| Wayne 2004-11-03, 10:07 pm |
| Medscape www.medscape.com
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http://www.medscape.com/viewarticle/491836
Penile Injection of Gene Therapy Appears Safe in Men With Erectile
Dysfunction
Yael Waknine
Medscape Medical News 2004. © 2004 Medscape
Oct. 25, 2004 — A single subtherapeutic intracavernous injection of the
human recombinant Maxi-K ion channel gene via a "naked DNA" plasmid
vector (hMaxi-K) is safe in men with moderate to severe erectile
dysfunction (ED), the results of a phase 1 trial presented at the 11th
World Congress of the International Society for Sexual and Impotence
Research (ISSIR) in Buenos Aires, Argentina, suggest.
"This is translational research; we actually made observations in the
laboratory first and then tried to apply them to a clinical problem,"
Arnold Melman, MD, told Medscape. Dr. Melman is affiliated with the
Montefiore Medical Center and holds posts as professor and chairman of
the department of urology at the Albert Einstein college of Medicine in
New York City.
Dr. Melman and colleagues found that smooth muscle cells of the
genitourinary system have four types of potassium channels that
hyperpolarize the cell when open, blocking the inflow of calcium
required for contraction. "The most common and the most active of these
potassium channels was the Maxi-K channel," Dr. Melman said.
The investigators created a "naked" DNA plasmid (hMaxi-K) by
incorporating the cDNA necessary to produce the pore-forming subunit of
the Maxi-K channel into a commercially available nonviral,
double-stranded circular DNA. "We demonstrated that when we took this
gene and put it into the penis, the [smooth muscle] cells took it up and
produced the protein," Dr. Melman explained.
The hMaxi-K injection increases the expression of the Maxi-K channel in
a small percentage of penile smooth muscle cells, whose signal for
smooth muscle relaxation upon neural stimulation is amplified by gap
junctions, according to Dr. Melman. The relaxation-signal amplification
eliminates the need for aggressive gene incorporation strategies (such
as adenoviral or retroviral vectors) that are associated with increased
risk of adverse immune responses and tissue inflammation, possibly
precluding their use.
Results of laboratory studies showed that an injection of hMaxi-K could
reverse diabetes-induced or age-related ED in animals for up to six
months. After a public presentation of this preliminary work to the
Recombinant DNA Advisory Committee of the Office of Biotechnological
Activity at the National Institutes of Health, Dr. Melman and colleagues
received investigational approval for hMaxi-K from the U.S. Food and
Drug Administration (FDA) Center for Biologics and Research. The phase 1
trial was conducted at New York university and the Mount Sinai School of
Medicine after institutional review board approval.
The FDA approval allowed testing of at least three levels of hMaxi-K
dosing, in three patients per level. According to Dr. Melman, safety in
humans was the primary concern at the 500-µg level. "The first level was
one that really didn't have an effect in animals — we're increasing the
dose sequentially to make it as safe as possible; when there are no
adverse events in patients [at one level], you then go to the next
level," he said.
Results showed that intracavernous injection of 500 µg of hMaxi-K in
three men with moderate to severe ED was safe. "There were no
treatment-related adverse events," Dr. Melman said, adding that the
animal equivalent of the next dose to be tested (1000 µg) was also low
but had been effective in laboratory studies.
"We are using the safest vector, which is naked DNA: it doesn't cause
allergic reactions, it doesn't get integrated into the chromosomal
apparatus...and [in animal models] the physiologic effect does seem to
last a long time," Dr. Melman said.
The science of ion channel gene transfer has been well accepted and its
applications potentially affect millions of people, according to Dr.
Melman. "All the major smooth muscle diseases are diseases that heighten
contractility, including hypertension, asthma, irritable bowel, benign
prostatic hyperplasia, and overactive bladder," he pointed out. "These
are all profound problems that together affect the majority of the
population — compared with cancer, it's another order of magnitude of
morbidity."
Dr. Melman and colleagues will also be seeking FDA approval for the
investigative use of hMaxi-K in women with overactive bladder. "We're
using a very safe vector to treat local organ disease. If it works — and
I think it will — it's going to really be a giant step forward in
medical therapy," he said.
Dr. Melman pointed out that although ED drugs such as sildenafil
(Viagra) and tadalafil (Cialis) are in use, "these work only in about
60% of people, they have side effects and some contraindications to
using them, and you have to plan ahead — you have to take a pill to have
sex," he said.
"If hMaxi-K works in people the way it does in animals, [the effect of]
a single treatment will last for a long duration," concluded Dr. Melman.
"It takes away the concept of having to plan ahead — patients want
something safe that they can count on, and I think that's what we have
to offer here."
The phase 1 study was funded by Ion Channel Innovations, LLC. Dr. Melman
is a directing member of the company.
ISSIR 11th World Congress: Abstract UP153. Presented Oct. 18, 2004.
Reviewed by Gary D. Vogin, MD
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