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However, all HSPCT\u2010treated patients exhibit severe deterioration in peripheral nervous system function characterized by major motor and expressive language pathologies. We hypothesize that a combination of several mechanisms contribute to this phenomenon, including 1) nonoptimal conditioning protocols with consequent inefficient engraftment and biodistribution of donor\u2010derived cells and 2) insufficient uptake of donor cell\u2010secreted galactocerebrosidease (GALC) secondary to a naturally low expression level of the cation\u2010independent mannose 6\u2010phosphate\u2010receptor (CI\u2010MPR). We have characterized the effects of a busulfan (Bu) based conditioning regimen on the efficacy of HSPCT in prolonging twi mouse average life span. There was no correlation between the efficiency of bone marrow engraftment of donor cells and twi mouse average life span. HSPCT prolonged the average life span of twi mice, which directly correlated with the aggressiveness of the Bu\u2010mediated conditioning protocols. HSPC transduced with lentiviral vectors carrying the GALC cDNA under control of cell\u2010specific promoters were efficiently engrafted in twi mouse bone marrow. To facilitate HSPCT\u2010mediated correction of GALC deficiency in target cells expressing low levels of CI\u2010MPR, a novel GALC fusion protein including the ApoE1 receptor was developed. Efficient cellular uptake of the novel fusion protein was mediated by a mannose\u20106\u2010phosphate\u2010independent mechanism. The novel findings described here elucidate some of the cellular mechanisms that impede the cure of KD patients by HSPCT and concomitantly open new directions to enhance the therapeutic efficacy of HSPCT protocols for KD. \u00a9 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/jnr.23847","type":"journal-article","created":{"date-parts":[[2016,9,17]],"date-time":"2016-09-17T11:22:31Z","timestamp":1474111351000},"page":"1152-1168","source":"Crossref","is-referenced-by-count":18,"title":["Hematopoietic Stem cell transplantation and lentiviral vector\u2010based gene therapy for Krabbe's disease: Present convictions and future prospects"],"prefix":"10.1002","volume":"94","author":[{"given":"Peirong","family":"Hu","sequence":"first","affiliation":[{"name":"Gene Therapy Center and Department of Microbiology and Immunology University of North Carolina at Chapel Hill Chapel Hill North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yedda","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Washington University in St. Louis, School of Medicine St Louis 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