New Faculty Physician Scientist
$3 084 000
One of the most promising approaches that physicians foresee for treating human disease is regenerative medicine. A major aim in this field is to restore function by repairing damaged organs. Inflammatory bowel disease (IBD) is a chronic disease characterized by intermittent episodes of intestinal inflammation and disruption of the intestinal epithelial barrier. It causes significant morbidity and can lead to multiple complications, including growth impairment, intestinal failure, malnutrition, and cancer. IBD has increased in incidence and prevalence globally over the past several decades, and the increasing number of patients suffering from IBD has translated into growing health care costs. Our goal is to bring regenerative medicine approaches to the treatment of IBD by making intestinal structures called “organoids” from human embryonic stem cells. These organoids will be delivered to the intestines in order to repair damage. If the aims of the application are achieved, our findings will make a critical contribution to development of a needed therapeutic.
Statement of Benefit to California:
The promise of stem cell biology lies in the ability of these remarkable cells to give rise to more differentiated cell types that can repair damaged or diseased tissues. We propose to develop translational approaches that will enable the utilization of human embryonic stem cells for therapeutic applications in inflammatory bowel disease. We anticipate that our research will be a significant step towards making the promise of regenerative medicine from stem cells a reality. Eventually, stem cell-based therapies will reduce health care costs for Californians by improving treatment for diseases for which we currently do not have effective therapies. Our work could provide economic benefits to the state by helping to lay the groundwork for commercial efforts to repair diseased tissues using stem cells. Such developments would be of great benefit to California by making the state a leader in a field that is poised to become economically important in the future.
Executive Summary Crohn’s Disease and Ulcerative Colitis are the two main manifestations of inflammatory bowel disease (IBD), which globally affects millions of children and adults and is growing in prevalence in the United States. IBD results in growth impairment, intestinal failure, malnutrition and, in some instances, can lead to bowel cancer with a fatal outcome. Present therapies are incompletely efficacious and are directed to immune response modulation and immunosuppression which can result in multiple and severe complications. This application proposes to use cell therapy to replace and restore the normal epithelium in the gut. To achieve this, the principal investigator (PI) has proposed three specific Aims: Aim 1 will optimize culture conditions to maximize efficiency of human embryonic stem cell (hESC) differentiation into intestinal organoids. Aim 2 will confirm that the hESC-derived organoids have the ability to engraft with the host tissue. Finally, Aim 3 will test the function of the newly engrafted organoids to treat the IBD caused injury in a preclinical model. Research Plan - Chronic IBD is a significant health issue and the goal of this proposal to regenerate the affected epithelium by replacing local epithelium is a novel and interesting approach. - The experimental design is feasible and given the collaborator’s experience with human embryonic stem cells (hESCs), reviewers’ enthusiasm was increased. - Reviewers generally found the proposed experimental plan to be novel and were assured by the convincing preliminary data that both the PI and his/her collaborators have mastered all the necessary techniques to successfully execute the proposed aims. - There was some question regarding the rationale for using hESCs as opposed to induced pluripotent stem cells (iPSCs) given the allogeneic barrier and some reviewers suggested the use of iPSC-derived organoids right from the start of the project. - Some reviewers raised minor concerns regarding the relevance of studying IBD, an inflammatory disease, in an animal model that is not immune competent. Principal Investigator (PI) - The PI is a previously CIRM funded investigator and with a very strong track record and impressive publications. She/he has extensive experience in his/her chosen field and in working with stem cells. This application represents a move to a new area of expertise: stem cell in the gastrointestinal (GI) tract. - Although this is the first attempt by the PI to carry out stem cell work in the GI tract and many reviewers were generally supportive for this extension to her/his work, not all reviewers agreed that this RFA is the appropriate vehicle for funding this work. - The application includes a sound mentoring plan, though reviewers were not certain this individual still requires a mentoring plan at this stage of his/her career. Institutional Commitment - There is excellent institutional support with substantial commitment to the research career of the PI. - The institution is supportive of both the PI and translational stem cell research. Responsiveness - While the candidate meets the threshold for eligibility of this RFA, the candidate has received several young investigator awards, and is extremely well funded by other agencies, including the National Institutes of Health (NIH). It is not clear that this award is necessary to the success of this candidate as a physician scientist, and in that regard, the application is minimally responsive to the objective of the RFA. - The proposal utilizes human stem cells and is translational in focus and the proposed research is responsive to the RFA.
- A motion was made to move this application into Tier 1, Recommended for Funding.
- While reviewers agreed that this is an impressive and highly productive individual, the panel was divided as to whether the PI meets the objective of the RFA. Some felt that this is a highly established investigator who has already benefited from several young investigator awards and, while recognizing the move by candidate into a new area of expertise, thought this particular research could be funded by the NIH. Others thought the proposed work expands the candidate’s expertise into a new area where he/she could have a substantial impact and pointed out that the candidate is challenging existing dogma from more established investigators and could have difficulty obtaining funding. It was noted by the panel that this project focuses on a serious disease and has a high promise for success and that the candidate does in fact meet the eligibility criteria. The motion carried.