Treating GM1 Gangliosidosis With Ex Vivo Hematopoietic Stem Cell Gene Therapy Without Using Total Body Irradiation: A Masters Thesis
Authors
Whalen, MichaelFaculty Advisor
Dr. Miguel Sena-Esteves, Ph.D.Academic Program
Interdisciplinary Graduate ProgramDocument Type
Master's ThesisPublication Date
2011-08-31Keywords
GangliosidosisGM1
Gene Therapy
Hematopoietic Stem Cell Transplantation
Transplantation Conditioning
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Enzymes and Coenzymes
Genetic Phenomena
Genetics and Genomics
Nervous System Diseases
Nutritional and Metabolic Diseases
Surgical Procedures, Operative
Therapeutics
Metadata
Show full item recordAbstract
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.DOI
10.13028/eqr8-hw89Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31899Rights
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10.13028/eqr8-hw89