1105
INVITED COMMENTARY Mesenchymal Stem Cell Therapy for the Treatment of Erectile Dysfunction Mohit Khera, MD, MBA, MPH,* Maarten Albersen, MD, PhD,† and John P. Mulhall, MD‡ *Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA; †Department of Urology, University Hospitals Leuven, Leuven, Belgium; ‡Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA DOI: 10.1111/jsm.12871
Stem Cell Therapy for the Treatment of Erectile Dysfunction
E
rectile dysfunction (ED) is defined as the consistent inability to achieve or maintain an erection sufficient for satisfactory sexual relations. ED is a common global problem affecting an estimated 150 million men worldwide, and it is estimated that by the year 2025, 322 million men will be affected by this disease [1]. However, there are many limitations with the current medications available for the treatment of ED. A study by Carvalheira et al. found that of those patients who were prescribed a phosphodiesterase type 5 inhibitors (PDE5), only 45% were still using the medication over the 3-year follow-up period [2]. Of the patients that discontinued the PDE5, 38% reported the reason to be ineffectiveness of the drug. Over the past decade, there has been growing interest in the use of stem cells to treat ED. Stem cells are by definition capable of selfrenewal and differentiation into one or several more terminally differentiated phenotypes. Furthermore, (mesenchymal) stem cells (MSC) have been described as site-regulated “drugstores” in vivo as a result of the discovery of their potent trophic and immunomodulatory activities [3]. Unlike conventional treatments currently used for the treatment of ED, these properties render stem cell therapy an excellent candidate to offer a potent treatment and potentially a cure for the ED patient. Contemporarily, a major concern regarding stem cell therapy for ED is the inappropriate claim made by centers regarding the efficacy of stem cells for ED patients. The majority of the research conducted with stem cells for this indication has
© 2015 International Society for Sexual Medicine
been in the preclinical investigational phase, and thus represents level 5 evidence at best. There has been only one published clinical trial with seven patients with diabetes suggesting some transient short-term benefits with umbilical cord stem cells to treat ED [4]. Despite the lack of clinical data, there are numerous centers throughout the world offering patients stem cells to treat this condition, charging cash for this treatment and in many cases not even offering true stem cells. The International Society for Cellular Therapy (ISCT) has recommended minimum criteria for defining multipotent human mesenchymal stem stromal cells. These cells must express CD105, CD73, and CD90, and they must lack expression of CD34, CD45, CD14, CD11b, CD79-α, CD19, and HLA-DR surface molecules. MSC must also differentiate into osteoblasts, chondroblasts, and adipocytes ex vivo. The concern is that many of the centers offering stem cell therapy for ED do not follow the recommended criteria set out by the ISCT, and these centers are not being monitored for what type of cells are actually being injected. The first stem cell study for the treatment of ED was published in 2004. This study was the only study to use embryonic stem cells to treat ED. There have up until now been a total of 34 published preclinical studies assessing stem cell therapy for ED. Of these studies, 19 have focused on cavernous nerve injury (CNI) and 10 focused on diabetes mellitus (DM). The majority of these studies have employed adipose-derived stem cells, and transplantation of the stem cells has mainly been performed via intracavernous injection. Some studies have attempted alternative strategies such as peri-prostatic application (either or not linked to a scaffold) and intravenous injection. J Sex Med 2015;12:1105–1106
1106 Although all of these studies have reported improvement in erectile function with stem cell transplantation, the mechanism of how stem cells improve ED has been debated. However, recent data, both in the field of ED as well as in other organ systems, suggests that stem cells exert their effect through a paracrine action. This is evidenced by studies reporting a lack of engraftment and differentiation of stem cells in the penis, whereas the injection of stem cell conditioned medium or stem cell lysate has been shown to improve erectile function in both DM and CNI rat models [5]. The injection of these media and lysates exposes the injured tissue to the bioactive molecules contained in—or secreted by stem cells, while precluding the possibility of engraftment and differentiation. These studies have led to the classical paradigm of differentiation or engraftment of transplanted stem cells becoming less popular, which has also been the case for the hypothesis that stem cells fuse into cells with two nuclei of different genetic origin (heterokaryons) with resident cells. As with any biologic therapy, there are safety concerns, such as immunogenicity and tumorigenicity of stem cells that warrant further investigation before translating these therapies into clinical practice. Furthermore, the results obtained in animals yet have to be corroborated in the human situation. Currently, various phase 1 and 2 studies have been registered for the