By David N. Leff

It¿s a harsh, cruel world out there. Which is why a wise parent advises his pugnacious son: ¿He who fights and runs away, will live to fight another day.¿

Both options ¿ fight and flight ¿ trigger the same neurohormones, epinephrine and norepinephrine. These signal the heart to beat faster and more strongly, in order to pump extra blood to the arm and leg muscles, which are in charge of fighting and fleeing.

¿The signal that¿s released by the fight-or-flight catecholamine hormones,¿ explained cardiologist H. Kirk Hammond, ¿interacts with the heart cells, and a protein on their surface. Then, that message is delivered to the interior of the cell by means of an enzyme called adenylate cyclase [AC]. It¿s the final protein in the pathway that makes the intracellular machinery of the heart cells respond with a cardiac contraction and increased beats per minute.

¿It also steps up the force of contraction,¿ Hammond went on. ¿So, you could take a heart that is not beating with much force at all, has very weakened contraction, and, using AC, convert that heart failure into a vigorous pumping contraction. This applies to patients with heart failure in particular, because they no longer respond well to these fight-or-flight hormones.¿

Hammond is an associate professor of medicine at the University of California in San Diego and vice president of research at Collateral Therapeutics Inc., a firm he co-founded in March 1995, also in San Diego.

Last Tuesday, at the meeting in Washington of the Federation of American Associations of Experimental Biology (FASEB), Hammond chaired a symposium on ¿Regulation of the Adenylyl Cyclases.¿

¿It¿s very interesting,¿ Hammond told BioWorld Today, ¿because in heart failure, ever since about 1982, the focus has been on the beta adrenergic receptor in the heart. People have for the most part ignored the adenylate cyclase protein. I think the fact that FASEB ¿ the major meeting for scientists in the country ¿ dedicated a whole symposium to adenylate cyclase indicates the dawning of a new age. It focuses on this pivotal protein, not only for biological mechanisms of disease, but also as a focus for treatment options.¿

In his own presentation to the symposium, Hammond reported on a still-ongoing preclinical gene therapy experiment, inserting AC genes into the coronary arteries of healthy pigs, via nonsurgical catheter. An accompanying poster described this study as ¿Intracoronary delivery of recombinant adenovirus expressing adenylyl cyclase increases left-ventricle contractility in conscious pigs.¿

Pig Studies Point Way To Human Trials

¿We had previously demonstrated,¿ Hammond said, ¿that we could put this gene into transgenic mice with chronic heart failure. After these animals received the AC-6 gene transfer construct, their cardiac contractility rate doubled. The next step was to confirm that we could do this in a way that would be applicable to man. And that¿s where the pig study came in.¿

Five 90-pound porkers received the gene transfer vector, which encoded AC-6, an isoform of the protein patented by Collateral. Upon hormonal stimulation, eight to 12 days after gene delivery, their hearts displayed substantially more contractility and output. Another five animals, which got irrelevant control genes, manifested no such cardiac responses.

¿In those five AC-6 gene-transferred pigs,¿ Hammond said, ¿we showed that we could deliver the gene in a way that could be applied clinically. We think it¿s likely that we will be in human Phase I clinical trials, in patients with heart failure, either at the end of this year or the very beginning of the year 2000. We¿re not in the business of making transgenic humans, so we have to be able to deliver this gene in a highly efficient nonsurgical way, in order for it to be clinically useful.

¿The AC gene that we put into pigs,¿ he said, ¿is the murine gene that we used in our transgenic mice. That¿s no problem, because the highly conserved protein that the gene makes has absolutely marked similarity ¿ homology ¿ across many species, even down to quail, with almost identical amino-acid sequences. Having said that, about two years ago we isolated, cloned and sequenced the human AC-6 isoform, the one that¿s down-regulated in heart failure. That¿s the one we¿ll put into human patients.

¿What our gene therapy does,¿ Hammond explained, ¿is take a situation ¿ heart failure, for example ¿ where we believe there¿s a diminished amount of this AC protein. Then, by our gene transfer, we¿re able to overexpress that protein in the heart cells.¿ (See BioWorld Today, Jan. 7, 1998, p. 2.)

Symptoms Severe, Mortality High, Therapies Inadequate

The symptoms of heart failure vary. They range from cyanosis ¿ blue nails and skin, reflecting oxygen deficiency ¿ to fatigue and breathlessness after exertion, to paroxysms of coughing and loss of breath at night, to restlessness, anxiety, sweating, a feeling of suffocation ¿ all the way to acute liver failure.

¿People don¿t realize what an important disease heart failure is,¿ Hammond said. ¿It affects 4.7 million Americans, with 400,000 new cases diagnosed each year. The surprising thing about heart failure is that it is one of the diseases that is becoming more prevalent, not less prevalent. The reason is that people are living longer. They¿re undergoing multiple bypass surgeries and angioplasties; their hearts are getting injured. And they¿re more susceptible to injury because of their advancing age. As for the therapies ¿ besides rest and exercise ¿ the successful drugs that we have for heart failure allow a patient to get perhaps six months more out of life than they otherwise would. And 50 percent of those patients are dead two years later. Maybe a year at most of a very shortened life.¿

Hammond is senior author of a paper in the March 30, 1999, issue of the twice-monthly journal Circulation, titled: ¿Adenylylcyclase increases responsiveness to catecholamine stimulation in transgenic mice.¿

The article concluded, ¿Our findings establish the importance of AC content in modulating b-adrenergic signaling in the heart, suggesting a new target for safely increasing cardiac responsiveness to bAR stimulation.¿ n