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 Lamp 2 -/- ( 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.