The proposed Disease Team is directed at developing new therapies for diabetes. There are two major forms of diabetes. The first is a disorder of the immune system in which immune cells kill the insulin producing cells in the pancreas, known as beta-cells. The lack of insulin makes is impossible for glucose to enter cells, leading the high levels of glucose in the blood that are characteristic of diabetes. This disorder usually begins in childhood. The second major form of diabetes is strongly associated with obesity. In this complex disorder, resistance to the effects of insulin leads to high levels of blood glucose. In addition, over time the beta-cells become dysfunctional and eventually die. Frank diabetes does not occur until there are too few beta-cells to secrete enough insulin to control the blood glucose. Thus, in both major forms of diabetes, beta-cell dysfunction and/or death is central to the disease process. The Diabetes Team that we are planning will pursue a number of approaches to increasing the number of beta-cells in people with diabetes. In one approach, we will use embryonic stem cells, developed with conventional and novel methods, to create beta-cells outside the body. Those cells will be transplanted, first into animal models of diabetes and then in small scale human trials. The goal will be to determine the most efficient and safest method of inducing embryonic stem cells to become beta-cells. In addition to embryonic stem cells, Disease Team members will work on inducing adult pancreatic cells to differentiate into beta-cells. These adult progenitor cells have been controversial, with some investigators even questioning their existence. However, more recent evidence indicates that there are beta-cell progenitors in the adult pancreas, but they remain quiescent for the most part. However, if we can understand more about how to induce those cells to become beta-cells, it may be possible to repopulate the pancreas of diabetics who have lost the beta-cells. Under most circumstances, beta-cells regenerate themselves by splitting into two, a process called replication. However, beta-cell replication occurs infrequently and we do not understand the factors that are required to signal to the beta-cell that it must replicate itself. Developing a sufficiently detailed understanding of those factors to allow us to stimulate beta-cell replication in patients with diabetes will be another area of focus for the proposed Disease Team. Finally, an important element of the team will be to test therapies that are developed in animal models and eventually in small-scale human clinical trials. We believe that combination of approaches that are planned by the members of the proposed Diabetes Disease Team will lead to new treatments for diabetes.
Statement of Benefit to California:
Diabetes, particularly type II diabetes, is rapidly increasing in prevalence in the United States, including California. This is due primarily to the rapid increase in the percentage of the population who are obese. It is clear that frank type II diabetes does not occur until beta-cells have been damaged to the point where they are unable to compensate for the increase demands placed upon them by peripheral insulin resistance. In the other major form of diabetes, autoimmune or Type I, beta-cells are destroyed by an aberrant immune response. Thus, in both major forms of diabetes afflicting citizens of California, beta-cells play a critical role in the development of diabetes. The focus of this proposal is on preventing or treating diabetes by increasing the number of beta-cells. Through interactions with biotechnology companies, the commercialization of new therapies for diabetes should benefit the economy of California. More directly, new therapies will benefit the citizens of California by improving the state of health of those citizens afflicted by diabetes.
The focus of this Disease Team Planning proposal is to develop a beta cell replacement / regeneration therapy for both type 1 and 2 diabetes. The proposal covers a diverse spectrum of approaches with 4 major components: developing beta cells from induced pluripotent stem (iPS) cells, inducing beta cell differentiation from adult endocrine progenitors, promoting replication of endogenous beta cells, and solving clinical translation issues.
While the science may be excellent in all 4 proposed components, it is clear that no component has reached the appropriate maturity to now be focused on moving into clinical trials within the 5 years, as stipulated in the Disease Team Planning RFA. The clinical translation component addresses the use of high throughput screens to identify potential therapeutic molecules, as well as the use of macroencapsulation devices for transplantation, but neither approach is discussed in the context of a clinical target. The proposal comprises an array of divergent approaches being explored rather than a focused effort to understand the gaps in the field and to create a team that will take the basic science to the clinic. It seems that each of the proposed components will continue to be studied individually without obvious integration, and it remains unclear what the planning approach will be to take the varied components to clinical trials. Therefore, the proposal itself does not focus on what was requested for this RFA.
