Hematopoietic Stem Cell Gene Therapy Alleviates Disease Phenotypes in a Murine Model of Danon Disease

Abstract: Danon disease is a fatal X-linked recessive disease caused by a lack of expression of the lysosomal associated membrane protein type 2 (LAMP2), leading to severe vacuolar cardiomyopathy. Most patients with Danon progress to end-stage heart failure or death without advanced therapies. In this study, we investigated the therapeutic efficacy of systemic transplantation of ex vivo gene-modified Lamp2^-/- (Lamp2 KO) hematopoietic stem and progenitor cells (HSPCs) using a lentiviral vector containing the human LAMP2B transgene, pCCL-LAMP2B, in the mouse model of Danon disease, Lamp2 KO mice. Transplanted pCCL-LAMP2B-HSPCs efficiently engrafted and differentiated into macrophages in heart. LAMP2B was found in cardiomyocytes and improved cardiac systolic as well as locomotor functions were observed in pCCL-LAMP2B-HSPCs recipient mice compared to non-treated or Lamp2 KO mice receiving Lamp2 KO HSPCs. In addition, we also demonstrated that pCCL-LAMP2B-HSPCs rescued autophagic flux and activity in the heart. In vitro, we cocultured WT macrophages with Lamp2 KO fibroblasts and observed transfer of LAMP2B and rescue of the autophagic flux in the diseased cells confirming cross-correction despite LAMP2B being a lysosomal transmembrane protein.