Publication Date
2011-08-31
Document Type
Master's Thesis
Academic Program
Interdisciplinary Graduate Program
Department
Gene Therapy Center; Department of Neurology
First Thesis Advisor
Dr. Miguel Sena-Esteves, Ph.D.
Keywords
Gangliosidosis, GM1, Gene Therapy, Hematopoietic Stem Cell Transplantation, Transplantation Conditioning
Abstract
GM1 gangliosidosis is an autosomal recessive lysosomal storage disease, caused by a deficiency in the enzyme β-galactosidase. The disease affects the CNS, liver, kidney, heart and skeletal system, leading to severe neurodegeneration and death. We propose to treat this disorder using ex vivo hematopoietic stem cell therapy. The effectiveness of this therapy requires the recruitment of transduced donor cells to the CNS. This is only found to occur after mice are conditioned with total body irradiation, due to the increase in CNS cytokine production and blood brain barrier permeability that occurs. As the use of total body irradiation in pediatric patients has been linked to future developmental problems, this myeloablation approach is often avoided in younger patients in favor of a conditioning regimen using the chemotherapy drugs, busulfan and cyclophosphamide. Whether donor cells can enter the CNS when a busulfan and cyclophosphamide conditioning regimen is used has not been determined. In this study we plan to quantify the cytokine and blood-brain barrier permeability increases necessary for donor cells to be recruited to the CNS after total body irradiation. We will then investigate whether busulfan and cyclophosphamide conditioning and/or the chronic neuroinflammation present in GM1 mice can produce similar conditions and facilitate the recruitment of donor hematopoietic stem cells to the CNS. Finally we will assess whether ex vivo hematopoietic stem cell gene therapy is still an effective therapy when busulfan and cyclophosphamide are used for myeloablative conditioning.
Repository Citation
Whalen M. (2011). Treating GM1 Gangliosidosis With Ex Vivo Hematopoietic Stem Cell Gene Therapy Without Using Total Body Irradiation: A Masters Thesis. Morningside Graduate School of Biomedical Sciences Dissertations and Theses. https://doi.org/10.13028/eqr8-hw89. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/558
DOI
10.13028/eqr8-hw89
DOI Link
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Copyright is held by the author, with all rights reserved.
Included in
Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Enzymes and Coenzymes Commons, Genetic Phenomena Commons, Genetics and Genomics Commons, Nervous System Diseases Commons, Nutritional and Metabolic Diseases Commons, Surgical Procedures, Operative Commons, Therapeutics Commons