Abstract
b-galactosidase (b-gal), a lysosomal enzyme involved the removal of b-linked terminal galactosyl residues of many glycoconjugates, is deficient the neurodegenerative lysosomal disorder GM1-gangliosidosis (GM1). GM1-/-mice closely mimic the most fundamental aspects of the neuropathological and neurochemical abnormalities of the human disorder. Bone marrow progenitor cells have been used as a source of corrective protein because of their ability to repopulate the recipients and to supply functional enzyme to different cells by in trans correction. Hematopoietic progenitors transduced with a murine stem cell virus (MSCV)-based bicistronic retroviral vector over-expressing b-gal and the green fluorescent protein (GFP) marker were used for transplantation into sublethally irradiated GM1-/-mice. Transduction efficiency of total BM cells with the MSCV-b-gal ranged from 25–89% prior to the transplantation. b-gal expressing BM-derived cells were detected histologically and enzymatically many tissues including spleen, liver, lungs, intestine and kidney after one, three and six months post transplantation (BMT). GFP-expressing cells of the erythroid, myeloid or lymphoid lineage were identified by FACS analysis of peripheral blood samples, collected at different time points after transplantation. Secondary transplantations demonstrated consistent long-term in vivo b-gal expression all tissues including brain. In addition, the thin layer chromatography of brain lipids showed a reduction the GM1-ganglioside content brainstem and cerebellum after three and six months post BMT. In line with the biochemical and histological findings, different behavioral tests including open field, rotorod and walking pattern, indicated a clear improvement of the neurological function transplanted GM1-/-compared to untreated littermates. Taken together these results have encouraged the use of ex-vivo gene therapy for the treatment of GM1.
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