Can you describe what angiogenesis is, as
it is applied to the problem of angina from
Dr. Engler: We have at our disposal
now two main ways to approach patients with angina.
One is with medications -- that either decrease
the oxygen needs of the heart, or that dilate
blood vessels that may be constricted, or that
alter the heart's need for oxygen in other ways.
The second approach we have is to perform bypass
surgery of specific areas where the coronary
arteries are narrowed and restrict the flow of
blood -- and by bypassing those, we can deliver
more blood downstream from the blockage. Another
technique is to do angioplasty with or without
stenting, and thus dilate the narrowing. Those
two types of interventions, drugs and revascularization,
are what we have available.
of the coronary arteries is a diffuse disease.
It's only in a few isolated areas that it causes
narrowing. So if we go in and dilate or put
a stent in one place that's narrowed, the patient
can come back a few months or a few years later
with another place that's become narrowed.
The heart's normal, natural
response to lack of blood flow is to grow new
blood vessels: the process of angiogenesis
that leads to what we call collateral blood
vessels that take blood from a well-perfused
area of the heart to an area of the heart that
needs more blood flow. Angiogenesis does occur
in virtually all of our patients with angina.
The problem is that it stops too soon. The
angiogenesis is insufficient to relieve the
patient's symptoms of angina, caused by myocardial
If we could find a method
to jump-start or restart that process, that
would be a powerful new mechanism for treating
patients with angina. And there's an awful
lot of hope and excitement that we will be
able to find a method to increase angiogenesis
in patients with angina.
Q: What is the
current status of angiogenesis therapy
for the heart?
Dr. Engler: Basically two major approaches have been tried.
The first one was protein or growth factor therapy. There
are two main types of proteins or growth factors, VEGF and
FGF, known respectively as Vascular Endothelial Growth Factor
and Fibroblast Growth Factor, that have been evaluated in
clinical trials. One from each family has been administered
as a protein infusion, and the trial results were very disappointing.
There was really no overall clinical effect that could be
measured in the patients. That was actually not too surprising
because proteins have a very short half-life in the blood.
These protein growth factors are gone literally in hours,
and in order to stimulate the growth of new blood vessels,
the process requires several weeks.
The second approach was
gene therapy. With gene therapy we're not really
altering or changing the genes in the patient,
as one would try to do with certain genetic
diseases. What we do is take a normal human
gene, and put it into some cells in the body
in a particular location and try to get the
intrinsic cells in the body to produce the
growth factor and secrete it. And when we do
that, the secretion of the growth factor usually
goes on for several weeks or several months,
which is sufficient time to get new blood vessels
This area was pioneered by
the late Jeff Isner in Boston who made enormous
contributions to the field. Jeff was using
naked DNA or plasma DNA for transfection of
cells; plasma DNA is not as efficient as using
a vector. One other large trial used the adenovirus
as a vector for putting the gene into the heart
by direct injection into the heart muscle.
The injection was done through a thoracotomy,
that is, a surgery. You actually open the chest
and do multiple injections in the surface of
The other method that's
been tried is with a catheter to go inside
the heart and have a small needle on the end
of the catheter and inject the DNA into the
inside wall of the heart. There was a large
trial initiated but that trial was stopped
because they had some problems with perforation
of the heart by the needle that caused some
bleeding into the sac around the heart, which
can be a very dangerous situation.
Another method was discovered
by Kirk Hammond at the VA Hospital in San Diego.
Kirk was trying to find a way to treat his
patients that had angina whose vessels were
such that he couldn't do angioplasty on them,
or who had already had all the angioplasty
they could get, and had bypass surgery, and
were still having angina.
So he tried, in a pig model,
to see what would happen if he put an adenovirus
into the coronary artery -- to see if he could
get the adenovirus to put the gene into the
heart, so the heart itself would become a source
of growth factor. And he made the remarkable
observation that if you infuse the adenovirus
directly into the coronary artery one time,
you get a remarkably highly efficient uptake
of the gene in the heart and very little escapes
the heart. What does escape the heart gets
so diluted in the rest of the body that it
has very little effect, virtually no effect
in the rest of the body.
Q: So it's not
going to go throughout the body and start
growing blood vessels everywhere?
Dr. Engler: Exactly. And we also believe that in most cases
these genes, at the level that we're giving them, actually
won't cause the uncontrolled growth of blood vessels because
we think you need to have some other growth factors that
are produced during ischemia. That's not completely true
with growth factors like VEGF, because if you just inject
a large amount of it, it will stimulate the growth of blood
vessels no matter where you put it.
In any event, Collateral
Therapeutics was formed and we developed Fibroblast
Growth Factor 4 in the Adenovector through
Phase II clinical trials. Schering AG acquired
the company and initiated two Phase 2b/3 clinical
trials. Schering took an interim look at the
results of one trial. The statistical analysis
indicated it would not reach statistical significance,
as the trial was designed, so they stopped
the gene therapy trials for angiogenesis.
At Cardium Therapeutics we
did a meta-analysis of the trial (which was
presented by Dr. Tim Henry at a recent gene
therapy meeting) and in the meta-analysis it
appears that there are actually some very remarkable
effects of the gene therapy. It was highly
effective in relieving angina and improving
exercise performance in women, but seemed to
have very little effect that we could detect
in men. So we have bought back the technology
from Schering, and Cardium is going forward
with the development of that product in a Phase
Q: Do you have
any theories as to why would this have
more of an effect in women than in men?
Dr. Engler: No one knows for sure the answer to your question.
And it's been an important question in cardiology for several
decades, because we've known for a long time that both the
rate of progression and the manifestation of coronary artery
disease are quite different in men than women.
