Early Translational I
$3 773 313
In this grant we propose to develop a cell-based treatment, using a woman’s own stem cells from her uterus, to regenerate weakened or damaged pelvic muscles and tissues resulting most commonly from childbirth and aging. Pelvic floor disorders affect millions of mid and older age women and cost the health care system > $20 billion annually. Symptoms include urinary and bowel problems, prolapse (herniation) of the pelvic organs, and sexual dysfunction. These disorders significantly impact women’s quality of life and productivity and their families. 10% of women have surgery for a pelvic floor disorder, and 30% of these have >2 operations due to surgical failure, comprising >500,000 procedures per year in the U.S. alone. Synthetic and biomaterial meshes are commonly used to provide improved long-term outcomes with surgical treatments; however, about a third of meshes cause scarring, erosion and pain. New methods need to be developed to address the underlying problem – i.e., damaged tissues in the pelvis that need to be regenerated and repaired, which meshes and surgery do not do. In this grant we propose to develop a candidate cell therapy using a woman’s own stem cells from the lining of her uterus to repair and regenerate her own damaged pelvic floor tissues. Some of the lining of the uterus (endometrium) can be obtained by gentle aspiration under local anesthesia in a doctor’s office in women having regular menstrual cycles or post-menopausal women taking estrogen for a short period of time. There are many cell types in the uterine lining, including stem cells that help to regenerate the tissue on a monthly basis. After isolating the stem cell population and growing them to increase their numbers, we are first proposing to incorporate them into novel, small bioengineered support structures (beads and “scaffolds”). Then, we shall test in vivo in animal models of pelvic floor disorders – specifically stress urinary incontinence and pelvic organ prolapse - whether the cells will generate the different cell types and proteins needed to repair damaged pelvic floor tissues, as they do in laboratory experiments in vitro AND prevent or reverse the associated clinical abnormalities. After extensive tests in animal models, this grant will set the stage to conduct trials in women with these pelvic floor disorders to assess whether the cell-based regenerative treatment is safe, with limited side effects, and has long-term efficacy. Our overarching goal is ameliorating symptoms associated with these debilitating disorders and potentially having the treatments office-based.
Statement of Benefit to California:
The proposed research will benefit the State of California and its citizens because it has the potential to fulfill an unmet medical need in a set of disorders that are common and debilitating in the rapidly growing population of mid-older age women in our State. Pelvic organ prolapse and stress urinary incontinence, the focus of this grant, are common disorders of the pelvic floor, affecting millions of mid and older age women and costing the California health care system billions of dollars annually. Symptoms include urinary and bowel dysfunction, urinary and fecal incontinence, and sexual dysfunction. Risk factors are childbearing, obesity, chronic respiratory disease, and age. In California, as in the rest of the U.S., obesity is highly prevalent, with approximately 50% of our citizens being overweight or obese and 25% not physically active. Many women require surgery for these disorders, and since the adjunctive use of meshes and other support materials cause major problems about 30% of the time, alternatives that address the underlying problems of pelvic floor disorders are imperative to pursue. This grant proposes a stem-cell based therapy for repair and regeneration of pelvic floor tissues in the setting of the pelvic floor disorders of stress urinary incontinence and pelvic organ prolapse that share a common abnormality of the fibromuscular tissue in the pelvis. Since our population is aging, and since obesity is so prevalent, it is anticipated that the hidden epidemic of pelvic floor disorders will become worse. The approaches proposed herein offer a biologically sound approach to these debilitating disorders, which will benefit the well being and productivity of a growing segment of California’s population. This proposal will also set the stage to conduct safety and efficacy trials for the development candidate stem cell-based therapy. The feasibility of conducting such trials in California is high, as we have a long-standing clinical trials network in incontinence research at our institution. Our Women’s Continence Center was recognized as the first “Outstanding Continence Center” by the National Association for Continence, a premier U.S. patient advocacy group that is working with us to provide a public forum on pelvic floor disorders at the International Continence Society meeting in San Francisco in September of 2009. Thus, our proposed research, our expertise in translational science and stem cell biology, and our clinical trials networking, along with our Victoria collaborators’ expertise in stem cell biology, biomaterials, and bioengineering, enhance the overall feasibility of success for this proposal that will greatly benefit women with pelvic floor disorders in our State. In addition, manufacturing the proposed stem cell therapy offers an opportunity to California companies for business development and marketing.
