Stem-cell therapy for erectile dysfunction

Abstract

Stem cell-based therapies have been recently investigated in the field of organic erectile dysfunctions, such as those associated with diabetes or the treatment of prostate cancer. The overall aim is to repair the repair the underlying penile cellular damage. Here, we review the rationale behind the use of stem cells injection in post-radical prostatectomy erectile dysfunction (pRP-ED).

Radical prostatectomy for prostate cancer induces complex neurologic and vascular injuries that cause one of the most difficult-to-treat forms of erectile dysfunction. Evidence from animal models replicating pRP-ED suggests that intracavernous injection of autologous bone marrow mononuclear cells (BM-MNCs) may represent the first curative approach. Several clinical trials are ongoing and two of them have been completed with encouraging results.

Keywords

Erectile dysfunction radical prostatectomy bone marrow cavernous nerves

1. Introduction

Erectile dysfunction (ED) is defined as the inability to initiate or maintain an erection satisfactory for sexual intercourse and may have a severe impact on the quality of life.

ED can be associated to psychological causes or can result from an underlying organic disease affecting erectile tissues. Organic ED is the result of metabolic and systemic changes in diseases such as diabetes and atherosclerosis or more localized causes such as direct injury to the penile neurovascular supply during prostate surgery. Phosphodiesterase type 5 inhibitors are used as a first-line treatment for ED, but these drugs are less effective in case of organic disease [1].

Recently, stem-cell based therapies have shown some potential to improve erectile function in various animal models mimicking organic ED related to diabetes [2] or radical prostatectomy for prostate cancer [3,4]. Preliminary clinical trials have been reported with encouraging results [5,6].

In this article, we expose the rationale behind the use of bone marrow-derived stem cells in the treatment of ED following radical prostatectomy (RP) for localized prostate cancer; we also reviewed the results of the first clinical trial investigating this new therapeutic strategy.

2. Pathophysiology of post-radical prostatectomy erectile dysfunction

RP remains the reference treatment for organ-confined prostate cancer. Despite a steady stream of technological improvements, RP carries a high risk of postoperative ED [7]. Postradical prostatectomy erectile dysfunction (pRP-ED) results from injury to the penile neurovascular bundles that course along the posterolateral aspects of the prostate. These bundles are composed of the cavernous nerves and arteries, and pRP-ED is therefore both vasculogenic and neurogenic [8–10]. Classically, the functional outcome of RP is determined by the extent to which the penile neurovascular bundles and intrapelvic accessory pudendal arteries are spared.

3. Treatment of pRP-ED

To prevent this sequence of events leading to penile fibrosis, early treatment with either oral erectogenic drugs such as phosphodiesterase 5 inhibitors (PDE5i) or intracavernous injection of vasoactive substances can be offered to patients who wish to recover sexual activity after RP [11]. The regular use of erectogenic drugs is believed to improve spontaneous erections and is therefore widely advocated for sexual rehabilitation after RP. However, the best therapeutic regimen remains undetermined and the effectiveness of oral or intracavernous pharmacotherapy in restoring the preoperative level of erectile function remains debated. When pharmacotherapy fails, implantation of a penile prosthesis is recommended to patients who wish to recover sexual activity [12].

4. Development of stem cell therapies for pRP-ED

Recent pathophysiological insights provided by animal studies have led to the development of new therapeutic strategies for pRP-ED that rely chiefly on intracavernous stem cell injection. Severe deficiencies in both neuronal (nNOS) and endothelial (eNOS) nitric oxide synthase have been found in the rat penis after experimental cavernous nerve injury and may explain both the development of pRP-ED and the ineffectiveness of PDE5i therapy after non-nerve-sparing RP [3]. Corporeal cell apoptosis has been documented in experimental models of pRP-ED and may contribute to post-RP veno-occlusive dysfunction [13]. Apoptosis affects multiple cell types in the penis including smooth-muscle cells [13], supportive stromal cells, and vascular smooth-muscle and endothelial cells [3]. Loss of these cells via apoptosis presumably contributes to the penile retraction seen after RP. Thus, pRP-ED can be viewed as a multifactorial disorder in which the interlinked mechanisms include denervation, endothelial dysfunction, and structural alterations in connective tissue and smooth-muscle cells.