One of the important differences
is that women appear to have what we call microvascular
disease -- that is, the very small blood vessels
are diseased. Atherosclerosis in general affects
only larger surface blood vessels, the main
vessels to the heart. The blood flow to the
heart is like a tree. There are the main trunks,
and then there are smaller branches, and even
smaller branches. And atherosclerosis generally
affects mostly the main trunks and the largest
branches. And that's true in men.
However, in women, we observe
something different. Nearly 50% of women who
get angiograms performed on their heart, to
look for narrowings in the arteries because
they have angina, 50% of those women do not
have significant or serious narrowings. And
the conclusion is that they must have microvascular
disease -- that is, small blood vessel dysfunction.
And angiogenesis starts in the microcirculation,
it starts with the smallest of blood vessels,
with budding and forming of new blood vessels.
And so it could be that because women's disease
tends to be microvascular and angiogenesis
is a microvascular treatment, it is much more
effective in women.
Q: So would it
be correct to say that you can grow new
blood vessels using angiogenesis?
Dr. Engler: Angiogenesis is not going to replace a large
main coronary artery. The angiogenic process does not generate
those large conduit vessels that take the blood from the
aorta, down to the smaller vessels. The collateral vessels
that grow from angiogenesis take blood from medium sized
arteries over to other medium sized arteries. So if there's
a medium to large-sized artery that's blocked, and one that's
not so severely blocked, the increased collateral blood vessels
will take blood through smaller channels from the unblocked
vessel over to the territory of the blocked vessel.
As you know, there are three
main coronary arteries: the circumflex, the
left anterior descending, and the right coronary
artery. If all three of those arteries are
severely blocked, angiogenesis by itself is
not likely to help that patient. The patients
that are good candidates for angiogenesis are
the ones that have at least one or two of their
major coronary arteries that do not have blockages,
or bypass grafts that are open. And that's
probably another aspect of why this therapy
appears to be effective in women but not in
men -- because of the fact that a lot of the
women that present with angina, their larger
vessels are not as diseased as men.
Q: A lot of patients
on our Forum write in with problems – patients
who have been through stents and angioplasty
and they're still not feeling well, still
having angina. Is there a possibility that
this is a patient population that might
be helped by angiogenesis?
Dr. Engler: Oh absolutely. You hit the nail on the head.
I think that's a very important population that angiogenesis
would be very helpful for -- patients who continue to have
persistent angina despite having had revascularization, either
by angioplasty, stent, or by bypass surgery.
There are a number of patients
who have persistent angina despite angioplasty
or bypass surgery. The repeat catheterization
shows the vessels and or bypass grafts are
open and they may say, "But I'm still
feeling this heaviness in my chest and I'm
getting these pains still". It does appear
that most of those patients are having persistent
angina. And that is exactly the type of population,
patients with persistent angina, that angiogenesis
therapy would be expected to help.
Q: Can you describe
more about the catheter-based system that
Cardium is working with right now? There's
no needle involved….
Dr. Engler: We do an ordinary diagnostic cardiac catheterization,
with a standard cardiac catheter that every cardiologist
who does angiography uses. We put the catheter into the main
coronary arteries, into each one separately, and we do a
single infusion of the adenovirus that has the growth factor
gene. The heart does its job, because it takes up avidly
a lot of that adenovirus on the first time through the heart.
That's why we have to infuse
it directly into the coronary arteries because
we want to get the growth factor concentrated
and targeted to the heart, and not have the
Fibroblast growth factor all over the body.
Fibroblast growth factors are locally acting
hormones. They are a type of hormone that is
produced, secreted by cells, stays local, and
has all of its activity in the environment
in which it is secreted. The adenovirus with
the gene that isn't taken up by the heart becomes
so diluted in the rest of the system that there's
not enough gene transfer there to produce detectable
amounts of growth factor.
So basically the cardiologist
delivers this in a matter of 15 minutes. Once
the cardiac catheterization is done, once you
get the catheters in the vessels and get all
ready to go, it'll take about 15 or 20 minutes,
to infuse the adenovirus into the coronary
arteries and then you're done.
There's no balloon involved,
there's no angioplasty involved and there's
no stent involved. The guiding catheter is
put in the main coronary artery, and then a
small selective catheter is passed down through
the guiding catheter and goes a short distance
further into the coronary arteries. And the
reason we do that is so we can be sure that
virtually all of the product that we're infusing
goes down the coronary arteries and doesn't
spill back into the aorta.
You have to do that because
when the heart contracts there's actually backward
flow of blood in the large surface coronary
arteries because the heart generates so much
pressure when it contracts. So if you were
to just infuse it through the guiding catheter,
when the heart contracts during systole, a
lot of that product would get pushed back into
the aorta and go to the rest of the body and
not be targeted to the heart.
Q: How many years
are we away from this therapy being used?
Dr. Engler: I can just give you a rough guideline. Cardium
is going forward with a phase 3 trial that typically would
take 12-18 months to complete. The FDA might require an additional
trial, even if the first trial showed the product to be effective,
in order to ensure that enough patients had been tested for
Q: Are there
other areas in the body that you see this
affecting, for example peripheral vessels
in the leg?
Dr. Engler: At Cardium we are not pursuing that application
at the current time, but there are others that are. And generally
those trials involve injecting genes for growth factors in
multiple locations in muscles of the leg to help increase
the growth of collateral blood vessels in the leg. And there
are a significant number of patients in the world with what
we call claudication. That is insufficient blood flow to
the legs when they walk, quite analogous to the patient who
gets angina because he gets insufficient blood flow to the
heart when he exercises, or when the demands on the heart
go up. And in theory, angiogenesis could well work in the
peripheral vascular disease area and there are trials still