This project addresses a bottleneck issue in cell transplant for the treatment of type 1 diabetes (T1D).
This project aims to identify an optimal site outside the liver for improved islet/stem cell transplant. We will test 2 sites: the omentum (OM, tissue around gut) and subcutaneous (SC, under the skin) in dogs.
The OM provides a large, easy-to-access area for transplant; but has poor blood supply. We will use 2 sheet designs to overcome this issue. Sheet 1 contains PVA, which has been successfully used to reverse diabetes in mice. Sheet 2 is an alginate-based sheet that protects cells between 2 layers. Transplant to the SC site is less invasive, but limitations include cell clumping, slow blood vessel growth, inflammation, and potential damage to transplanted cells because they are close to the body’s surface. A small stainless-steel mesh cage will be constructed to allow blood vessels to grow before the islet cells are placed inside. The OM sheets and SC cage will be treated with the factors to help blood vessels grow. A drug to prevent inflammation with also be tested to improve results. Results at the liver, OM and SC sites will be compared to identify the best transplant site. We will also test our stem cell’s function at the selected transplant site.
This study will address problems facing the use of cell therapy for T1D by improving cell survival and the safety of future stem cell transplants by allowing the retrieval of cells, if rejection or cancer develops.
Statement of Benefit to California:
It is estimated that 1 out of 7 California (CA) residents has diabetes or is at high risk of developing the disease. Up to 10% (300,000) are thought to have or be at risk for type 1 diabetes (T1D). T1D is an autoimmune disease that destroys insulin producing cells. Patients with T1D must take insulin injections to survive. Even with insulin, it is difficult to achieve good blood sugar control, which can lead to devastating complications, including heart disease, blindness, limb amputation, and kidney failure. A quarter of the Medicare budget is spent on diabetes-related care, which is a financial burden to State and Federal health care programs, and the taxpayers who support them.
Islet transplantation is capable of restoring euglycemia in patients with type 1 diabetes (T1D). However, longevity of the transpanted islet cells at the portal site has been limited. This is a proposal to determine whether alternative sites of islet transplantation could improve the level of metabolic control and islet longevity compared to the traditional intraportal sites. The applicant believes that exposure to toxins and bacterial products induce inflammatory cell activation and cytokine release in the liver that are destructive to islets injected intraportally. Moreover, the intraportally-dispersed insulin-producing cells derived from stem cells may become inaccessible for biopsy and untraceable for monitoring of abnormal transformation to teratomas. The applicant plans to investigate omentum and subcutaneous islet transplantation as an alternate approach and to evaluate these alternative sites in a preclinical model. Investigations will attempt to solve the problem of vascularization by providing scaffolds and growth factors. The addition of mesenchymal stem cells to the graft to induce anti-inflammatory effects will also be explored.
Although the rationale for the proposed studies seems logical, reviewers were not convinced that the proposal addresses a significant bottleneck in stem cell transplantation. Reviewers found the design of the study to be unfocused and overly ambitious. The application does not advance the development of a specific product candidate and mixes desperate studies of optimum location for islet cell therapy, use of immune modulating helper cells, and efforts to generate insulin-producing cells in an in vivo model system using gene therapy. Reviewers did not find the mélange compelling. Reviewers were particularly critical of what they perceived as a superficially described aim of reprogramming pancreatic cells to insulin producing islet cells in vivo. No details on the experimental design of the transduction were provided in the proposal and no consideration was given to the possibility of tumor formation from the induced pluripotent stem cells (IPSc). Additionally, reviewer enthusiasm for monitoring of inflammation and immunosuppression with blood-based mRNA profiling and examination of other inflammatory markers was low, as many groups have attempted to identify such markers without much success.
The PI is a well-known expert in clinical studies of transplantation and the use of preclinical models. The research team is well qualified to carry out most of the studies. However, it was somewhat unclear whether the team has appropriate expertise in molecular biology and stem cell reprogramming. The environment at the host institution contains all the tools needed for the proposed studies of islet transplantation. Collaborators seem appropriate.
In summary, the applicant proposes to explore novel sites for implantation of pancreatic islet cells. Though the idea is noteworthy, reviewers were not convinced that it addresses a critical bottleneck. They also raised serious doubts about the research design and its feasibility.