For patients with severe angina, excruciating pain and
shortness of breath can mar even the simplest activities,
despite excellent existing therapies. A novel genetic
therapy is renewing these patients' hopes of leading normal
lives. Two ongoing trials have pitted cash-poor Canadian
researchers against well-funded Americans in a race to
develop gene therapies to promote blood vessel growth,
or angiogenesis, in cardiac muscle.
STARS
AND STRIPES
The US study, GENASIS (Genetic Angiogenic Stimulation
Investigational Study), funded by Atlanta-based Corautus
Genetics, kicked off in August 2004. Participating patients
have severe angina (Class 3 or 4) and are not candidates
for standard treatments, such as coronary artery bypass
graft (CABG) or balloon angioplasty. Study subjects
receive either a placebo or one of three doses of a
recombinant plasmid DNA (ie, human DNA produced in bacteria)
to promote development of supplemental collateral blood
vessels.
The DNA is delivered in an hour-long
procedure using a direct injection cardiac catheter
system via the groin. The injected DNA is taken up by
the myocardium where it promotes production of vascular
endothelial growth factor-2 (VEGF-2).
While it's still too soon to call,
prior studies have shown that VEGF-2 causes endothelial
cells to move into the area and grow into new blood
vessels, a process known as angiogenesis. Over the course
of six months, this improves oxygen delivery to the
damaged tissues, relieving the painful angina. However,
this approach has its dangers, including the possibility
of blood vessel growth in unwanted areas, such as in
tumours or in the retina. But a safety analysis conducted
in March gave GENASIS the green light to continue; the
research team plans to enrol a total of 404 patients
in about 30 US centres.
'NORTHERN'
EXPOSURE
The Canadian trial, fittingly called NORTHERN (The NOGA
Angiogenesis Revascularization Therapy: Evaluation by
RadioNuclide Imaging), has been underway since October
2002. NORTHERN has at least three advantages over the
GENASIS trial, according to Dr Duncan Stewart, Chief
of Cardiology at St Michael's Hospital in Toronto and
the study's lead investigator.
First, it uses a novel delivery
method that enables the cardiologist to place the catheter
much more precisely. "[GENASIS researchers] have no
way of really confirming that the catheter is where
they think it is," notes Dr Stewart, whereas NORTHERN's
cardiologists use a visualization system, called NOGA,
to precisely target ischemic myocardium. Second, NORTHERN
uses DNA developed at St Michael's that produces a superior
type of VEGF: VEGF-A165. Finally, says Dr Stewart, the
dosage used in NORTHERN — 2000µg — promises
good efficacy, while the highest dose of VEGF-2 being
used in GENASIS — 800µg — could be too
low for maximum therapeutic effect.
A total of 110 patients are being
enrolled at seven Canadian heart centres and results
are expected by early 2006. However, Dr Stewart says
funding shortages have already slowed his team's progress.
The only commercial support is from Cordis/Biosense
Webster, who supplied the catheters and the NOGA imaging
systems. Dr Stewart's team must patch together the remaining
funding from government agencies and private foundations.
Given the study's potential
applicability and its advances over the American trial,
any delays are lamentable. "Real evidence is needed
on the benefits of these kinds of therapies," says Dr
Stewart. "If it's trivial or nonexistent we won't persist
in this strategy.... With a good result you'll see the
therapy being made available."
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