Adenosine compound promising in treatment of spinal cord injury

Photo by Rebecca Arrington

(left to right) Drs. Joel Linden, Timothy MacDonald and David Cassada

By Elizabeth Kiem

In 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.

Today, his patented Adenocard is a staple in ambulances and paramedic kits and has netted the University more than $30 million in drug royalties.

Berne 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.

“For those who are in the position where they have complete severance of the cord, there’s nothing you can do to prevent paralysis,” said Dr. Irving Kron, chief of thoracic cardiovascular surgery in the School of Medicine. “But there’s 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 it’s the real deal.”

Linden 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 adenosine’s 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.

So he went to MacDonald, who, as chair of the chemistry department since 1982, has developed a strong rapport with the Medical School faculty.

“Tim 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.

MacDonald grasped the chemical task immediately. “You’ve 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.

To 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.

Linden 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.

The 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 body’s response to invasive surgery presupposes infection.

“In 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.

A2A 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.

Dr. Misha Sitkofsky is the chief of biochemistry and immunopharmocology section of the National Institute of Allergy and Infectious Diseases, part of the NIH. He’s not surprised that this major advance came out of Linden’s lab. “Joel Linden is a major figure and original contributor who came up with extremely clever designs and compounds.”

Only 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.

In 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.

Cassada 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.

“No one knew about this. It was brand new. We had done some models on ischemia but, truthfully I didn’t 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.”

But 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.”

Enderson is president of the Eastern Association for the Surgery of Trauma, a society that chose Cassada’s presentation for its annual award. Cassada’s 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.”

Meanwhile, researchers in the neuroscience department are looking into adenosine’s use in the brain, with the hope that it will prove as effective on brain aneurysms as in heart attack and stroke models.

Linden’s 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.

Linden 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.”

Regardless 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.

Cassada related it to the founder’s legacy: “Mr. Jefferson’s 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.”