SBIR-STTR Award

?Both type 1 and type 2 diabetes involve loss of insulin-producing pancreatic ?-cells resulting in inadequate insulin secretion to control blood glucose. Eventually, daily injections of insulin are required to avoid the constellation of pathologies that arise from hyperglycemia. While transplantation of cadaveric pancreatic islets that contain ? -cells has been successful for treating a small number of patients the supply is fa too limited. Production of functional ? -cells from embryonic stem cells remains an exciting possibility for future treatments but will still involve transplantation with immune protection unless patient-specific ? -cells can be produced. Induction of proliferation in remaining ? -cell has progressed in rodent studies but has not yet been successfully adapted for human ?-cells. Expansion of endogenous ?-cell mass, such as through transdifferentiation of ? -cells into functional ? -cells represent appealing potential therapeutic solutions to restoring glucose control. Our prior research has identified the activin signaling pathway and its regulation by a natural antagonist, FSTL3, as having influence on islet cell fate such that loss of FSTL3 (FSTL3 KO mouse) results in expansion of ? -cell mass and islet size, resulting in improved glucose regulation. Preliminary results suggests that this ? -cell expansion is due, at least in part, to increased ?- to ? -cell transdifferentiation. Therefore, the long term goal of Fairbanks Pharmaceuticals is to identify antagonists of FSTL3 that will replicate the phenotype of the FSTL3 KO mouse and thus have therapeutic potential. The research proposed here will address the clinical need for new diabetes therapies by developing a new FSTL3 antagonist (Specific Aim 1) as well as characterizing this antagonist for site-specific interactions with FSTL3 that lead to its neutralization (Specific Aim 2). The net effect of FSTL3 neutralization will be increased activin bioactivity which will be detected using an in vitro bioassay in which luciferase expression is enhanced in the presence of activin signaling. This will facilitate screening panels of inhibitors to identify candidates with the desired characteristics and thus, the highest probability for in vivo activity. Together, the two Specific Aims will identify the top 2 to 3 candidate FSTL3 neutralizing compounds that will be tested in animal models of diabetes in vivo as well as on human islets in a Phase 2 application. Successful FSTL3 antagonists can then be tested in clinical trials for effectiveness in treating diabetes in humans during Phase 3 activitie. The ultimate goal is to produce a new diabetes therapy that can increase the number of a patient's own ? -cells that will restore glucose control and thus, prevent development of diabetes.

Public Health Relevance Statement:


Public Health Relevance:
The proposed research is relevant to public health because it addresses the critical issue of developing new treatments for diabetes, a major national health care concern. These patients cannot synthesize sufficient insulin to control blood glucose leading to life-long health complications. The research proposed here will capitalize on our prior research through development of a new therapy that will stimulate replacement of lost insulin-producing cells.

Project Terms:
No Project Terms available.

Both type 1 and type 2 diabetes involve loss of insulin-producing pancreatic ?-cells resulting in inadequate insulin secretion to control blood glucose, and ultimately requiring daily insulin injections to avoid the constellation of life-threatening complications that arise from long-term hyperglycemia. While transplantation of cadaveric pancreatic islets that contain ? -cells has been successful for treating a small number of type 1 diabetic patients the supply is too limited for the number of type 1 diabetics. Production of functional ?-cells from embryonic stem cells remains an exciting possibility for future treatments but will still involve transplantation with immune protection unless patient-specific ?-cells can be produced. Induction of proliferation in remaining ?-cells has progressed in rodent studies but has not yet been successfully adapted for human ?-cells. Recently, both mouse and human islet cells have been demonstrated to undergo transdifferentiation to different cell types revealing a previously unappreciated flexibility in cell fate. This observation suggests that expansion of endogenous ?-cell mass through enhancing transdifferentiation of ?- cells into functional ?-cells represents an appealing therapeutic solution to restoring glucose control and curing diabetes. Prior research identified the activin signaling pathway and its regulation by a natural antagonist, FSTL3, as having influence on islet cell fate through enhancing ?- to ?-cell transdifferentiation. Our Phase 1 research was directed toward developing FSTL3 antagonist compounds that could block its binding to activin, thereby increasing bioactive activin signaling and enhancing islet function. As demonstrated in the progress report, feasibility of this approach was established and a lead prototype compound generated that could disrupt activin-FSTL3 complexes, was specific for FSTL3, and stimulated glucose mediated insulin release from diabetic islets in vitro. The goal of the proposed Phase 2 research is to demonstrate that FSTL3 neutralization is an effective treatment in vivo and in human islets that can restore glucose homeostasis through enhanced ?- cell regeneration. The top candidate compound from Phase 1 will be tested for restoration of glucose control in mouse models of type 1 and type 2 diabetes as well as in human islets transplanted into mice (Specific Aim 1). In Specific Aim 2, mouse and human ?-cells will be labeled, treated with the top candidate compound, and ?- to ?-cell transdifferentiation quantitated as a measure of ?-cell regeneration. Specific Aim 3 will entail humanization of the lead compound along with large scale production and toxicity testing to prepare for large animal and eventual human testing. The long-term goal of this research is to develop a humanized version of our top compound, demonstrate its safety, obtain an IND and test safety and effectiveness of this therapy in phase 1 and 2 clinical trials. The ultimate goal is to produce a transformative diabetes therapy that can increase the number of a patient’s own ?-cells to restore glucose control and thus reduce or eliminate diabetes.

Public Health Relevance Statement:
The proposed research is relevant to public health because it addresses the critical issue of developing new treatments for diabetes, a major national health care concern. These patients cannot synthesize sufficient insulin to control blood glucose leading to life-long health complications due to loss of beta cells and our therapy will speed up regeneration of these cells. The Phase 2 research proposed here will capitalize on our Phase 1 progress that established feasibility and in vitro activity of our lead prototype therapy that will be further evaluated in mouse diabetes models.

Project Terms:
Activins; Acute; Address; Affinity; Animals; Antibody Therapy; Area; Autoimmunity; base; Beta Cell; Binding; Blood Glucose; blood glucose regulation; Cadaver; cell type; Cells; Chronic; Complex; cost; Detection; Development; Diabetes Mellitus; diabetes mellitus therapy; diabetic; Diabetic mouse; diabetic patient; Diet; Dose; Drug Kinetics; effective therapy; Effectiveness; embryonic stem cell; experience; Failure; flexibility; Flow Cytometry; Follistatin; FSTL3 gene; Future; Glucose; Goals; Grant; Health; Healthcare; Human; humanized antibody; humanized monoclonal antibodies; Hyperglycemia; Immune; Immunocompromised Host; immunocytochemistry; improved; In Vitro; in vitro activity; in vitro testing; in vivo; Injectable; Injections; Insulin; Insulin Resistance; insulin secretion; Insulin-Dependent Diabetes Mellitus; islet; Islet Cell; Islets of Langerhans; Label; large scale production; Lead; Life; Maximum Tolerated Dose; Measures; Mediating; Medical; Modeling; Monoclonal Antibodies; mouse model; Mus; Natural regeneration; neutralizing antibody; neutralizing monoclonal antibodies; Non-Insulin-Dependent Diabetes Mellitus; novel; Nude Mice; Obesity; Patients; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Preparation; prevent; Prevention therapy; Process; Production; Progress Reports; Proteins; prototype; Public Health; Regulation; Research; restoration; Rodent; Rodent Model; Safety; safety testing; Signal Pathway; Signal Transduction; Specificity; Speed; Streptozocin; Structure of beta Cell of islet; Target Populations; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Toxicity Tests; Toxicology; transdifferentiation; Transplantation; type I diabetic