM, EUF, NLHI) will prepare for immediate start of clinical trials upon project completion, and apply for orphan drug designation. EUPATI, a patient organisation and KUL ethics partner will ensure that the project is continuously aligned with patient needs and ethical perspectives. The whole consortium will contribute to communicate an disseminate the results to ensure maximum exploitation of this breakthrough technology.