Urology Times Innovation Celebration: Expert Insights - Episode 3

SUI treatment reaches "new frontier” with regenerative medicine and stem cell–based therapies

SAP Partner | <b>Vanderbilt University Medical Center</b>

Urology Times is celebrating its 50th anniversary in 2022. To mark the occasion, we are highlighting 50 of the top innovations and developments that have transformed the field of urology over the past 50 years. In this installment, Melissa R. Kaufman, MD, PhD, FACS, discusses the innovative use of stem cell–derived treatments in urologic conditions such as stress urinary incontinence. Kaufman is a Professor of urology, Patricia and Rodes Hart Endowed Chair of Urologic Surgery, and Chief of Reconstructive Urology and Pelvic Health at Vanderbilt University Medical Center, Nashville, Tennessee.

Could you provide a brief overview of the development of stem cell–derived therapy and the treatment of stress urinary incontinence?

The newest frontier of therapy for stress incontinence is regenerative medicine and stem cell–based therapies. The basis of these are defined as embryonic stem cells or adult stem cells. Of course, there is continued scientific and ethical debate regarding the use of pluripotent embryonic stem cells. Our current cell-based therapies are somatic multipotent cells that are derived from adult tissues. These cells are terminally differentiated, and they serve in the body as progenitor cells for renewal of local tissues. These therapies have the potential to restore, in stress incontinence, the external striated sphincter, and potentially even smooth muscle within the bladder, neuromuscular transmission, as well as blood supply. There have been several different cell types that have been studied for this over the decades—both animal and human studies include bone marrow cells, mesenchymal stem cells, adipose-derived cells, umbilical cord cells, [and] total nucleated cells, but the most well-studied population has been muscle-derived cells. This focuses on harvesting skeletal muscle, and it's delivered back to the external urethral sphincter after being expanded with the goal of regenerating this muscle and restoring function and, hopefully, continence.

The first successful clinical trial of autologous myoblast was used in the Austrian group in 2007. This was for female stress incontinence and was published in The Lancet.1 This was pioneering work well over a decade ago. Unfortunately, in 2008, that publication was retracted due to numerous concerns about the trial design and data interpretation.2 This setback undoubtedly resulted in a substantial delay in advancing this technology. However, at the 2021 AUA meeting, data were presented from a large randomized, double blind placebo-controlled trial of autologous muscle-derived cells, revealing really promising results for several subsets of stress incontinence patients, including those with persistent or recurrent incontinence following surgical interventions.

What makes this type of therapy an innovative treatment for SUI?

Stem cell technology is truly a transformational opportunity in urology, and the first regenerative option to complete really rigorous clinical evaluation. The autologous muscle-derived cell product are muscle progenitor cells [that] originate from tissue harvested from a muscle biopsy in the thigh and, upon injection, engraft into existing dysfunctional target tissue to improve muscle function. The product is in clinical trials for not just stress incontinence in females, but post-prostatectomy incontinence in men, fecal incontinence, underactive bladder, tongue dysphasia, and even cardiac applications—broad-ranging reach of a technology that is pioneered for a urologic indication. It's most studied, however, in stress incontinence. There have been over 500 women who have been treated with this product across several continents during all the iterations of the clinical trials. It augments urethral sphincter function and has the potential to be a really durable treatment. It produces some local tissue changes, but not systemic effects. Most of the subjects were in a broader stress incontinence treatment group. There was a sub population of women with a very troublesome condition of persistent or recurrent incontinence following prior surgical interventions. They demonstrated remarkable efficacy, with up to 30% having basically 0 to 1 stress leaks on their diaries in the trial. This was a very afflicted baseline with very phenomenal results. Because this was an unmet medical need and a very serious condition, this technology was granted expedited regenerative medicine advanced therapy designation by the FDA, which should really help facilitate future trials and bringing us to millions of patients who could benefit.

If approved, how will this technology improve the treatment of patients with us SUI?

Stress incontinence has an enormous impact on a woman's quality of life. The gamut of this impact ranges beyond the direct symptoms, including an increased risk for depression and anxiety, reduced participation in physical activity and all the profound effects that can have, negative impacts on productivity at work, and the ability to maintain healthy sexual relationships. It leads to a substantial reduction in day-to-day functioning for women suffering from this disease. Recurrent or persistent incontinence for women who have undergone prior interventions is not short lived. It's not self-limiting, and [it] can progress in severity over time. This can cause additional stress. Women in this particular group have really limited options for treatment, that's not responded to what we consider gold-standard therapies for stress incontinence. Due to this wide range of an increasing number of patients and an aging population who suffer from stress incontinence, we really needed development of novel and effective therapeutic options with minimal patient morbidity, which was a paramount concern. We're embarking on the next frontier in urology with cellular therapies, and this is a gratifying opportunity to be practicing today, and have the ability to potentially provide durable, safe treatments that really reverse pathology and regenerate native tissue. The applications of this technology are very broad, and the next decade of innovations in this space will be astounding and transformative of our current treatment strategies for countless urology patients to improve both the quantity and quality of life.

References

1. Strasser H, Marksteiner R, Margreiter E, et al. Autologous myoblasts and fibroblasts versus collagen for treatment of stress urinary incontinence in women: a randomised controlled trial. Lancet. 2007;369(9580):2179-2186. doi:10.1016/S0140-6736(07)61014-9

2. Kleinert S, Horton R. Retraction--autologous myoblasts and fibroblasts versus collagen [corrected] for treatment of stress urinary incontinence in women: a [corrected] randomised controlled trial. Lancet. 2008;372(9641):789-790. doi:10.1016/S0140-6736(08)61320-3