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Published on: November 4, 2018
Hematopoietic Stem cell transplantation and lentiviral vector-based gene therapy for Krabbe's disease: Present
Peirong Hu1, Yedda Li2, Nana Nikolaishvili-Feinberg3
1Gene Therapy Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Insights
Hematopoietic stem cell transplantation (HSPCT) shows promise for Krabbe disease (KD) but faces challenges. New strategies involving enhanced conditioning and novel GALC fusion proteins aim to improve therapeutic efficacy for KD patients.
Area of Science:
- Neuroscience
- Gene Therapy
- Cell Biology
Background:
- Krabbe disease (KD) is a fatal lysosomal storage disorder.
- Hematopoietic stem and progenitor cell transplantation (HSPCT) is the only treatment for CNS damage in KD.
- HSPCT leads to peripheral nervous system dysfunction in KD patients.
Purpose of the Study:
- To investigate mechanisms limiting HSPCT efficacy in KD.
- To evaluate busulfan (Bu)-based conditioning regimens for HSPCT in a mouse model.
- To develop novel strategies for enhancing GALC delivery in KD.
Main Methods:
- Assessed HSPCT efficacy using a busulfan conditioning regimen in twi mice.
- Correlated bone marrow engraftment with lifespan.
- Developed and tested a novel GALC fusion protein for enhanced cellular uptake.
Main Results:
- HSPCT prolonged lifespan in twi mice, correlating with conditioning intensity, not engraftment efficiency.
- GALC-corrected HSPCs were efficiently engrafted.
- A novel GALC fusion protein demonstrated mannose-6-phosphate-independent cellular uptake.
Conclusions:
- Conditioning intensity, not engraftment, impacts lifespan extension via HSPCT in KD mice.
- Novel GALC fusion proteins offer a promising strategy for overcoming cellular uptake limitations in KD therapy.
- Findings provide insights into improving HSPCT protocols for Krabbe disease.
Abstract:
Currently, presymtomatic hematopoietic stem and progenitor cell transplantation (HSPCT) is the only therapeutic modality that alleviates Krabbe's disease (KD)-induced central nervous system damage. However, all HSPCT-treated 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-derived cells and 2) insufficient uptake of donor cell-secreted galactocerebrosidease (GALC) secondary to a naturally low expression level of the cation-independent mannose 6-phosphate-receptor (CI-MPR). 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-mediated conditioning protocols. HSPC transduced with lentiviral vectors carrying the GALC cDNA under control of cell-specific promoters were efficiently engrafted in twi mouse bone marrow. To facilitate HSPCT-mediated correction of GALC deficiency in target cells expressing low levels of CI-MPR, a novel GALC fusion protein including the ApoE1 receptor was developed. Efficient cellular uptake of the novel fusion protein was mediated by a mannose-6-phosphate-independent 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. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.
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