First successful step taken in gene therapy for ED

That was the hopeful projection from Arnold Melman, MD, professor and chair of urology at Albert Einstein College of Medicine in New York. A phase I dose escalation study of gene transfer therapy showed no drug-related adverse events and no evidence of the transferred gene in the semen of any study participants.

"We have shown that gene transfer therapy for ED is safe and we have seen some evidence of efficacy at higher doses," Dr. Melman told the AUA meeting here. "We need placebo trials to confirm that result."

Without the presence of calcium ions, Dr. Melman explained, smooth muscle cells relax and the tissue relaxes. A similar cellular and tissue relaxation mechanism mediated by the K+ channel can correct hypertension, asthma, overactive bladder, and numerous other conditions that involve smooth muscle tissues. The effect of gene transfer can last up to 6 months with a single treatment, which eliminates the need for on-demand or daily dosing of oral medications. It also offers the possibility of allowing some allied drugs to work effectively at lower doses, which may reduce their side-effect profile.

Dr. Melman said erectile dysfunction offered the first promising therapeutic target because more is known about the molecular and ionic mechanisms of the condition. He is in the process of applying to test gene therapy for OAB this spring.

Naked DNA vector used

Early results in ED are very encouraging, Dr. Melman said. Eleven men had gene transfer with hMaxi-K using a naked DNA plasmid vector. Naked DNA is not often used as a vector, he noted, because it is relatively inefficient at moving the target gene inside cells compared with viral vectors. That inefficiency seems to be a benefit in ED, where only about 10% of cells need to be transformed in order to boost intracellular signaling and enhance K+ channel activity. Naked DNA also lacks the potential toxic side effects that have been seen in viral vector trials.

The goal of the study was to increase K+ channel expression in order to enhance smooth muscle relaxation and restore erectile capacity. The 11 men, who ranged in age from 46 to 79 years, were divided into four groups for sequential dose escalation of hMaxi-K, injected intracavernously: 500 μg, 1,000 μg, 5,000 μg, and 7,500 μg. The gene transfers were performed by independent investigators at New York University Medical Center and Mount Sinai Medical Center in 2004 and 2005.

There have been no drug-related adverse events, no cardiac issues, nor any significant laboratory changes since transfer in any of the 11 men, Dr. Melman reported. No hMaxi-K was detected in the semen of any of the men at a sensitivity of 1 copy/mg total DNA. Two participants, at the 5,000-and 7,500-μg doses, reported a sustained 100% increase to questions 3 and 4 of the International Index of Erectile Function (dealing with duration and hardness of erection), from 2 to 4. Phase II dose-ranging and placebo-controlled studies are being planned.

Dr. Melman is a board member, officer, and trustee of Ion Channel Innovations.