Piras Giuseppa, Montiel-Equihua Claudia, Chan Yee-Ka Agnes, Wantuch Slawomir, Stuckey Daniel, Burke Derek, Prunty Helen, Phadke Rahul, Chambers Darren, Partida-Gaytan Armando, Leon-Rico Diego, Panchal Neelam, Whitmore Kathryn, Calero Miguel, Benedetti Sara, Santilli Giorgia, Thrasher Adrian J, Gaspar H Bobby
Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Centre for Advanced Biomedical Imaging, University College London, London WC1E 6DD, UK.
Mol Ther Methods Clin Dev. 2020 Jul 6;18:558-570. doi: 10.1016/j.omtm.2020.07.001. eCollection 2020 Sep 11.
Pompe disease is a lysosomal storage disorder caused by malfunctions of the acid alpha-glucosidase (GAA) enzyme with a consequent toxic accumulation of glycogen in cells. Muscle wasting and hypertrophic cardiomyopathy are the most common clinical signs that can lead to cardiac and respiratory failure within the first year of age in the more severe infantile forms. Currently available treatments have significant limitations and are not curative, highlighting a need for the development of alternative therapies. In this study, we investigated the use of a clinically relevant lentiviral vector to deliver systemically GAA through genetic modification of hematopoietic stem and progenitor cells (HSPCs). The overexpression of GAA in human HSPCs did not exert any toxic effect on this cell population, which conserved its stem cell capacity in xenograft experiments. In a murine model of Pompe disease treated at young age, we observed phenotypic correction of heart and muscle function with a significant reduction of glycogen accumulation in tissues after 6 months of treatment. These findings suggest that lentiviral-mediated HSPC gene therapy can be a safe alternative therapy for Pompe disease.
庞贝氏病是一种溶酶体贮积症，由酸性α-葡萄糖苷酶（GAA）酶功能异常引起，导致糖原在细胞内毒性蓄积。肌肉萎缩和肥厚性心肌病是最常见的临床症状，在病情较重的婴儿型中，可在一岁内导致心脏和呼吸衰竭。目前可用的治疗方法有显著局限性且无法治愈，这凸显了开发替代疗法的必要性。在本研究中，我们研究了使用具有临床相关性的慢病毒载体，通过对造血干细胞和祖细胞（HSPCs）进行基因改造来全身递送GAA。GAA在人HSPCs中的过表达对该细胞群体未产生任何毒性作用，在异种移植实验中该细胞群体保留了其干细胞能力。在幼年时接受治疗的庞贝氏病小鼠模型中，我们观察到心脏和肌肉功能的表型纠正，治疗6个月后组织中的糖原蓄积显著减少。这些发现表明，慢病毒介导的HSPC基因治疗可能是治疗庞贝氏病的一种安全替代疗法。