The applicant is a well-established Professor of Pediatrics and acting Chief of a Division at the home institution. S/he is well funded for research relevant to this application. The principal investigator’s CV demonstrates proficiency in the topics proposed. His/her area of interest has been to develop a method to obtain human beta cell surrogates using various approaches; s/he has contributed substantially to this area. It remains unclear what experience s/he has had in orchestrating large groups of independent investigators. Many of the scientists involved are excellent and committed. The proposed team includes basic and clinical scientists and industry personnel, a diverse team which was considered a plus by one reviewer, whereas another reviewer felt that expertise with clinical trials was not properly represented in the proposed team.
In summary, the proposal was judged to be more like a collection of basic science projects rather than multidisciplinary translational or clinical research, and reviewers were not confident that any of the four components would be ready for clinical trials within five years. Therefore, this application did not warrant a planning award at this time.
Reviewer One Comments
The focus of this Disease Team is to develop a beta cell replacement / regeneration therapy for both type 1 and 2 diabetes. The proposal covers a spectrum of approaches with 4 major components: developing beta cells from induced pluripotent stem cells (iPS), inducing beta cell differentiation from adult endocrine progenitors, beta cell replication, and clinical translation via in vivo regeneration and ex vivo approaches. The clinical translation component as presented only addresses the use of high throughput screens to determine potential molecules (the PI has been funded to do such screens for two years already) and the use of macrodevices for transplantation. Many of the scientists involved are excellent and committed. While the science may be excellent in all these components, it is clear that none has reached the appropriate maturity to now be focused on extending to clinical trials within the 5 years of this program. In fact, the proposal is an array of divergent approaches being explored rather than a focused effort to understand what are the gaps in the field and how to combine a team that will take the basic science to the clinic. The proposal itself does not focus on what was requested for this RFA.
Dr. Fred Levine is a Professor of Pediatrics at UCSD, Adjunct Professor at the Burnham Institute, and Acting Chief of the Division of Genetics, Department of Pediatrics, UCSD. His area of interest has been to develop a means to obtain human beta cell surrogates using viral vectors, genetic engineering and either human or fetal human tissue; he has contributed substantially to this area. His most recent research is on small molecule screening for enhancing beta cell number and function whether by replication or by differentiation. It is unclear, either from his CV or from the Principal Investigator and Feasibility page of this application, what experience he has had in orchestrating large groups of independent investigators.
There are 4 components listed but it seems that each one will continue studying the research area without obvious integration. It is unclear from the application what the planning approach will be to take the varied components to clinical trials. It is listed as “the composition will be modified during the planning process, consisting of a series of meetings, both broad and focused on one of the four target areas”.
Reviewer Two Comments
The team includes basic and clinical scientists and industry personnel. A plus from the standpoint of diversity. Importantly, the team will not just try to make islets, but will explore the immune aspect of proposed future transplants. Since the immune system seems to hold the key to sustaining beta cell function, any application that does not include investigation of immune mechanisms is incomplete.
Dr. Levine received his MD in 1986 from the Univ. Washington. He did postgraduate work at the University of Pennsylvania and UCSD. He has been a member of the department of Pediatrics at UCSD since 1989. He is now Professor and acting Chief of the Division of Genetics, Department of Pediatrics. He is well funded for research relevant to this application. His CV demonstrates proficiency in the topics proposed here.
Dr. Levine will rely mainly on the help of Dr. Maike Sander, an expert in mouse models of beta cell development to help develop the application. Others included in the application come from La Jolla, UC Irvine, and UCLA. A significant role is proposed for researchers from Novocell. Dr. Yang Xu from USCD will provide genetically modified hES and iPS cells to the project. Additional personnel will contribute specifically to projects directed towards differentiation of endocrine progenitors, beta cell replication, and macroencapsulation. The approach seems much more like a renewal of NIH-funded basic science projects rather than translational research. There does not appear to be a team of individuals conducting clinical or translational research or with real expertise in clinical trials.