Urinary incontinence (UI) is a major health issue that affects more than 200 million people worldwide. Stress urinary incontinence (SUI), which accounts for half of all UI cases, is the involuntary loss of urine in the absence of a detrusor contraction. SUI occurs as a result of weakened muscles of the pelvic floor and urethra, producing urine loss whenever there is an increase of intra-abdominal pressure, such as coughing, sneezing, and laughing. Currently there is no effective treatment for SUI. Because weakened muscles and nerves in the urethra are the underlying cause of SUI, this proposed study seeks to correct such deficiencies by replenishing the affected urethra with human embryonic stem cells (hESC).
Human ESC are capable of differentiating into various cell types including smooth muscle, striated muscle, and nerves. These cell types are also found in the urethra and are affected during the disease progression of SUI. In Specific Aim 1 of this proposed project we will investigate whether hESC can be induced to turn into cell types found in the healthy urethra.
In Specific Aim 2 we will test the therapeutic efficacy of hESC. Because it is unethical to conduct this research in patients, we will employ a rat SUI model that was developed in our laboratory 11 years ago. We have shown in several publications that this SUI model closely mimics human SUI in both the disease progression and pathology. We are therefore confident that this rat model will allow us to assess the therapeutic effectiveness of hESC. This assessment will then help us to decide whether hESC is suitable for human therapy.
Statement of Benefit to California:
Urinary incontinence (UI) is a major health problem worldwide; therefore, this proposed study will not just benefit California but the whole world. If there is anything specifically Californian, that would be the research team and the use of human embryonic stem cells (hESC) that are federally restricted. In other words, the research has the potential to strengthen California's leadership in both the UI and hESC research fields. In the long term this enhanced leadership may translate into economic gains for California such as investment in the biotech industry and health care system. If permitted by regulatory agencies at the federal and state levels, clinical trials for this stem cell therapy could perhaps be initiated in California and therefore benefit Californians firsthand.
SYNOPSIS: Dr. Ching-Shwun Lin of UCSF proposes to assess the effects of human embryonic stem cell (hESC) implants on stress urinary incontinence model in rats. They will first try to differentiate hESCs into cells that would be more suitable for implantation to the urethra. After that, they will transplant the cells to the urethra of rats that have stress incontinence, to see if there is a therapeutic effect.
SIGNIFICANCE AND INNOVATION: While many investigators are interested in hESC effects on brain and bone, relatively few are looking at muscle and particularly the urethra. In this respect, this is a an innovative and original proposal. The PI is a urology researcher and the goal of the proposed research is to investigate the utility of HESCs for the treatment of urinary stress incontinence. The specific aims are (1) to examine the differentiation of hESCs into smooth and striated muscle and whether cells along this differentiation pathway express neurotrophins and (2) to use a rat stress incontinence model to examine the utility of transplanted HESCs to fix the pathology.
STRENGTHS: The model of stress urinary incontinence in the rat appears to be a novel and clinically relevant model of the pathology. The PI is an experienced investigator with experience in studying stress incontinence in a rat model. Althought the investigator started out studying molecular and cellular biology of tumors, he/she has been working on stress incontinence and erectile dysfunction for 11 years. The PI's laboratory is strongly supported by several NIH grants studying urinary incontience and impotence. Collaborators with experience in the models are proposed. Probably few groups are making a connection between stress urinary incontinence and hESCs.
WEAKNESSES: The ability to get hESCs to generate smooth and striated muscle in the proposal as outlined in Aim 1 willl not lead to new insights in this area as outlined in the application. There are no good plans for dealing with inefficient differentiation. In addition the use of myf5 and MyoD to look for skeletal muscle has the pitfalls of (i) potentially identifying early cardiac muscle and (ii) identifying early muscle differentiation in cells that won’t go on to terminal differentiation of contractile muscle. The information about the neurotrophic factors could probably be derived from the literature with very little effort.
Other significant weaknesses were identified. First, no alternative plans is provided for the case if the applicant does not succeed in differentiating hESCs into smooth muscle cells. At what point will they consider the differentiation of the cells sufficient to go ahead with the second specific aim. Second, the researchers do not mention immune rejection of the cells. While they clearly expect the stem cells to have some effects due to release of neurotrophin and other factors, they need to consider immune rejection. There is also insufficient details concerning the in vivo experiments. Finally, they should rule out cell fusion and use human protein staining to identify the cells.
DISCUSSION: There was no further discussion following the reviewers' comments.