Ex vivo gene therapy using bone marrow-derived cells: combined effects of intracerebral and intravenous transplantation in a mouse model of Niemann-Pick disease.

Normal murine bone marrow cells were transduced with a retroviral vector to overexpress and release human acid sphingomyelinase (ASM). The transduced cells were then transplanted intravenously into 3-day-old, irradiated ASM-deficient mice, a model of human Niemann-Pick disease (NPD). At 4 weeks, engrafted mice received intracerebral injections of mesenchymal stem cells obtained from the original, transduced bone marrow. By 16 weeks, most of the treated NPD mice had near-normal levels of ASM activity in their tissues, including the brain; dramatically improved histology; and marked reductions in sphingomyelin. Cerebellar function also was normal, and the number of Purkinje cells was > 80% of normal. Remarkably, in certain regions of the cerebellum many of the surviving Purkinje cells expressed human ASM RNA, suggesting that either they were donor-derived or that the transplanted bone marrow cells had fused with existing Purkinje cells. However, despite these positive results, by 24 weeks the ASM activities were dramatically reduced and cerebellar function began to decline, coincident with the detection of anti-human ASM antibodies in the plasma. We conclude that this gene therapy procedure might be useful in Type A NPD and other neurological lysosomal storage disorders, particularly since it is an approach that could be beneficial for both the neurological and the visceral organ features of these diseases.