Disease Team Therapy Planning I
Urinary incontinence (UI) is a common and debilitating condition, with two-thirds of the burden borne by women. Women with UI suffer debilitating falls, experience social isolation and are clinically-depressed more commonly than continent women. UI impacts both quality and length of life and adversely impacts families as they plan care for older female family members. Indeed, UI is the most common reason for institutionalization of aging women and carries staggering financial costs, as tragically illustrated by the fact that annual sales of adult diapers surpass that of baby diapers. Nationwide, the annual cost of UI exceeds $20 billion, a cost comparable to that of arthritis, and greater than that of breast cancer. Here we propose to develop a target product to treat UI. Our studies will not only address one of the most prevalent and debilitating conditions in women and the aging population but will also lay the groundwork for critical clinical studies of other common conditions. Consequently, this proposed target product will have a tremendous impact on women’s health in California. Our target product involves derivation of stem cells called induced pluripotent stem cells (iPSCs) from skin biopsies, with subsequent production of a key cell type that degenerates in UI, muscle precursor cells. Cells are then injected into the urethral sphincter to aid regeneration of the damaged or deficient sphincter muscles. We suggest that iPSCs are the best source of stem cells that can be used to restore urethral sphincter function and propose a multidisciplinary effort aimed at developing and optimizing this minimally invasive treatment for UI. Our ultimate goal is to restore the urethral sphincter to its normal function. Towards accomplishing this goal, we propose four specific aims that when complete in the four years of funding, will enable IND filing and address issues of safety, toxicity, dosage, delivery system, purification protocols, quality control parameters, and safety biomarkers for cell selection, differentiation, and expansion. Because our team has extensive experience and expertise in each of these areas, and given that the proof of principle for the target product has already been determined using adult stem (progenitor) cells, we are confident that we will develop a product ready to move into IND testing by the end of the funding period. We emphasize that improving current treatment options for UI provides substantial primary benefits and even more significant secondary benefits to the individual and California including relief of UI and UI-linked depression, social isolation, and institutionalization. Thus, the proposed therapy also translates into a very substantial reduction in costs due to secondary issues associated with UI in the growing aging population in our state. Although this proposal is focused on women with UI, treatments will likely translate to men with UI that commonly occurs following prostate surgery.
Statement of Benefit to California:
Californians are living longer such that the life expectancy of women now exceeds 80 years. As Californians age, common aging-associated tissue degeneration represents a major physical, social, cultural and financial burden. Urinary incontinence (UI) has become a major quality of life issue and public health concern both in terms of health care and health care budgets. Indeed, a recent study found that urinary incontinence, Alzheimer’s disease, and stroke were the 3 chronic health conditions that most adversely effect an individual’s health-related quality of life. Overall, UI affects a staggering number of women -- up to one-third of premenopausal women and roughly half of postmenopausal women, resulting in colossal health costs that are difficult to bear. According to the US Census Bureau in 2004, the California female population age 18-65+ totals roughly 13 million women, thus up to 7 million Californian women may suffer from urinary incontinence. Nationwide, the total annual cost of urinary incontinence exceeded $20 billion in the year 2000. This cost is comparable to that associated with arthritis and greater than that of breast cancer and all gynecological cancers combined. Consider further the tragic statistic that the annual sale of adult diapers for UI now exceeds that of baby diapers and that UI is the most common reason for families to institutionalize their elderly female relatives. Yet today we lack effective treatments that would alleviate primary and secondary consequences of UI. We suggest that we can “do better” for the women of California through a step-wise proposal of research that takes advantage of small clinical trials that have already been conducted, the ability to differentiate large numbers of muscle presursor cells from pluripotent stem cells, and unique expertise of our clinical team. Currently surgery is the most common treatment for UI, with good short-term but poor long-term results. Repeat surgeries are more morbid, cause scarring and tissue destruction, and have decreased efficacy. Injection of bulking agents provides only partial relief. Thus, many women have no options for relief. Our target product consists of autologous-iPSC derived muscle precursor cell injection into the urethral sphincter for treatment of urinary incontinence. Stem cell therapies are well suited for regeneration of injured or aged tissues. One such therapy has progressed from animal models to clinical trials for urinary incontinence and involved the injection of autologous skeletal muscle-derived stem (progenitor) cells (MDSC) into the urethra. One-year follow-up found improvement in five of eight women, with one subject achieving total continence while none reporting serious adverse events. However, due to limitations, this approach is not feasible for wide-spread clinical use. Our target product overcomes major limitations to provide a ready cell source that we anticipate will be safe and effective for treatment of UI.