Preclinical studies have investigated the use of intracavernous stem cell injections as a mean to repair the complex set of cell injuries caused by RP and improve erectile function. Potential sources of stem cells include the adipose tissue [4,14] and bone marrow (BM) [3]. We previously used a rat model to investigate whether intracavernous injection of BM-mononuclear cells (BM-MNCs) corrected the histological and functional abnormalities caused by bilateral removal of the penile neurovascular bundles [3]. BM-MNCs are a heterogeneous stem cell population composed chiefly of mesenchymal stem cells, endothelial progenitor cells and hematopoietic stem cells all of which can differentiate into the cell types affected by apoptosis in pRP-ED. In our rat model, BM-MNC injection protected against cell apoptosis and improved erectile function and penile vascularization as compared to control animals [3]. In addition, BM-MNCs accelerated the recovery of nNOS and eNOS levels, suggesting neurotrophic and angiogenic effects. Similar functional effects have been obtained using mesenchymal stem cells from adipose tissue [4,15] or the adipose stromal vascular fraction, another heterogeneous population of mesenchymal stem cells and endothelial progenitors [14].

5. Clinical trial

We recently reported the first phase 1/2 clinical trial investigating intracavernous injection of autologous BM-MNCs to treat pRP-ED in humans (NCT01089387) [5]. Tolerance was the primary endpoint. The secondary endpoints were the effects of BM-MNC injection on erectile function measured using validated scores and on penile vascularization assessed using color duplex Doppler ultrasound (CDDU). Sexual function was evaluated at baseline then 1, 3, 6, and 12 months postinjection, using the Erection Hardness Score (EHS) and the International Index of Erectile Function (IIEF-15) assessing erectile function (EF), orgasmic function (OF), sexual drive (SD), intercourse satisfaction (IS), and overall satisfaction (OS). Patients could use their preferred erectogenic treatment starting 1 week after the BM-MNC injection. In order to evaluate natural erections, they were also asked to complete the EHS when not using any treatment. We measured changes in stretched penile length in the flaccid state at each study visit.

Twelve patients received one intracavernous injection of BM-MNCs. Four doses (4 successive group, $n = 3$ ) of BM-MNCs were tested ( $2 \cdot 10^{7}$ , $2 \cdot 10^{8}$ , $1 \cdot 10^{9}$ , $2 \cdot 10^{9}$ ). Mean age of the 12 patients was $63.6 \pm 4.2$ years and mean time from RP to BM-MNC injection was $22.9 \pm 9.8$ months. Before BM-MNC injection, all patients had followed a sexual rehabilitation program consisting in intracavernous alprostadil injections starting 1 month after RP and had failed to obtain erections allowing penetration (Erection Hardness Score [EHS] <3) despite at least 10 trials of sildenafil 100 mg combined with intracavernous alprostadil and use of a vacuum device.

Mild postoperative pain at the bone marrow aspiration site (mean VAS score, $2 \pm 1$ ) was the most common side effect. VAS pain scores did not differ significantly across the four dose groups. No patient reported pain at the 1-month (M1) visit. No cases of penile hematoma, abscess, or priapism were recorded. All prostate cancers were staged pT2, N0, M0 and all surgical margins were negative. At all follow-up visits, PSA was undetectable in all patients and digital rectal examination showed no evidence of local recurrence. Mean hemoglobin decreased by $- 1.9 \pm 0.7$ g/dL overall. No patient required blood transfusion.

