Objective
Our main objective is to test a subcutaneous route of administration for THR-184, first in diabetic mice (specific aim 1) and then in non-human primates (specific aim 2). Our enabling data in mice demonstrates the effectiveness of THR molecules when administered intraperitoneally (i.p.). However, this route is potentially dangerous and would be highly impractical in the context of diabetes therapies. Hence the need to test the much less invasive subcutaneous means of administration. A third specific aim is geared towards establishing the safety of THR-184 as well as its pharmacological profile, including bioavailability, tissue distribution, half-life in the body, etc. Collectively, the successful completion of these studies will prepare us to submit an Investigational New Drug (IND) application to the FDA in anticipation of clinical trials for the replenishment of beta cells in T1D patients.
Background Rationale
Beta cell dysfunction/death is at the root of all insulin-dependent types of diabetes, including T1D and T2D.
For several years now, our team has been looking beyond islet or stem cell transplantation to restore insulin-producing beta-cells. We asked ourselves: what if we could stimulate resident stem/progenitor cells within the pancreas of the patient? Would they give rise to new beta cells right in the place that nature intended for them, thus bypassing entirely the need for transplantation? We are not the only ones asking these questions. Decades of research strongly support the notion that specific cells within the adult pancreas act as progenitors —stem-like cells with the ability to proliferate and give rise to new adult cell types, including beta cells. In spite of the abundant evidence, this idea remains controversial. This is chiefly due to some experiments on transgenic mice conducted in the early 2000s that seemed to exclude any meaningful role for progenitor cells in the regenerative process. However, there are now mounting concerns that a significant part of the mouse data may be flawed owing to limitations of the model.
Our team has recently identified a unique population of human pancreatic progenitor cells that remain intact in every T1D donor examined thus far, regardless of the duration of the disease. These stem cells are located within the ductal tree (the channels that conduct the digestive juices) of the pancreas. This location makes perfect sense, as the entire pancreas forms from ductal progenitor cells during embryonic development, and islets are nearly always in the proximity of ducts. We can selectively extract these cells from human donors and culture them for extended periods. Using a naturally occurring protein called bone morphogenetic protein 7 (BMP-7), we demonstrated that those pancreatic progenitor cells can become new islets in a dish. We confirmed this outcome when we transplanted these human cells into immunodeficient mice and then gave the mice BMP-7-like agents (THR molecules), showing for the first time that a pharmacological intervention (a “drug”, so to speak) was sufficient to induce the formation of beta cells from human pancreatic progenitors inside a living host. We have also been able to prove, for the first time, functional beta cell regeneration in living slices of the pancreas from T1D donors exposed to BMP-7 and THR molecules. Only after proving the concept using human cells, we went back to a diabetic mouse model. Diabetic mice received daily injections of a THR molecule. After just three weeks of treatment, the sugar levels of the treated mice dropped to near normal levels. When we analyzed the pancreas of the treated mice, the entire organ was literally teeming with new insulin-producing cells sprouting from the exact anatomical regions where we had first discovered the progenitor cells. One of these THR molecules, termed THR-184, has already been used in clinical trials for an unrelated application. We intend to repurpose it for beta cell regeneration in T1D patients.
Description of Project
The restoration of insulin-producing cell mass is of paramount importance in the development of any effective therapy for type 1, as well as severe cases of type 2 diabetes (T1D/T2D). Our enabling data show that small peptides that mimic the activity of BMP-7 –a naturally occurring protein that acts like fuel for progenitor (stem-like) cells across the body– induce the formation of new, functional insulin-producing beta cells in the pancreas of diabetic mice as well as in human pancreatic slices from T1D donors. This proposal aims at conducting a thorough preclinical evaluation of one such peptide, termed THR-184, as a lead candidate for clinical development. Our research will further our knowledge on human beta-cell regeneration while speeding up the development of potential therapies for diabetes. These studies are highly relevant to the mission of the Juvenile Diabetes Research Foundation (JDRF) and are expected to have a significant impact on public health.
Anticipated Outcome
We expect the subcutaneous route ofTHR-184 administration to be as effective as the intraperitoneal one to induce functional islet regeneration in mice (specific aim 1). Additionally, we anticipate this approach to reverse chemically-induced diabetes in non-human primates, a model much closer to humans than mice (specific aim 2). Finally, a battery of toxicology/pharmacological assays (specific aim 3) is expected to confirm the safety and suitability of THR-184 for clinical applications, thus paving the way to the design of clinical trials aimed at restoring beta cell mass in T1D patients. Given that beta-cell regeneration in T1D subjects would likely result in rapid rejection, the target population for the first clinical trials will be T1D patients already on immunosuppression for kidney transplantation. Since autoimmunity usually takes years to recur when subjects are immunosuppresed, this strategy would allow us to assess THR-184’s effectiveness without the confounding effects of underlying autoimmunity. Our longer-term objective is to clinically implement a THR-184-based beta-cell regeneration strategy as part of a combination therapy with suitable immunomodulation agents.
Relevance to T1D
The possibility of inducing endogenous regeneration of beta-cells directly in the pancreas of patients, without the need for transplantation, would be a groundbreaking advance in our quest to cure type 1 diabetes. Such objective is in direct alignment with the JDRF mission.