Preservation of pancreatic islet grafts in the extrahepatic space
Inventors
Ward, Casey • Tang, Qizhi • Stock, Peter • FALEO, Gaetano • NAIR, Gopika • Hebrok, Matthias • CHANG, Wenhan • Vo, Thuy • Bluestone, Jeffrey A. • DE KLERK, Eleonora
Assignees
US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-11951136-B2
Publication Date
2024-04-09
Expiration Date
2038-12-12
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Abstract
Provided herein, inter alia, are methods and compositions for treating diabetes mellitus comprising co-transplantation of an insulin-producing cell and a cell derived from a parathyroid gland (PTG), a CD34+ cell derived from a parathyroid gland, a CD34+ cell derived from a stem cell, or other progenitor cell-derived CD34+ cell.
Core Innovation
Diabetes Mellitus (DM) is characterized by elevated fasting glucose levels due to insufficient or deficient insulin production. Current pancreatic islet transplantation into the liver by portal vein infusion suffers from compromised survival and engraftment, limiting efficacy. Other transplant sites like subcutaneous or intramuscular spaces are more accessible but impair graft survival due to poor engraftment and inadequate blood supply. Encapsulation devices further hinder graft viability by limiting blood supply.
The invention provides novel methods and compositions involving co-transplantation of insulin-producing cells (such as pancreatic islet beta cells or stem cell-derived beta cells) with parathyroid gland (PTG)-derived cells or CD34+ cells, enabling successful engraftment in extrahepatic spaces like subcutaneous or intramuscular sites. Co-transplantation enhances survival, vascularization, and function of insulin-producing grafts, enabling reversal of diabetes in mouse models. The disclosure also includes generating CD34+ vascular endothelial progenitor cells (VEPC) from pluripotent stem cells to promote engraftment.
This approach addresses the unmet need for improved beta cell survival and engraftment in extrahepatic transplant sites, overcoming limitations of the hepatic site and poor outcomes at other sites. Co-transplanting insulin-producing cells with PTG cells or CD34+ progenitors promotes angiogenesis and supports graft survival, potentially enabling monitoring, retrieval, and safer transplantation of beta cells derived from stem cells or xenogeneic sources.
Claims Coverage
There are two independent claims that describe methods of treating diabetes mellitus by co-transplanting an insulin-producing cell with either a parathyroid gland (PTG)-derived cell or a CD34+ cell, where the co-transplanted cell produces proangiogenic factors, PTG hormones, or both.
Method for treating diabetes mellitus by co-transplantation of insulin-producing cells and PTG-derived or CD34+ cells producing proangiogenic and/or PTG hormone factors
A method for treating diabetes mellitus comprising administering a transplant with (a) an insulin-producing cell and (b) a cell derived from a parathyroid gland or a CD34+ cell, wherein the co-transplanted cell produces one or more factors selected from proangiogenic factors, PTG hormones, or combinations thereof.
Insulin-producing cell differentiation and types
The insulin-producing cell can be differentiated from a stem cell, including stem cell-derived insulin-producing cells (SCIPC) or enhanced beta clusters (eBC), or can be a pancreatic islet beta cell.
Nature of co-transplanted factors and sites of administration
The co-transplanted cells produce factors selected from vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), angiopoietin, gamma-aminobutyric acid (GABA), parathormone (PTH), PTH-related peptide (PTHrP), or combinations thereof. The transplant is administered to an extrahepatic site, preferably subcutaneous or intramuscular sites, using devices such as catheters, cannulas, syringes, or implantable devices.
Combination of distinct cell types producing different factors
A method for treating diabetes with a transplant comprising an insulin-producing cell, a cell producing one or more PTG hormones, and a cell producing one or more proangiogenic factors, wherein the hormone-producing cell is derived from PTG and includes hormones GABA, PTH, PTHrP, and the proangiogenic cell is a CD34+ cell producing VEGF, PDGF, angiopoietin, or combinations thereof.
The independent claims cover co-transplantation methods using insulin-producing cells combined with PTG-derived or CD34+ cells that produce proangiogenic factors and/or PTG hormones, administered to extrahepatic sites to treat diabetes mellitus, with specific emphasis on stem cell-derived and mature beta cells, and various modes of transplantation.
Stated Advantages
Improved survival of transplanted insulin-producing cells in extrahepatic sites by co-transplanting with PTG cells or CD34+ cells.
Enhanced vascularization and engraftment of the insulin-producing cell grafts resulting in sustained insulin production.
Achievement of diabetes reversal and insulin independence in animal models post co-transplantation.
Permits use of accessible transplant sites such as subcutaneous and intramuscular spaces enabling monitoring and retrieval.
Potential for renewable sources of supporting CD34+ cells derived from pluripotent stem cells for scalable therapeutic use.
Documented Applications
Treatment of diabetes mellitus including type 1 diabetes, type 2 diabetes, and surgical diabetes through co-transplantation of insulin-producing cells and parathyroid gland-derived cells or CD34+ cells.
Engraftment of pancreatic islet beta cells or stem cell-derived insulin-producing cells in extrahepatic sites such as subcutaneous or intramuscular spaces to reverse diabetes in patients.
Use of renewable vascular endothelial progenitor cells derived from pluripotent stem cells to promote engraftment of therapeutic insulin-producing cell grafts.
Development of pharmaceutical compositions comprising insulin-producing cells combined with PTG-derived and/or CD34+ cells for transplantation.
Use of delivery devices such as catheters, cannulas, syringes, and implantable scaffolds or encapsulation devices for co-transplanting cells.
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