: Next-generation models and genetic therapies for rare neuromuscular diseases

：罕见神经肌肉疾病的下一代模型和基因疗法

• 批准号: 10080927
• 金额: $ 70.01万
• 依托单位: THE FRANCIS CRICK INSTITUTE
• 依托单位国家: 英国
• 项目类别: EU-Funded
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=10080927
• 关键词: Next; generation; models; genetic; therapies

Muscular dystrophies are severe genetic disorders characterised by muscle wasting, impaired mobility and premature death, which to date remain incurable. Although preclinical and clinical evidence position genetic therapies amongst the key emerging treatments for several genetic conditions, no gene therapy or genome editing strategy has been approved for any muscular dystrophies yet. The lack of robust, human(ised) models enabling precise development of such advanced therapies is a major barrier towards their clinical translation for muscle diseases. To overcome this limitation, we have assembled the multidisciplinary MAGIC consortium to build novel, high-fidelity, models of human skeletal muscle pathophysiology which will be used to develop new vectorsforsafe and efficacious neuromuscular gene therapy and genome editing. Specific rare (paediatric) diseases targeted by our consortium are Duchenne muscular dystrophy (DMD), X-linked centronuclear myopathy (XLCNM), LMNA- and COL6-related congenital muscular dystrophies (CMDs). Microfabrication, microfluidics and human stem cell differentiation technologies will be used to generate disease-specific muscle-on-chip devices qualified for commercialisation, capable of screening toxicity and cell-specificity of new adeno-associated viral vector (AAV) capsid variants, and unique muscle-specific lentiviruses. Selected vectors will be equipped with novel lineage-specific regulatory elements to further restrict transgene expression to myofibres, muscle stem cells or interstitial fibroblasts, reducing also potential immunogenicity. The same vectors will be loaded with therapeutic genes or with new mutationindependent (for DMD and XLCNM) or mutation-specific (for LMNA and COL6-CMD) gene editing tools, which will then be validated in dystrophic rodents. Finally, GMP-compatible batches of the top performing vectors will undergo advanced preclinical testing in large animals, preparing them for future clinical translation.

肌营养不良症是一种严重的遗传性疾病，其特征是肌肉萎缩、活动能力受损和过早死亡，迄今为止仍无法治愈。尽管临床前和临床证据将基因疗法定位为几种遗传性疾病的关键新兴疗法之一，但尚未批准任何基因疗法或基因组编辑策略用于任何肌营养不良症。缺乏能够精确开发此类先进疗法的强大的人类模型是其肌肉疾病临床转化的主要障碍。为了克服这一限制，我们组建了多学科 MAGIC 联盟来构建新颖、高保真的人类骨骼肌病理生理学模型，该模型将用于开发安全有效的神经肌肉基因治疗和基因组编辑的新载体。我们联盟针对的特定罕见（儿科）疾病包括杜氏肌营养不良症 (DMD)、X 连锁中心核肌病 (XLCNM)、LMNA 和 COL6 相关先天性肌营养不良症 (CMD)。微加工、微流体和人类干细胞分化技术将用于生成具有商业化资格的疾病特异性肌肉芯片设备，能够筛选新型腺相关病毒载体（AAV）衣壳变体的毒性和细胞特异性，以及独特的肌肉特异性慢病毒。选定的载体将配备新型谱系特异性调控元件，以进一步限制转基因表达至肌纤维、肌肉干细胞或间质成纤维细胞，从而降低潜在的免疫原性。相同的载体将装载治疗基因或新的突变无关（对于 DMD 和 XLCNM）或突变特异性（对于 LMNA 和 COL6-CMD）基因编辑工具，然后将在营养不良的啮齿动物中进行验证。最后，符合 GMP 要求的高性能载体批次将在大型动物中进行先进的临床前测试，为未来的临床转化做好准备。