The generation and expansion of tissue-engineered small intestine from human stem/ progenitor cells: a preclinical study of functional translation
New Faculty Physician Scientist
This proposal aims to complete the preclinical steps to develop tissue-engineered intestine (TESI) as a functional replacement of the small intestine to treat short bowel syndrome (SBS). Common birth conditions especially those associated with prematurity result in SBS wherein 50-75% of the small intestine is gone. SBS children cannot get adequate nutrition and supportive medical care is morbid with liver failure a common problem. Small bowel transplants, the only current salvage therapy have many problems including poor graft survival, rejection, limited donor supply, surgical morbidity, and lifelong immunosuppression. We hypothesize that TESI from the patient's own cells offers a potential, durable human progenitor-cell based treatment option for SBS. We have shown that TESI forms when autologous cells are implanted on a polymer scaffold, and that TESI exactly recapitulates native intestine: all four differentiated epithelial cell types in conjunction with the key supporting structure such as nerves, and muscle, grow from the transplanted OU. Importantly, Lewis rats recover from massive small bowel resection with TESI. Other regions of the gut can also reengineered via this approach. Our goal is to translate TESI from rodents to an autologous human cell based therapy. Patients who needed emergency surgery for their intestine, which might leave the remaining amount of intestine too short to absorb enough nutrition could potentially be treated with TESI.
Statement of Benefit to California:
In the pediatric population, the incidence of SBS is estimated to be 24.5 per 100,000 live births and associated with a 30% 5-year mortality. To put this in perspective, the NCI reports the cumulative incidence of all invasive childhood cancers is 14.5 per 100,000. In addition, cancer, inflammatory bowel disease and mesenteric ischemia put the adult population at risk. In fact, the incidence of SBS is increasing with a striking 30% 5-year mortality. Annual cost per patient in Europe ranges from $100,000 – 150,000 and is double that in the US . SBS is an unsolved problem with unacceptable human and financial cost. An autologous engineered tissue approach would surpass current therapies. Usable engineered intestine would be far less expensive, more durable, and require less maintenance than any current therapy. California would benefit from this research in many ways- we have a large population and improved and less expensive medical care with less suffering for patients would be the most important benefit to the state and to the people of California. In addition, being at the leading edge of this translational approach will make our state and our institutions experts in the translation of stem cell research, a focus point for attracting scientists and innovators to the state and opening up future therapies building on these results. Finally, this approach will generate intellectual property that can be protected and will also benefit the state and its economy.
Executive Summary The goal of this application is the conduct of preclinical studies to contribute to an IND filing for autologous Tissue Engineered Small Intestine (TESI) as a functional replacement for patients with short bowel syndrome (SBS). The applicant proposed to first develop GLP and GMP processes for harvest, storage, and in vitro expansion of autologous human organoid units (OU) containing intestine progenitor/stem cells. Transplanted human TESI function will be evaluated in a relevant preclinical model to support clinical development. Research Plan -The rationale for the proposed research is logical and compelling from both a scientific and medical perspective. The project goal is significant and addresses an unmet clinical need. TESI has the potential to advance stem cell derived therapy, and represents a realistic approach to fundamentally alter the need for intestinal transplantation by using an autologous approach to intestinal replacement. This would be a transformational breakthrough. - Although reviewers were overall enthusiastic about the proposed project, they noted that a primary hurdle is the scale-up of TESI for testing in a relevant preclinical model and were mixed as to whether this should occur prior to or concomitant with development of autologous human GMP processes rather than later in the project as proposed. - Reviewers considered the project to be exceedingly ambitious in the sheer scope of work proposed but considered even partial success to be money well spent. Principle Investigator - The PI has impeccable credentials, having trained with one of the founders of tissue engineering field. S/he has an excellent track record, has published on research related to the proposed project and has clinical duties related to this area of research. - The milestones for career development are realistic and the chosen mentors are excellent. -The PI is well positioned to be a leader in this field. Institutional commitment - The institutional support for the PI is very good. The reviewers also considered both the environment and the collaborators to be good. - The institution has an excellent track record for development of new faculty and is committed to translational efforts in stem cell therapy. Responsiveness -The proposal is responsive to the RFA and is unlikely to be federally funded. - Human endogenous intestinal stem cells and mesenchymal stem cells are required for the ultimate success of the work. The research is highly translational and addresses a translational hurdle.