investigation of the safety and effects of human MSC application for the treatment of ED (clinicaltrials.gov identifiers: general ED: NCT02087397, NCT02107118, NCT01953523, NCT01601353; postradical prostatectomy ED: NCT02240823, NCT01089387, NCT01983709). Initial promising data from a small dose-escalating phase 1 trial investigating the safety of intracavernous stem-cell injection in prostate cancer patients was presented at the EAU 2014 by Rene Yiou from France (NCT01089387). More large randomized placebo-controlled clinical studies are needed to further assess the true safety and efficacy of stem cells to treat ED. In the final analysis, in the absence of clear and robust data demonstrating the efficacy AND safety of stem cell therapy for ED, the leading scientists and clinicians in sexual medicine must not allow stem cell therapy to be driven by industry or
J Sex Med 2015;12:1105–1106
Khera et al. physicians hungry for profit, taking advantage of desperate patients. It is our opinion that until these data are known, no stem cell treatment should be offered to ED patients outside of an ethics committee-approved protocol. Corresponding Author: Mohit Khera, MD, MBA, MPH, Scott Department of Urology, Baylor College of Medicine, 6620 Main Street, 1325, Houston, TX 77030, USA. Tel: (713) 798-6593; Fax: (713) 798-5553; E-mail: [email protected] Conflict of Interest: Mohit Khera (Endo Pharmaceuticals—consultant, AMS—consultant, and Coloplast—consultant). Maarten Albersen reports no conflicts of interest. Statement of Authorship
Category 1 (a) Conception and Design Mohit Khera; Maarten Albersen (b) Acquisition of Data Mohit Khera; Maarten Albersen (c) Analysis and Interpretation of Data Mohit Khera; Maarten Albersen
Category 2 (a) Drafting the Article Mohit Khera; Maarten Albersen (b) Revising It for Intellectual Content Mohit Khera; Maarten Albersen
Category 3 (a) Final Approval of the Completed Article Mohit Khera; Maarten Albersen References 1 Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999;84:50–6. 2 Carvalheira AA, Pereira NM, Maroco J, Forjaz V. Dropout in the treatment of erectile dysfunction with PDE5: A study on predictors and a qualitative analysis of reasons for discontinuation. J Sex Med 2012;9:2361–9. 3 Caplan AI, Correa D. The MSC: An injury drugstore. Cell Stem Cell 2011;9:11–5. 4 Bahk JY, Jung JH, Han H, Min SK, Lee YS. Treatment of diabetic impotence with umbilical cord blood stem cell intracavernosal transplant: Preliminary report of 7 cases. Exp Clin Transplant 2010;8:150–60. 5 Albersen M, Weyne E, Bivalacqua TJ. Stem cell therapy for erectile dysfunction: Progress and future directions. Sex Med Rev 2013;1:50–64.
INVITED COMMENTARY Mesenchymal Stem Cell Therapy for the Treatment of Erectile Dysfunction Mohit Khera, MD, MBA, MPH,* Maarten Albersen, MD, PhD,† and John P. Mulhall, MD‡ *Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA; †Department of Urology, University Hospitals Leuven, Leuven, Belgium; ‡Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA DOI: 10.1111/jsm.12871
Stem Cell Therapy for the Treatment of Erectile Dysfunction
E
rectile dysfunction (ED) is defined as the consistent inability to achieve or maintain an erection sufficient for satisfactory sexual relations. ED is a common global problem affecting an estimated 150 million men worldwide, and it is estimated that by the year 2025, 322 million men will be affected by this disease [1]. However, there are many limitations with the current medications available for the treatment of ED. A study by Carvalheira et al. found that of those patients who were prescribed a phosphodiesterase type 5 inhibitors (PDE5), only 45% were still using the medication over the 3-year follow-up period [2]. Of the patients that discontinued the PDE5, 38% reported the reason to be ineffectiveness of the drug. Over the past decade, there has been growing interest in the use of stem cells to treat ED. Stem cells are by definition capable of selfrenewal and differentiation into one or several more terminally differentiated phenotypes. Furthermore, (mesenchymal) stem cells (MSC) have been described as site-regulated “drugstores” in vivo as a result of the discovery of their potent trophic and immunomodulatory activities [3]. Unlike conventional treatments currently used for the treatment of ED, these properties render stem cell therapy an excellent candidate to offer a potent treatment and potentially a cure for the ED patient. Contemporarily, a major concern regarding stem cell therapy for ED is the inappropriate claim made by centers regarding the efficacy of stem cells for ED patients. The majority of the research conducted with stem cells for this indication has
© 2015 International Society for Sexual Medicine
