Ex vivo gene therapy using bone marrow-derived cells: combined effects of intracerebral and intravenous transplantation in a mouse model of niemann–pick disease

Abstract

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.

Combination brain and systemic injections of AAV provide maximal functional and survival benefits in the Niemann-Pick mouse

“…In another ASMKO study, systemic injections of bone marrow cells into ablated newborn mice, in combination with mesenchymal stem cell injections into the brain, resulted in Purkinje cell survival and a modest preservation of motor function in the ASMKO mouse (30). However, there was an eventual decline in behavioral function that correlated with a rise in anti-hASM antibodies (30).…”

Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Improve Neurological Abnormalities of Niemann-Pick Type C Mouse by Modulation of Neuroinflammatory Condition

“…BM-MSCs have great therapeutic potential for neurological disease because of their self-renewal and multipotent differentiative capacity and their immunosuppressive function [39]. They have been used extensively for intracerebral engraftment in animal models of neurological disease [16,19,28,36,38]. However, bone marrow may be detrimental because of the highly invasive donation procedure and BM-MSCs decline number with increasing age [31].…”

“…hUCB-MSCs which were labeled with nanoparticles (0.1 mg/ml, NFP-STEM Silanol TMSR-RITC 50, BITERIALS, Seoul, Korea), were transplanted into the cerebellum by use of a glass capillary (1.2  0.6 mm) [19]. The injection coordinates were 5.52 mm posterior to the bregma and the injection depth was 2.50 mm.…”

Central nervous system therapy for lysosomal storage disorders

“…However, the effects were reversed following the development of anti-human ASM antibodies by Week 24. 60 Following initial encouraging studies in animal models, allogenic bone marrow-derived MSCs were transplanted into 5 patients with MPS I (Hurler syndrome) and 6 with MLD; all patients had previously undergone successful BMT with bone marrow from an HLA-identical sibling. Cell infusions were tolerated well, but there was no apparent change in overall health or physical development, although bone mineral density was either maintained or slightly improved.…”