In a small safety study, higher doses resulted in clinically significant and sustained improvement.
The first human study using gene transfer to treat erectile dysfunction (ED) shows promising results, according to researchers.
In the wake of widely publicized adverse results using viruses as vectors to transfer genes into humans, the researchers, George Christ, PhD, and Arnold Melman, MD, transferred the hMaxi-K gene using “naked DNA,” a form of circular DNA that remains independent and does not integrate with chromosomal DNA in muscle cells.
“The hMaxi-K stimulates potas-sium ion transfer in the smooth muscle cells of the penis,” said
Dr. Melman, professor and chair-man of urology at Albert Einstein College of Medicine and Montefiore Medical Center in New York City.
“While this phase I safety trial was not designed to provide efficacy answers, one patient in each of the higher dose groups (5,000 and 7,500 micrograms) reported clinically significant and sustained improvements in ED. And there have been no adverse effects.” Findings appear in Human Gene Therapy (2006;18:1165-1176).
The hMaxi-K gene works by creating additional potassium channels in smooth muscle cells of the penis. This relaxes the muscles and allows for greater blood flow. The study, of 11 men with ED, was conducted from May 2004 to May 2006 at Mount Sinai School of Medicine and New York University School of Medicine, both in New York City. Men in the study ranged in age from 42-80 years (mean 59 years).
Six of the men were white, four were black, and one was Hispanic. In half of the subjects, the cause of ED was diabetes or CVD. With this approach, DNA segments were mixed into plasma and injected into the corpus cavernosum. A variety of clinical and laboratory tests were used to assess safety. Effectiveness was measured using the International Index of Erectile Function scale; patient responses were validated by their partners.
“I am excited about this,” Dr. Christ said. “As far as I know, this is the first human clinical trial for gene transfer for a non-life threatening disease, and that is a big deal because if you can show it is safe and effective for ED, that would be a huge boon for the age of molecular medicine.
“Right now,” he continued, “we know it lasts six months, so if the pre-clinical data matches the clinical data then we would expect to deliver this twice a year. One of the problems with all the PDE-5 inhibitors is their side effects, so conceivably we could combine this approach with much lower doses of Viagra (sildenafil), Levitra (vardenafil) or Cialis (tadalafil) and avoid some of the side effects, maybe increase the efficacy, and perhaps see responses in some of the patients who previously did not respond.”
Dr. Christ, a senior researcher at the Institute of Regenerative Medicine at Wake Forest University School of Medicine in Winston-Salem, N.C., said this therapy is known as ion channel therapy because the proteins it targets are potassium channels. These potassium channels act as “gates” within cells that are critical for contraction and relaxation of smooth muscle,
Dr. Christ explained.
“We are moving into a new era,” Dr. Melman told Renal & Urology News. “By completing this trial we have proved a concept that we can take a plasmid and inject safely into a targeted organ. It looks like we got an effect, but it was not placebo-controlled, so there is a note of caution. It has worked in thousands of animals before, and it should work in people, but the final proof will come with the placebo-controlled trial.”
He said a trial using this same approach is now being planned for the treatment of overactive bladder. Instead of injecting the plasmid into the penis, the gene product will be injected directly into the bladder through a catheter. Forty patients will be enrolled at 10 sites starting in the first quarter of 2007.