Overall, BM-MNC injection significantly improved most of the sexual function scores at 6 months. At M6, 9/12 patients were using erectogenic drugs including alprostadil ( $n = 6$ ), PDE5i ( $n = 1$ ), combined PDE5i and vacuum ( $n = 1$ ), and vacuum alone ( $n = 1$ ). None of the patients used the combination of the 3 treatments (PDE5i, alprostadil, vacuum). On-medication, the IS, EF, and OF IIEF- 15 subscores were significantly better at M3 than at baseline and these improvements were sustained at M6, when the on-medication EHS was also significantly higher than at baseline. At M6 versus baseline, mean gains were $+ 1.3 \pm 1$ for on-medication EHS, $+ 0.8 \pm 1.2$ for off-medication EHS, and $+ 10.1 \pm 8.6$ for the EF subscore. Overall, 9/12 patients reported successful intercourses with vaginal penetration on medication. Penile length was significantly increased versus baseline at M1 and M3 ( $+ 1.1$ cm, $P = 0.0031$ ) but not at M6. After M6, 2 patients in the lowest dose group asked for a penile implant because they felt their on-medication erections were unsatisfactory. No technical difficulties associated with the previous BM-MNC injection occurred during implantation. Comparing the four dose groups showed no significant differences in sexual function scores (IIEF15 EF subscore and EHS). However, the off-medication EHS at M6 exhibited a greater improvement with the two highest doses ( $+ 1.3 \pm 1.5$ ) compared to $+ 0.2 \pm 0.4$ with the two lowest doses ( $P = 0.012$ ), indicating a better improvement of natural erection for doses 3 and 4. No significant difference in EHS gain was seen between the two highest doses.

Sexual function scores at M12 were not significantly different from those at M6 in the 10 patients without penile implants, suggesting sustained beneficial effects of BM-MNC injection. Improvements of sexual score were associated with improvement in peak systolic velocity (PSV) and penile endothelial function in cavernous arteries (%PNORT) after intracavernous BM-MNC injection.

6. Discussion

The results of this first clinical trial suggest both a good safety profile and efficacy in improving erectile function. Importantly, all 12 study patients had severe vasculogenic pRP-ED at baseline and did not respond to maximal-dose injected alprostadil and oral PDE5i therapy combined with the use of a vacuum device. These characteristics indicate a very low likelihood of recovering sexual function with or without erectogenic pharmacotherapy [16]. In such patients, surgical implantation of a penile prosthesis is the recommended treatment [12]. Although we had no control group, the improvements in sexual function scores combined with the improved penile vascularization and increased penile length 3 months after BM-MNC injection strongly suggest a beneficial trophic effect of this treatment on the erectile tissues. Interestingly, Haahr et al. [6] found similar results using injection of autologous adipose-derived cells freshly isolated by liposuction in patients with pRPED with a mean gain in the IIEF-EF score of 10 point (7 at baseline versus 17 at M6).

In our study, the erectile function improvements were associated with a significant PSV increase and a trend toward improved endothelial function, suggesting an angiogenic effect of BM-MNC injection. Such an effect would be consistent with studies of critical limb ischemia [17] and myocardial infarction [18]. The prevailing hypothesis to explain the beneficial effects of BM-MNCs introduced into myocardial infarction sites is angiogenesis mediated by a paracrine effect rather than stem cell transdifferentiation into endothelial cells [19]. Similar paracrine effects may occur after intracavernous injection, as previously observed in animal models of ED [3]. Other potential mechanisms of action suggested by animal studies include cell protective and antiapoptotic effects [20], neurotrophic effects on the cavernous nerves, mitochondrial transfer through nanotube formation, and activation of host progenitor cells [21]. Evaluating these potential mechanisms in human patients would raise ethical challenges, as preoperative and postoperative penile biopsies would be required.

Finally, the improvements in CDDU parameters suggest that BM-MNC injection might also hold promise in other forms of ED due to arterial disease, such as diabetes or peripheral atheroma, in which the effectiveness of PDE5i therapy is limited.

Conflict of interest

The author has no conflict of interest to report.

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