Novel Targets in Treating Erectile Dysfunction

Erectile dysfunction (ED) is a major health problem affecting approximately 30 million men in the United States. Population-based estimates of ED prevalence and current use trends show the cost of treatment nationwide could reach $15 billion if all men with ED sought treatment. The number of men with ED will double within the next 20 years as the male population ages. This, together with the fact that awareness of this condition is on the rise, will undoubtedly increase the number of patients seeking treatment.

The current clinical guidelines by the American Urological Association recommend phosphodiesterase 5 inhibitors (PDE5I) as the first line therapy for organic ED. Interestingly, 20–50 percent of ED patients do not respond to PDE5Is. Non-responders do have a variety of treatment options available, including the use of (1) vacuum constriction devices, (2) alprostadil intraurethral suppositories, (3) intracavernous drug injections and (4) penile prosthetic implant surgery. Many of these options are invasive, most with relatively high discontinuation rates.

Nitric oxide (NO) is the principal mediator in the erectile response. NO bioavailability is determined by the activation of nitric oxide synthase (NOS) isoforms. Potential targets in the treatment of erectile dysfunction may be a protein or proteins that regulate NOS activity through post-translational modification. Pharmacologically targeting novel enzymes upstream of the targets of PDE5 inhibition would allow for treatment of PDE5 inhibitor non-responders.

Jeffrey J. Lysiak, Ph.D., and colleagues at the University of Virginia Department of Urology have discovered an enzyme doing just that. The team describes this enzyme to be one of the major players in regulating NOS, and subsequently NO bioavailability, in corpora cavernosum during the erectile response that influences the physiological processes of tumescence (rigidity) and detumescence (flaccidity). They researchers have found this protein in penile tissues in both mouse and human, where it exists in the same cell type as endothelial NOS (eNOS).

A knockout mouse, or even a heterozygote mouse having only one copy of the gene to this enzyme, shows a significant decrease the ability to maintain an erection (see Figure 1). As this novel target may allow for a therapy to help patients maintain erections, the pathway may potentially also be manipulated to treat de-tumescence in cases of priapism or prolonged erections.

In summary, Lysiak and colleagues have described a mechanism of regulating NO bioavailability during penile tumescence and de-tumescence. The University of Virginia is actively seeking a commercial partner interested in aiding in the development of inhibitors to this enzyme.