Adenosine compound promising
in treatment of spinal cord injury
by Rebecca Arrington
to right) Drs. Joel Linden, Timothy MacDonald and David Cassada
By Elizabeth Kiem
the 1960s when the University of Virginia was considered a world
hub for cardiovascular physiology, Dr. Robert Berne developed
a drug to treat cardiac arrhythmia using the naturally occurring
chemical adenosine as his model.
his patented Adenocard is a staple in ambulances and paramedic
kits and has netted the University more than $30 million in drug
died late last fall, just a few months before U.Va. made headlines
again with groundbreaking work in adenosine therapy. Professors
Joel Linden and Timothy MacDonald have patented new compounds
that activate adenosine receptors, and one of these compounds
offers the promise of saving thousands of people each year from
debilitating paralysis as a result of spinal cord injuries.
those who are in the position where they have complete severance
of the cord, theres nothing you can do to prevent paralysis,
said Dr. Irving Kron, chief of thoracic cardiovascular surgery
in the School of Medicine.
But theres a whole crowd who bruise their cord diving
into swimming pools or in car wrecks and get damage from the inflammation
of that cord, and if this drug works as well as I think it will
for those situations, then its the real deal.
and MacDonald have been developing the compounds (dubbed A2A for
the particular receptor they activate) for four years, supported
by grants from the National Institutes of Health and private funding
through their biotech start-up company, Adenosine Therapeutics.
The collaboration began when Linden, a Berne recruit, realized
that adenosines anti-inflammatory characteristics held wider
therapeutic promise, but only if the chemical could be modified
to be more potent and more selective than found in the human body.
he went to MacDonald, who, as chair of the chemistry
department since 1982, has developed a strong rapport with
the Medical School faculty.
is an unusual academic chemist because he is interested in medicinal
chemistry, not just the esoteric, and he has a long history of
excellent work, Linden said.
grasped the chemical task immediately. Youve got four
receptors [that are activated by adenosine] and selecting one
over the other requires a lot of molecular manipulation. But you
really have to dial in like a laser on one of them, because the
others have opposing or undesirable activities, he said.
illustrate the importance of selectivity, Linden tells the story
of some hapless predecessors. In the late 1950s, a team of German
scientists developed a model that targeted all four adenosine
receptors, including one that significantly slows brain activity.
Their drug was ultimately marketed as a rodenticide,
he said with a chuckle.
and MacDonald did hit upon the right receptor, with a compound
even more powerful than they had hoped for. They found that when
introduced to sites of injury or ischemia (temporary loss of blood
flow), A2A halted the cycle of tissue damage that has come to
be expected after traumatic insult or vascular blockage.
thinking is that the compound helps turn off an aggressive immune
system which often does more harm than good by attacking areas
outside the immediate zone of injury. This frequently occurs during
organ transplantations and heart surgery as well, when the bodys
response to invasive surgery presupposes infection.
a natural setting, when you have an injury, you would expect bacteria
to enter the wound, so the immune system has evolved to attack
any tissue that is involved. Injury is associated with infection,
and since infection is so deadly in the absence of antibiotics,
the immune system is very aggressive, Linden explained.
coaxes the body to delegate its ancient function to the modern
reality of antibiotics. It is a utility that physicians have longed
for for close to a decade, and one scientists have attempted to
fashion for even longer.
Misha Sitkofsky is the chief of biochemistry and immunopharmocology
section of the National Institute of Allergy and Infectious Diseases,
part of the NIH. Hes not surprised that this major advance
came out of Lindens lab. Joel Linden is a major figure
and original contributor who came up with extremely clever designs
after success in models of heart, lung and kidney injury did Linden
propose collaboration with researchers in the thoracic cardiovascular
division, who had been working with adenosine models of their
own for some time as well.
January, David Cassada, a thoracic cardiovascular surgery fellow,
presented his findings on the application of A2A in rabbits that
had suffered trauma or ischemia to the spinal cord. Of those rabbits
administered the compound within 10 minutes of injury, 90 percent
showed significantly better function than those not given the
drug. He concluded that A2A not only reduces tissue inflammation,
but it also can prevent damaged nerve cells from spinning into
a death cycle.
also believes the compound may prevent or lessen spinal cord paralysis
that occurs as a result of blood loss during certain vascular
surgeries, such as repair of an aortic aneurysm. While spinal
cord ischemia is a rather rare occurrence, Cassada said that the
vast numbers of young people who regularly suffer spinal cord
injury as the result of car accidents are enough to cause considerable
excitement about the possibilities.
one knew about this. It was brand new. We had done some models
on ischemia but, truthfully I didnt think it would work
on trauma, Kron recalled. The assumption before was
always that the paralysis occurs as a direct result of the injury,
and what David proved was that it comes from the inflammatory
response. So this drug has the unique promise of something you
can use after the injury takes place. And what a neat thing if
emergency response teams could give it even before the victim
gets into the operating room.
the accolades are tempered with caution. Said Blaine Enderson
of University of Tennessee Medical Center: Unfortunately,
moving from a carefully controlled study as conducted by Dr. Cassada
to the uncontrolled, multifactorial process that we see clinically
in multisystem trauma has led to many previous disappointments
in this area and other areas of trauma care.
is president of the Eastern Association for the Surgery of Trauma,
a society that chose Cassadas presentation for its annual
award. Cassadas findings also helped land a $1.5 million
grant from the Falk Medical Research Trust, a gift that Robert
Carey, outgoing dean of the School of Medicine, said, will
help catapult our outstanding adenosine research program into
useful treatment of cardiovascular and inflammatory diseases.
researchers in the neuroscience department are looking into adenosines
use in the brain, with the hope that it will prove as effective
on brain aneurysms as in heart attack and stroke models.
belief in the promise of A2A is apparent from the two decades
he has devoted to adenosine research and from his new commercial
venture, Adenosine Therapeutics, LLC, which was started by Linden
and local entrepreneur Robert Capon in February 1999. It employs
10 scientists full-time.
hopes to see his work materialize into a viable drug and is aiming
for phase one clinical trials in the next three years. He and
MacDonald already are in talks with half a dozen major drug companies.
With FDA approval, A2A could be a golden goose for his team and
for the University, but Linden says his main goal is to
see this stuff get into patients.
of the commercial fate of A2A, Linden, MacDonald and Cassada agree
that a portion of their reward comes from being integral to one
of the earliest interdisciplinary research projects at the University.
related it to the founders legacy: Mr. Jeffersons
academical village describes the interactive discussions between
disciplines. And this is easily an example where different, specific
disciplines are collaborating a major social and medical problem.