Gene and stem cell therapy for erectile dysfunction

Abstract

Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. ED is a highly prevalent health problem with considerable impact on the quality of life of men and their partners. Although the treatment of ED with oral phosphodiesterase type V (PDE5) inhibitors is effective in a wide range of individuals, it is not efficacious in all patients. The failure of PDE5 inhibitors happens mainly in men with diabetes, non-nerve sparing radical prostatectomy, and high disease severity. Therefore, improved therapies based on a better understanding of the fundamental issues in erectile physiology and pathophysiology have recently been proposed. Here, we summarize studies on ED treatment using gene and stem cell therapies. Adenoviral-mediated intracavernosal transfer of therapeutic genes, such as endothelial nitric oxide synthase (eNOS), calcitonin gene-related peptide (CGRP), superoxide dismutase (SOD), and RhoA/Rho kinase and mesenchymal stem cell-based cell and gene therapy strategy for the treatment of age-and diabetes-related ED are the focus of this review. Penile erection, referred to as engorgement of the penis with blood, is the result of the penile arterial dilation which increases blood inflow, the relaxation of smooth muscle of the corpus cavernosum which increases blood storage, and penile venous occlusion which decreases blood outflow. The physiology of penile erection is complicated and this neurovascular event requires the functional integrity of nerves, endothelium, and smooth muscle. 1 Nitric oxide (NO), produced by both neuronal nitric oxide synthase (nNOS) in the nonadrenergic noncholinergic (NANC) nerves and endothelial nitric oxide synthase (eNOS) in the endothelium of penile arteries and cavernosal sinusoids is the principal mediator of penile erection. 2-5 NO formed in nerves or endothelial cells then diffuses to neighboring smooth muscle cells and activates soluble guanylyl cyclase. This activation results in increased cGMP formation, which mediates smooth muscle relaxation. 5 Besides NO, other molecules such as vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), substance P, and pituitary adenylate cyclase-activating polypeptide (PACAP) are also important for penile erection. 6 Causes contributing to erectile dysfunction (ED) can be broadly classified into two categories: organic and psychological. Aging, vascular diseases, neurological injuries, and diabetes mellitus are the common causes of organic ED. 7 Depressive stress is the common cause of psychological ED. 8,9 Although the treatment of ED with oral phosphodiesterase type V (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil) is effective in a wide range of individuals with ED, it is not efficacious in all patients. For example, the response rate to sildenafil decreased from 72% in men 18-49 y of age to 53% in men 50 y or older. 10 The failure of sildenafil therapy happened mainly in men with diabetes, non-nerve sparing radical pr...

Additive effects of Artemisia capillaris extract and scopoletin on the relaxation of penile corpus cavernosum smooth muscle

“…These oral medications are proven to be valuable in the management of ED, but are reported to have limitations. 4,43 There are difficulties in the development of a new chemical medicine with complete efficacy as well. Therefore, we are focusing on finding a new herbal medicine or a supplement from the natural products, especially herbal medicine.…”

“…Upon penile erection, release of NO from nitrergic nerve and endothelial cells activates guanylyl cyclase resulting in increase of cyclic guanosine monophosphate (cGMP) formation, which mediates cavernosum smooth muscle relaxation. 4,5 Adenyl cyclase is also an important stimulator on the production of cyclic adenosine monophosphate (cAMP), which will act in ion channel, leading to relaxation of penile corpus cavernosum. [6][7][8] Natural products provide a valuable and rich pool for the discovery of drug candidates.…”

“…Effects of Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME, 1 mM) or 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 μM) in Artemisia capillaris extract (ACE, 1 mg ml − 1 ) (a) or scopoletin (Scop, 10 μM) (b) induced eNOS and nNOS protein in the penile corpus cavernosum smooth muscle (PCCSM) by western blot (n = 6). eNOS is endothelial nitric oxide synthase and nNOS is neuronal nitric oxide synthase.…”

Gene therapy as future treatment of erectile dysfunction

“…The etiology of ED can be classified into two major categories: organic and psychological3. Major causes for organic ED include aging, particularly in men older than 50 years4–6, cardiovascular diseases such as atherosclerosis and hypertension 7, 8 diabetes 9, and radical prostatectomy10–12.…”

Quercetin Relaxed the Smooth Muscle of Rabbit Penile Corpus Cavernosum by Activating the NO-cGMP Signaling Pathway

“…6 Upon penile erection, NO is formed in niterergic nerves or endothelial cells and then it diffuses into the smooth muscle cells and activates soluble guanylyl cyclase. 7 This enzyme causes an increase in the formation of cyclic guanosine monophosphate (cGMP), which acts on the calcium channels and decreases the intracellular level of calcium ions, leading to cavernosum smooth muscle relaxation.…”