Gene Therapy for Erectile Dysfunction

Jesse N Mills; Joseph E Dall'Era; Soren N Carlsen; Hari Koul; Randall B Meacham


Pharmacogenomics. 2007;8(8):979-984. 

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Expert Commentary

The translational aspect of gene therapy for ED is in its infancy. Several clear advantages to developing gene therapy to treat ED are evident. The penis is easily accessible, with an easily-compressible blood supply to enhance the uptake of injectable transfection agents and prevent spread to surrounding organs. Furthermore, the low blood supply found in the flaccid penis decreases the concentration of DNA required for efficient cellular uptake of transfected material. Multiple trials using a variety of agents have taken advantage of these qualities and have shown great promise in animal models.

To date, there is one group that has published their data on Phase I trials of human gene therapy for ED. That group, led by Arnold Melman, has long been studying the feasibility of gene therapy for ED. To that end, the group has published multiple papers on rat models leading up to a breakthrough publication pertaining to human subjects.[20] The gene that Melman's group has chosen to transfect is hSlo. This gene codes for the pore-forming subunit of human smooth muscle, hMaxi-K.

Although not designed to assess efficacy, this trial did show successful transfection, with an excellent safety profile. A total of 11 men enrolled in the study. The etiologies of ED included six men with diabetes and/or coronary artery disease, one man with traumatic penile fracture, one with postradical prostatectomy ED, two men with unspecified organic ED and one man with psychogenic ED. Ethnicities were distributed between white, black and Hispanic men. To qualify for the study, all men had to be unable to have erections suitable for vaginal penetration for at least 6 months prior to enrollment. All of these men had tried oral, intracavernosal or intraurethral ED therapies prior to enrollment. The key findings of this paper are that the gene, transmitted in a naked DNA plasmid, can be injected into human penises without untoward events. Also important is that the semen from these men did not show any copies of the gene. This is critical in that germ-cell transfer of gene products might have potential unforeseen progenic effects. What is unclear from this study is whether or not the gene product actually increases translation of the desired protein in human subjects. Given the morbidity of the procedure, no tissue biopsies were performed to confirm presence of the product. Interestingly, two men reported a significant improvement in their erections after transfection with the product. However, these two men were given higher doses of the gene product. In addition, the one male who reported psychogenic ED was one of two that had received the highest dose of gene product in the study. Therefore, we can assume a 50% chance that one of the two that showed improvement had a primary diagnosis of psychogenic ED and could have benefited substantially from a placebo effect. Such criticisms aside, this is a landmark paper that should serve as a springboard for larger, randomized, placebo-controlled trials on the efficacy of gene therapy for ED.

The goals of gene therapy for ED are to establish a safe, effective agent that can restore spontaneous erections in most men who use it. Ideally, this will be an intracavernosal injection with a durational effect of around a month. The medication could be self-administered in a fashion similar to current injection agents. Our laboratory has been studying VEGF as a potential gene target. The rationale is that increasing endothelial cell number will lead to increased levels of NO to mediate vasodilation and subsequent erection. We placed VEGF in a nonviral plasmid vector and delivered it as a nanoparticle suspension using linearized polyethyleneimine (PEI). We then injected this product, tagged to green fluorescent protein (GFP), into diabetic rats. Results from these studies demonstrated successful transfection and translation of the GFP-VEGF gene fusion product in the rat penis. Moreover, our data indicate that we also demonstrated improved erectile function in these rats and, perhaps most important, demonstrated a synergistic response with phosphodiesterase type-5 inhibitors.[21,22] This suggests that inhibiting the degradation of cGMP, along with increasing expression of VEGF, is a viable and potent pharmacogenetic and pharmacologic combination. The expression of transfected VEGF in these rats appears to peak at about 3 weeks. We therefore envision a human product that is injected on a monthly basis and provides a static erectogenic response that can be augmented with as-needed phosphodiesterase inhibitors. The advantage of PEI vectors over viral vectors is that there appears to be no immunogenic response. PEI has successfully been used to transfect the rat corpus cavernosum with high efficacy when studied 2 days after injection.[23] We used an alternate, water soluble, linear PEI (in vivo jet PEI) to deliver plasmid DNA expressing GFP into the rat corpus cavernosum and found a significantly longer duration of gene expression. This technology has previously been used in several investigations, including human trials for gene therapies to treat bladder cancer,[24] rat studies of novel DNA vaccinations,[25] and the development of new treatments of glomerulonephritis in a rat model.[26] To our knowledge, this is the first application of this specific PEI formulation to the rat corpus cavernosum.

Polyethyleneimines are powerful DNA carriers and efficient gene-delivery systems. Their strength is derived from their ability to accommodate a large number of protons within the acidic environment of endosomes. At a physiologic pH, PEIs remain only partially protonated. However, within the acidic endosome, PEIs capture enough protons to increase the osmolarity to the point of endosome rupture. This leads to successful release of the DNA/PEI complexes within the target cell.[27]

Concerns regarding injecting a gene that codes for a neovascularization protein include the potential for tumorigenesis. Although this represents a valid concern, we have seen no expression of our product outside the penis. The next step for our laboratory is to carry out survival trials on our rat models to ensure no adverse events occur as a result of our construct. Based on the focal expression of VEGF in cavernosal tissue, we do not anticipate adverse long-term sequelae.


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