Pelvic floor disorders, such as stress urinary incontinence, fecal incontinence and vaginal prolapse, are the major public health concerns in women. These conditions are quite common, greatly affect the quality of life, and represent significant health care costs. The prevalence of these disorders in women ranges from 15% in younger ages to 78% in nursing home residents. The yearly direct costs of urinary incontinence in the US alone were 19.5 billion dollars in 2000, an amount higher than the costs generated by HIV or breast cancer in 2005. The treatment of pelvic floor disorders in women still poses a significant challenge in current medical practice because of poor long-term success rates. Although the etiologies of these conditions in women vary, dysfunctions of the pelvic floor and vaginal support caused by damaged skeletal and smooth muscles are involved. This proposed project focuses on the use of human adult stem cells, namely muscle derived stem cells, to regenerate the defective skeletal and smooth muscles in the pelvic floor and vaginal tissues. Another goal of this study is to regenerate and repair the damaged sphincters that control urine and feces. The data obtained with this translational study could revolutionize the clinical management of pelvic floor disorders in women. Application of human muscle-derived stem cells also has the potential to alter our understanding of these debilitating conditions.
Statement of Benefit to California:
Pelvic floor disorders, including urinary incontinence, fecal incontinence, vaginal prolapse, and pelvic organ prolapse, affect a significant number of women in California with a prevalence that ranges from 15% in younger ages to 78% in nursing home residents. Risk factors for pelvic floor disorders include age, the number of childbirth, and obesity. Child birth injury to pelvic muscles, connective tissues, and nerves appears to be the most important risk factor. Aging and hormonal changes with menopause are other important risks for pelvic floor disorders. Californians are not immune to any of these risks. This translational study focuses on the investigation of the therapeutic potential of human adult stem cells derived from skeletal muscles for the treatment of pelvic floor disorders in an animal model. The long-term objective is to devise a clinical trial using autologous stem cells derived from muscles for treatment of these debilitating conditions in humans. Autologous adult stem cells are advantageous for clinical applications because they can be easily obtained in large quantities under local anesthesia and possess the capabilities to undergo long-term proliferation, self-renewal, hypo-immunogenicity, and multipotent differentiation. Safety issues regarding the use of viral transduction vectors and non-human components, such as animal feeder cells and fetal bovine serum (FBS), are not a concern because genetic manipulation is not required and autologous human serum can be used for the culture and expansion of these stem cells. The data obtained with this study could revolutionize the clinical management of these debilitating conditions for women in California. This research project will, therefore, greatly benefit the State of California and its citizens.
This proposal is to investigate the therapeutic utility of human muscle-derived stem cells (hMDSC) for the treatment of pelvic floor disorders (including urinary incontinence, fecal incontinence and vaginal prolapse). The cause of these disorders can be traced to damage or dysfunction of urogenital skeletal and smooth muscles. This is a significant public health problem especially for older women. In this proposal, the investigator will assess the differentiation potential (for skeletal myofibers and smooth muscle cells) of hMDSC isolated in two different ways utilizing in vitro assays and in vivo xenotransplant models of pelvic disorders. The investigator will also evaluate the impact of specific hormones on the cell differentiation potential. Readouts will include immunostaining for markers, as well as functional assessments.
The proposed research follows a research design that has been used by other labs to evaluate the utility of cell implantation for the treatment of pelvic floor disorders and that the investigative team itself has used to assess mouse muscle-forming stem cell populations. Previous studies have investigated the ability of related cell types (including satellite cells, myoblasts, and fibroblasts) to function in muscle repair in similar models, and have had relatively disappointing results. However, the investigator believes that the MDSCs that will be studied in this application will be superior because of properties exhibited by these cells. Reviewers commented that these properties were not well-demonstrated in the preliminary data. In addition, much of the research plan seems to be aimed at testing these properties. In general, a significant portion of the research plan is dedicated to describing the techniques that will be employed. The application lacks sufficient rationale for the choice of technique or critical evaluation of expected outcomes and presents an inadequate discussion of potential pitfalls. It is also unclear how the in vitro and in vivo data will be quantified or correlated.
The entire proposal is dependent upon the successful isolation of primary cultures of MDSCs from biopsies obtained from volunteer donors. The lack of any evidence showing that human cells can be purified for the proposed experiments detracts from the proposal. All preliminary data are from experiments performed with mouse cells. Finally, the data provided in the preliminary data section are not directly correlated with the research design and in some cases are somewhat superficial. The preliminary data section also mentions the use of scaffolds, but these are not described in the research design, and so it is unclear under which conditions scaffolds will be used. Likewise, the applicant introduces the use of transgenic reporter mice in this section, but this is not discussed as part of the project, and has not been confirmed for human cells. Overall the reviewers felt the proposal was weak and questioned its feasibility.
The reviewers noted that the PI has taken a nontraditional path towards obtaining both an M.D. and Ph.D. Following graduate training, s/he was a tenured faculty member for over 10 years, then attended medical school and completed a residency and a clinical fellowship prior to obtaining a faculty position in 2007. The reviewers commented that the PI had 13 published papers in specialty journals. One reviewer noted that the PI has one abstract and a number of papers in “various stages of completion” but since these are not published it is not possible to determine the quality of the PI’s recent research in the field of stem cell biology. The applicant is co-PI on NIH funded clinical studies and is also PI of several pilot grants investigating similar preclinical models of cell implantation for repair of the urogenital musculature. The reviewers noted that the PI has recruited a large team of co-investigators including a number of faculty in the applicant’s Division with significant percent efforts, who will participate in, or advise on, various aspects of the study. Although each requests support for ~10% effort, much of their expertise appears to be overlapping, and it is unclear exactly which aspects of the proposal will be performed by each investigator. The mentoring plan is adequate; the applicant will be mentored by accomplished investigators including an expert in human embryonic stem cell biology and his/her fellowship advisor. This person is also listed as a co-investigator on the project and will directly supervise some of the major parts of the proposal, leading at least one reviewer to question the PI’s independence.
The institutional environment and mentorship plans are supportive, but discussion of the candidate’s independence is lacking. It is unclear what institutional funds have been provided specifically to support this investigator. It is unclear whether the PI currently has any space and it appears that the PI will only be awarded space if funded. This suggests that the PI functions more as a clinician than a research scientist and currently does not perform any research. This is particularly worrying since the PI has made it clear that s/he requires CIRM funding to obtain protected time to devote solely to stem cell research. From both the PI’s development plan and the letter of support from the institution it is very unclear how much time the PI will be able to devote to this project.