This proposal focuses on the development of human endometrial mesenchymal stem cells (eMSCs) as a treatment for pelvic floor disorders. The endometrium has recently been identified as a source for highly replicative stem cells that can be harvested without significant pain or other morbidities. The applicant proposes to first characterize these eMSCs and optimize their growth and differentiation into various cell types. Then the applicant proposes to develop novel synthetic scaffold patches and injectable beads to aid delivery and engraftment of eMSCs. Finally, the applicant will test these cells and delivery constructs in preclinical models of pelvic floor disorders in three species, and develop a product plan for an autologous eMSC-based therapy for human patients. The reviewers were enthusiastic about the potential impact of this proposal and agreed that it addresses an important, often overlooked, unmet medical need. There is a high incidence of pelvic floor disorders in the aging female population, including pelvic organ prolapse and stress urinary incontinence. The reviewers noted that pelvic floor disorders are understudied, present therapies are suboptimal and a regenerative approach could markedly improve the quality of life for patients. In addition, the eMSCs developed in this proposal have potential utility in regenerating other tissues besides the pelvic muscles. The reviewers praised some aspects of the research plan but felt that others were underdeveloped. They noted that a large-scale body of work is proposed, raising questions about feasibility. One reviewer commented that the characterization studies of the putative eMSCs would demonstrate multipotency, assess differentiation potential and the immunomodulatory properties of the eMSCs. Comparisons with MSCs from other sources (e.g. bone marrow) will be done, but one reviewer speculated the cells would likely have similar properties. One reviewer noted that while differentiation studies may be important in understanding the regenerative capacity of eMSCs, undifferentiated cells may have greater potential to drive tissue repair, and that the undifferentiated vs. differentiated eMSC comparison might be a richer translational approach. Most of the reviewers’ concerns were with Aim 3, which describes the development of novel synthetic implantable scaffolds that promote attachment and differentiation of eMSCs. Reviewers felt that this aim could be critical to the success of the project but was not developed thoroughly enough in the proposal. They acknowledged that the research team has considerable expertise in the development of polymeric scaffolds but pointed out that this is a new application that may be accompanied by unanticipated problems, such as the development of adhesions within pelvic organs. Reviewers would have appreciated a discussion of potential pitfalls and alternative approaches, and suggested that more preliminary work be done to determine how the cells interact with the materials in vivo, highlighting the degradation rate as an important variable that might impact the mechanics of the repaired tissue. One reviewer noted the preliminary data presented with existing microbead technology and encouraged the applicant to pursue existing biomaterials for scaffold design while developing novel materials in parallel. The reviewers also raised issue with the use of four animal models (in three different species) for testing in Aim 5, doubting feasibility and suggesting that the large animal preclinical studies may be beyond the scope of a 3-year study. Finally, one reviewer expressed emphatic support for the use of female stem cells to treat female patients, noting a growing body of data suggesting that donor sex influences engraftment success. The reviewers praised the applicant’s experience and publication record and felt that the research team is well-qualified to carry out the proposed research. One reviewer commented that the collaborative team assembled represents an optimal combination of skills and talents for this proposal, and that responsibilities were appropriately distributed between the collaborating groups given their respective domains of expertise. Reviewers agreed that the resources and research environments at all institutions are excellent and should fully support the proposal. Overall, the reviewers felt that while this proposal could have significant impact, certain aspects of the research plan were underdeveloped, leading them to question its feasibility.