{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/86468"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/86468","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"Utilization of Lyso-Phosphatidylserine Nanoparticles to Reduce Immunogenicity and Improve Clinical Utility of Acid Alpha-Glucosidase in the Treatment of Pompe Disease","abstract":"Ph.D.","abstract_html":"Ph.D.","abstract_has_math":false,"creators":["Dingman, Robert"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Balu-Iyer, Sathy","Pharmaceutical Sciences"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-02-21T17:22:43Z","date_published":"2025-02-21T17:22:43Z","updated_at":"2026-07-27T19:05:32Z","subjects":["pharmaceutical sciences"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/86468","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Balu-Iyer, Sathy","Pharmaceutical Sciences"]},{"key":"dc:creator","label":"Author","values":["Dingman, Robert"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2025-02-21T17:22:43Z","2020"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Text","Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["pharmaceutical sciences"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/86468"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Ph.D.","Pompe Disease is an autosomal recessive disease that is characterized by a mutation in the GAA gene, encoding the production of the enzyme acid alpha-glucosidase (GAA). Residing in the lysosome of healthy cells, GAA is responsible for the catabolism of glycogen into glucose, critical molecules for basic cellular function. In the absence of GAA, glycogen accumulates in the lysosome and leads to impaired cellular function, eventually resulting in muscle fatigue, hypotonia, cardiomegaly, and eventually cardiac and respiratory failure. The first line of treatment for Pompe Disease is recombinant GAA (rhGAA) that is administered via intravenous infusion every two weeks. While effective, virtually all patients (89-100%) receiving rhGAA eventually develop anti-rhGAA antibodies that severely inhibit the activity of the protein, leaving the patient with no relief from therapy. Once antibodies develop, patients typically die within 12-18 months, and with no alternative therapies, the circumstances are dire for these patients. Previously, our lab has harnessed the biological function of phosphatidylserine (PS) to develop a subcutaneous immunotherapy 'reverse vaccination' strategy that has shown to be effective at preventing antibody development against therapeutic proteins such as Factor VIII (FVIII) and rhGAA. PS is a naturally occurring anionic phospholipid that is present on the inner leaflet of cell membranes. When cells undergo apoptosis, PS flips to the outer membrane and signals to circulating macrophages and resident dendritic cells to engulf the cellular debris in a tolerogenic manner. The presence of PS on the membrane of the cellular debris initiates a signaling cascade resulting in removal with no immune response. We have shown that through subcutaneous administration of antigen in the presence of PS, we can reduce the generation of antibodies against the protein by converting it from an immunogen to a tolerogen. Further experiments in our lab have shown that PS-mediated tolerance induction is modulated by tolerogenic dendritic cells that secrete anti-inflammatory cytokines such as TGF-β, initiate the generation of regulatory T-cells, and inhibit memory B cell production. The overall aim of this dissertation is to advance our knowledge of PS mediated tolerance induction and advance our ‘reverse vaccination’ towards clinical translatability...Overall, this dissertation has harnessed a unique property of PS and shown that tolerance can be induced to rhGAA orally, potentially solving a major medical need. We developed an improved nanoparticle containing Lyso-PS, showing oral administration as an effective tolerance induction method, and we identified supplementing rhGAA administration with oral Lyso-PS-rhGAA as a highly effective method of tolerance induction that does not interfere with clinical rhGAA dosing. Further, we suggest that Lyso-PS-rhGAA can operate as a standalone therapy, showing similar efficacy as free rhGAA, with reduced immunogenicity. This dissertation highlights the use of Lyso-PS nanoparticles to reduce immunogenicity of rhGAA and be an effective therapy, addressing an unmet clinical need for Pompe Disease patients.","**To request an accessible version of the file(s) associated with this item, contact library@buffalo.edu. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.**"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Utilization of Lyso-Phosphatidylserine Nanoparticles to Reduce Immunogenicity and Improve Clinical Utility of Acid Alpha-Glucosidase in the Treatment of Pompe Disease"]}]}],"canonical_facts":{"dc:contributor":["Balu-Iyer, Sathy","Pharmaceutical Sciences"],"dc:creator":["Dingman, Robert"],"dc:date":["2025-02-21T17:22:43Z","2020"],"dc:description":["Ph.D.","Pompe Disease is an autosomal recessive disease that is characterized by a mutation in the GAA gene, encoding the production of the enzyme acid alpha-glucosidase (GAA). Residing in the lysosome of healthy cells, GAA is responsible for the catabolism of glycogen into glucose, critical molecules for basic cellular function. In the absence of GAA, glycogen accumulates in the lysosome and leads to impaired cellular function, eventually resulting in muscle fatigue, hypotonia, cardiomegaly, and eventually cardiac and respiratory failure. The first line of treatment for Pompe Disease is recombinant GAA (rhGAA) that is administered via intravenous infusion every two weeks. While effective, virtually all patients (89-100%) receiving rhGAA eventually develop anti-rhGAA antibodies that severely inhibit the activity of the protein, leaving the patient with no relief from therapy. Once antibodies develop, patients typically die within 12-18 months, and with no alternative therapies, the circumstances are dire for these patients. Previously, our lab has harnessed the biological function of phosphatidylserine (PS) to develop a subcutaneous immunotherapy 'reverse vaccination' strategy that has shown to be effective at preventing antibody development against therapeutic proteins such as Factor VIII (FVIII) and rhGAA. PS is a naturally occurring anionic phospholipid that is present on the inner leaflet of cell membranes. When cells undergo apoptosis, PS flips to the outer membrane and signals to circulating macrophages and resident dendritic cells to engulf the cellular debris in a tolerogenic manner. The presence of PS on the membrane of the cellular debris initiates a signaling cascade resulting in removal with no immune response. We have shown that through subcutaneous administration of antigen in the presence of PS, we can reduce the generation of antibodies against the protein by converting it from an immunogen to a tolerogen. Further experiments in our lab have shown that PS-mediated tolerance induction is modulated by tolerogenic dendritic cells that secrete anti-inflammatory cytokines such as TGF-β, initiate the generation of regulatory T-cells, and inhibit memory B cell production. The overall aim of this dissertation is to advance our knowledge of PS mediated tolerance induction and advance our ‘reverse vaccination’ towards clinical translatability...Overall, this dissertation has harnessed a unique property of PS and shown that tolerance can be induced to rhGAA orally, potentially solving a major medical need. We developed an improved nanoparticle containing Lyso-PS, showing oral administration as an effective tolerance induction method, and we identified supplementing rhGAA administration with oral Lyso-PS-rhGAA as a highly effective method of tolerance induction that does not interfere with clinical rhGAA dosing. Further, we suggest that Lyso-PS-rhGAA can operate as a standalone therapy, showing similar efficacy as free rhGAA, with reduced immunogenicity. This dissertation highlights the use of Lyso-PS nanoparticles to reduce immunogenicity of rhGAA and be an effective therapy, addressing an unmet clinical need for Pompe Disease patients.","**To request an accessible version of the file(s) associated with this item, contact library@buffalo.edu. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.**"],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/86468"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["pharmaceutical sciences"],"dc:title":["Utilization of Lyso-Phosphatidylserine Nanoparticles to Reduce Immunogenicity and Improve Clinical Utility of Acid Alpha-Glucosidase in the Treatment of Pompe Disease"],"dc:type":["Text","Dissertation"]},"updated_at":"2026-07-27T19:05:32Z"}