Early Translational III
Urinary incontinence (UI) is common and serious, with two-thirds of the burden borne by women. UI impacts both quality and length of life; women with UI suffer debilitating falls, experience social isolation and are clinically-depressed more commonly than continent women. UI is the primary reason for elderly women to be institutionalized and carries an annual healthcare cost that exceeds $20 billion in the USA. Up to 7 million Californian women are affected with UI, a number forecast to increase by 55% in 2010 to 2050. Surgery is the main treatment today but results can be variable with a need for repeat surgeries in 30-50% of women. Here, we describe our intended target product for UI based on FDA-compatible stem cells and a minimally-invasive route of delivery that is very familiar to physicians and is currently used for injection of bulking materials to treat UI. Our stem cell approach has the potential to provide an unlimited source of cells for tissue engineering and regenerative medicine. Thus, as an added benefit associated with this research, we establish a foundation for broad applications in women’s health including disorders that affect the same type of cells as in UI, smooth muscle, such as diseases of the blood vessels, respiratory tract (e.g., chronic obstructive pulmonary disease-COPD and asthma), digestive system (e.g. gastroesopageal reflux disorder-GERD and motility disorders) and others secondary to diabetes, neurodegeneration and common health problems.
Statement of Benefit to California:
Consider the tragic statistics that today the annual sale of diapers for urinary incontinence (UI) in women exceeds that of diapers for babies and that UI is the most common reason for families to institutionalize their elderly female relatives. The life expectancy of California women now exceeds 82 years. As we age, common age-associated tissue degeneration is a major physical, social, cultural and financial burden. Thus, UI is a major quality of life issue and public health concern both in terms of care and budgets. Overall, UI affects a staggering number of women resulting in annual health costs that exceed $20 billion nationally, a cost comparable to that of arthritis and greater than that of breast cancer and all gynecological cancers combined. Currently surgery is the most common treatment for UI, with good short-term but poor long-term data. Repeat surgeries are more morbid and have decreased efficacy; current alternatives provide even less relief. We suggest that we can “do better” by the women of California through step-wise research that leverages: 1) Small clinical trials that have already been conducted, 2) ability to produce large numbers of relevant cell types for UI treatment, and 3) unique expertise of our team. Our research overcomes major limitations to provide a ready stem cell-derived target product that we anticipate will provide a safe and effective treatment of UI resulting in improved quality of life of a significant fraction of our population.
In this Development Candidate (DC) application, the investigators propose cell therapy with smooth muscle precursor cells (SMPCs) and differentiated smooth muscle cells (SMCs) derived from autologous induced pluripotent stem (iPS) cells to treat stress urinary incontinence (UI). The DC will be a mix of SMPCs and SMCs differentiated in vitro, purified, and injected into the urethral sphincter, possibly along with materials selected to promote cell survival, engraftment and maturation. Toward this goal, good manufacturing practice (GMP)-compatible iPS cell lines will be generated from 3 women with UI, differentiation will be optimized, and benchmark assays will be developed to assess cell quality. Initial tumorigenicity, engraftment and differentiation studies will be followed by assays for disease-modifying activity in a rat UI model. Finally, a clinical strategy will be devised for subsequent human studies. Objective and Milestones - The target product profile (TPP) is scientifically and clinically reasonable. - The possible use of biomaterials together with cells would significantly raise the regulatory hurdles for clinical testing and implementation. While some reviewers felt the investigators did not adequately address the development of a possible combination product, others were less concerned as long as the decision to add materials was made early in the project. - Six milestones are laid out logically and generally appear feasible. Rationale and Significance - The medical need to treat UI is significant. Surgery is the most common and effective treatment for UI but often only provides partial relief or requires repeat surgery. - The rationale for cell therapy for UI is reasonable especially since proof of concept was established in a small clinical trial that involved injection of skeletal muscle-derived stem cells. - The investigators should consider the possibility that beneficial effects of cell therapy might result primarily from trophic activities of injected cells or from adding bulk to the sphincter, rather than from incorporation of injected cells into smooth muscle with specialized properties required for urethral sphincter function. - Reviewers did not find the applicant’s arguments for the potential advantages of SMPCs and SMCs derived from iPS cells over other cell types that have been proposed for treatment of UI compelling. As the proposed indication is not a life-threatening condition, the higher costs and potential risks of teratoma formation associated with iPS cells must be balanced against the theoretical argument that SMCs would be superior to other cell types. - The applicant should provide a rationale for considering a 50% improvement in the proposed outcome measure as therapeutic. Research Project Feasibility and Design - The investigators provided impressive data supporting their ability to generate iPS cells and to identify lines that have the greatest tumorigenic risk. - Preliminary data on differentiation protocols represents a reasonable start but does not take into account the substantial phenotypic heterogeneity of smooth muscle. - Critical testing of the injected cells for appropriate SMC function in urethral sphincter should be included in this study. - The choice of the UI model in rats is reasonable. - Reviewers judged the proposed dose range as too narrow, and recommended that establishment of dose response should include maximum feasible dose for safety. - The potential for immunogenicity of the differentiated iPS cells needs to be addressed. Qualifications of the Principal Investigator (PI) and Research Team - The high quality team represents an important strength of this proposal, the PI brings strong credentials in working with human embryonic stem cells and iPS cells and the Co-PI has excellent credentials as a clinician and with clinical trials. - Other key personnel bring relevant expertise to the project; strengths include highly relevant experience in the use of the rodent disease model, biomaterials expertise and collaboration with a GMP facility. - The team does not appear to include a member with specific, deep expertise in physiology/pharmacology of smooth muscle, particularly in the genitourinary system. This is a significant deficiency. Collaborations, Assets, Resources and Environment - Since the team appears to be involved in an ongoing collaboration, there are no apparent issues with coordination of collaborative activities. - Resources and environment are excellent; the proposal draws on multiple strengths and resources of outstanding investigators at three institutions. Responsiveness to the RFA - The proposal is responsive to the RFA.
- - A motion was made to move this application into Tier 1, Recommended for Funding. The clinical area under investigation is not yet represented in CIRM’s portfolio. The application targets inoperable UI, a major problem that occurs predominantly in women. The motion carried.