Juvenile GM2 gangliosidosis (jGM2) is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal β-hexosaminidase A (Hex A) resulting in GM2 ganglioside accumulation in brain. Like many other lysosomal storage diseases (LSDs), no specific treatment currently exists. In order to establish clinical outcomes for the investigation of potential therapies for jGM2, I collected comprehensive information on the natural history of the condition by studying retrospective and prospectively a cohort of 21 patients with the disease, and reviewing previously published reports of 134 patients. Several symptoms at disease onset, symptom latencies, and the survival curve were described. Genotype-phenotype correlations and neuroradiological findings were also studied. Based on pre-clinical results in animal models, we studied substrate reduction therapy (SRT), with miglustat, in a phase I/II clinical trial to assess its pharmacokinetics (PK), safety, tolerability in infantile and jGM2. Miglustat showed a PK profile similar to the one found in adult patients. The drug was found to be safe and well-tolerated in patients with jGM2, with diarrhea and weight loss being the most common drug-related adverse events. The analysis of efficacy showed that SRT was unable to arrest the full neurological progression of the condition; however, relative stabilization of cognitive function was noted, which was consistent with brain MRI findings. Because of the limited efficacy obtained with SRT, enzyme-enhancement therapy was considered to be an attractive alternative therapy for the late onset forms of GM2 gangliosidosis. Screening of a FDA-approved library of approved therapeutic compounds resulted in the identification of pyrimethamine, as a potential pharmacological chaperone for mutant forms of Hex A. Relative enhancements of enzyme activity and protein levels were observed in patient cells treated with therapeutic concentrations of drug. Applying the same principles, ambroxol was identified as a potential PC for mutant glucocerebrosidase (GCC), the lysosomal enzyme that when deficient causes Gaucher disease (GD). Significant increases of residual mutant GCC were observed in cultured patients cells with type 1 GD. In conclusion, principles developed in the course of studies on jGM2 were shown to be useful for the investigation of novel small-molecule therapies for LSDs, associated with significant neurodegeneration.

Thesis (M.S.)--Oregon State University, 1989. / Typescript (photocopy). Includes bibliographical references. Also available on the World Wide Web.

Thesis (M.S.)--University of North Texas, Dec., 2007. / Title from title page display. Includes bibliographical references.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1954. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 119-122).

Thesis (Ph. D.)--Chemical Engineering, Georgia Institute of Technology, 2009. / Committee Co-Chair: Eckert, Charles; Committee Co-Chair: Liotta, Charles; Committee Member: Bommarius, Andreas; Committee Member: Fernández, Facundo; Committee Member: Lu, Hang. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Thesis (PhD) - Faculty of Life and Social Sciences, Swinburne University of Technology, 2009. / Submitted for the degree of Doctor of Philosophy, [Faculty of Life and Social Sciences], Swinburne University of Technology - 2009. Typescript. Includes bibliographical references (p. 210-227)

Thesis (M. Phil.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 141-162). Also available online.

Thesis (M. Phil.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 141-162). Also available in print.

Thesis (M.A.)--University of Missouri-Columbia, 2004. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (June 30, 2006) Vita. Includes bibliographical references.