Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
Light Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA.
JCI Insight. 2023 Aug 22;8(16):e170199. doi: 10.1172/jci.insight.170199.
Gene therapy is under advanced clinical development for several lysosomal storage disorders. Pompe disease, a debilitating neuromuscular illness affecting infants, children, and adults with different severity, is caused by a deficiency of lysosomal glycogen-degrading enzyme acid α-glucosidase (GAA). Here, we demonstrated that adeno-associated virus-mediated (AAV-mediated) systemic gene transfer reversed glycogen storage in all key therapeutic targets - skeletal and cardiac muscles, the diaphragm, and the central nervous system - in both young and severely affected old Gaa-knockout mice. Furthermore, the therapy reversed secondary cellular abnormalities in skeletal muscle, such as those in autophagy and mTORC1/AMPK signaling. We used an AAV9 vector encoding a chimeric human GAA protein with enhanced uptake and secretion to facilitate efficient spread of the expressed protein among multiple target tissues. These results lay the groundwork for a future clinical development strategy in Pompe disease.
基因治疗正在为几种溶酶体贮积症进行深入的临床开发。庞贝病是一种影响婴儿、儿童和成人的进行性神经肌肉疾病，由溶酶体糖原降解酶酸性α-葡萄糖苷酶（GAA）的缺乏引起。在这里，我们证明了腺相关病毒介导（AAV 介导）的系统基因转移可以逆转年轻和严重影响的 Gaa 基因敲除小鼠所有关键治疗靶点——骨骼肌和心肌、横膈膜和中枢神经系统——中的糖原储存。此外，该疗法还逆转了骨骼肌中的继发性细胞异常，如自噬和 mTORC1/AMPK 信号通路。我们使用了一种编码具有增强摄取和分泌能力的嵌合人 GAA 蛋白的 AAV9 载体，以促进表达的蛋白在多个靶组织中的有效扩散。这些结果为庞贝病的未来临床开发策略奠定了基础。
