Hematopoietic stem cell gene therapy leads to marked visceral organ improvements and a delayed onset of neurological abnormalities in the acid sphingomyelinase deficient mouse model of Niemann-Pick disease.

Types A and B Niemann-Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM). Currently, no treatment is available for either form of NPD. Using the ASM knockout (ASMKO) mouse model, we evaluated the effects of ex vivo hematopoietic stem cell gene therapy on the NPD phenotype. Thirty-two newborn ASMKO mice were preconditioned with low dose radiation (200 cGy) and transplanted with ASMKO bone marrow cells which had been transduced with an ecotropic retroviral vector encoding human ASM. Engraftment of donor-derived cells ranged from 15 to 60% based on Y-chromosome in situ hybridization analysis of peripheral white blood cells, and was achieved in 92% of the transplanted animals. High levels of ASM activity (up to five-fold above normal) were found in the engrafted animals for up to 10 months after transplantation, and their life-span was extended from a mean of 5 to 9 months by the gene therapy procedure. Biochemical and histological analysis of tissues obtained 4-5 months after transplantation indicated that the ASM activities were increased and the sphingomyelin storage was significantly reduced in the spleens, livers and lungs of the treated mice, major sites of pathology in type B NPD. The presence of Purkinje cell neurons was also markedly increased in the treatment group as compared with non-treated animals at 5 months after transplantation, and a reduction of storage in spinal cord neurons was observed. However, all of the transplanted mice eventually developed ataxia and died earlier than normal mice. Overall, these results indicated that hematopoietic stem cell gene therapy should be effective for the treatment of non-neurological type B NPD, but improved techniques for targeting the transplanted cells and/or expressed enzyme to specific sites of pathology in the central nervous system must be developed in order to achieve effective treatment for type A NPD.