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 e ither 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 phe notype. Thirty-two newborn ASMKO mice were preconditioned with low dose rad iation (200 cGy) and transplanted with ASMKO bone marrow cells which had be en transduced with an ecotropic retroviral vector encoding human ASM. Engra ftment of donor-derived cells ranged from 15 to 60% based on Y-chromosome i n situ hybridization analysis of peripheral white blood cells, and was achi eved in 92% of the transplanted animals. High levels of ASM activity (up to live-fold above normal) were found in the engrafted animals for up to 10 m onths after transplantation, and their life-span was extended from a mean o f 5 to 9 months by the gene therapy procedure. Biochemical and histological analysis of tissues obtained 4-5 months after transplantation indicated th at the ASM activities were increased and the sphingomyelin storage was sign ificantly reduced in the spleens, livers and lungs of the treated mice, maj or 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-tre ated animals at 5 months after transplantation, and a reduction of storage in spinal cord neurons was observed However, all of the transplanted mice e ventually developed ataxia and died earlier than normal mice. Overall, thes e results indicated that hematopoietic stem cell gene therapy should be eff ective for the treatment of non-neurological type B NPD, but improved techn iques for targeting the transplanted cells and/or expressed enzyme to speci fic sites of pathology in the central nervous system must be developed in o rder to achieve effective treatment for type A NPD.