been in the preclinical investigational phase, and thus represents level 5 evidence at best. There has been only one published clinical trial with seven patients with diabetes suggesting some transient short-term benefits with umbilical cord stem cells to treat ED [4]. Despite the lack of clinical data, there are numerous centers throughout the world offering patients stem cells to treat this condition, charging cash for this treatment and in many cases not even offering true stem cells. The International Society for Cellular Therapy (ISCT) has recommended minimum criteria for defining multipotent human mesenchymal stem stromal cells. These cells must express CD105, CD73, and CD90, and they must lack expression of CD34, CD45, CD14, CD11b, CD79-α, CD19, and HLA-DR surface molecules. MSC must also differentiate into osteoblasts, chondroblasts, and adipocytes ex vivo. The concern is that many of the centers offering stem cell therapy for ED do not follow the recommended criteria set out by the ISCT, and these centers are not being monitored for what type of cells are actually being injected. The first stem cell study for the treatment of ED was published in 2004. This study was the only study to use embryonic stem cells to treat ED. There have up until now been a total of 34 published preclinical studies assessing stem cell therapy for ED. Of these studies, 19 have focused on cavernous nerve injury (CNI) and 10 focused on diabetes mellitus (DM). The majority of these studies have employed adipose-derived stem cells, and transplantation of the stem cells has mainly been performed via intracavernous injection. Some studies have attempted alternative strategies such as peri-prostatic application (either or not linked to a scaffold) and intravenous injection. J Sex Med 2015;12:1105–1106
1106 Although all of these studies have reported improvement in erectile function with stem cell transplantation, the mechanism of how stem cells improve ED has been debated. However, recent data, both in the field of ED as well as in other organ systems, suggests that stem cells exert their effect through a paracrine action. This is evidenced by studies reporting a lack of engraftment and differentiation of stem cells in the penis, whereas the injection of stem cell conditioned medium or stem cell lysate has been shown to improve erectile function in both DM and CNI rat models [5]. The injection of these media and lysates exposes the injured tissue to the bioactive molecules contained in—or secreted by stem cells, while precluding the possibility of engraftment and differentiation. These studies have led to the classical paradigm of differentiation or engraftment of transplanted stem cells becoming less popular, which has also been the case for the hypothesis that stem cells fuse into cells with two nuclei of different genetic origin (heterokaryons) with resident cells. As with any biologic therapy, there are safety concerns, such as immunogenicity and tumorigenicity of stem cells that warrant further investigation before translating these therapies into clinical practice. Furthermore, the results obtained in animals yet have to be corroborated in the human situation. Currently, various phase 1 and 2 studies have been registered for the investigation of the safety and effects of human MSC application for the treatment of ED (clinicaltrials.gov identifiers: general ED: NCT02087397, NCT02107118, NCT01953523, NCT01601353; postradical prostatectomy ED: NCT02240823, NCT01089387, NCT01983709). Initial promising data from a small dose-escalating phase 1 trial investigating the safety of intracavernous stem-cell injection in prostate cancer patients was presented at the EAU 2014 by Rene Yiou from France (NCT01089387). More large randomized placebo-controlled clinical studies are needed to further assess the true safety and efficacy of stem cells to treat ED. In the final analysis, in the absence of clear and robust data demonstrating the efficacy AND safety of stem cell therapy for ED, the leading scientists and clinicians in sexual medicine must not allow stem cell therapy to be driven by industry or
J Sex Med 2015;12:1105–1106
Khera et al. physicians hungry for profit, taking advantage of desperate patients. It is our opinion that until these data are known, no stem cell treatment should be offered to ED patients outside of an ethics committee-approved protocol. Corresponding Author: Mohit Khera, MD, MBA, MPH, Scott Department of Urology, Baylor College of Medicine, 6620 Main Street, 1325, Houston, TX 77030, USA. Tel: (713) 798-6593; Fax: (713) 798-5553; E-mail: [email protected] Conflict of Interest: Mohit Khera (Endo Pharmaceuticals—consultant, AMS—consultant, and Coloplast—consultant). Maarten Albersen reports no conflicts of interest. Statement of Authorship
Category 1 (a) Conception and Design Mohit Khera; Maarten Albersen (b) Acquisition of Data Mohit Khera; Maarten Albersen (c) Analysis and Interpretation of Data Mohit Khera; Maarten Albersen
Category 2 (a) Drafting the Article Mohit Khera; Maarten Albersen (b) Revising It for Intellectual Content Mohit Khera; Maarten Albersen
Category 3 (a) Final Approval of the Completed Article Mohit Khera; Maarten Albersen References 1 Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999;84:50–6. 2 Carvalheira AA, Pereira NM, Maroco J, Forjaz V. Dropout in the treatment of erectile dysfunction with PDE5: A study on predictors and a qualitative analysis of reasons for discontinuation. J Sex Med 2012;9:2361–9. 3 Caplan AI, Correa D. The MSC: An injury drugstore. Cell Stem Cell 2011;9:11–5. 4 Bahk JY, Jung JH, Han H, Min SK, Lee YS. Treatment of diabetic impotence with umbilical cord blood stem cell intracavernosal transplant: Preliminary report of 7 cases. Exp Clin Transplant 2010;8:150–60. 5 Albersen M, Weyne E, Bivalacqua TJ. Stem cell therapy for erectile dysfunction: Progress and future directions. Sex Med Rev 2013;1:50–64.
