An unusual synthetic drug is now in the early stages of expedited clinical trials. If proven effective, it could become the newest cardiac emergency drug, says John Burnett, M.D., director of the Mayo Clinic's Cardiorenal Research Laboratory.

The drug, called CD-NP, was co-designed by Dr. Burnett and Ondrej Lisy, M.D. It is designed, when given intravenously, to relieve pressure on a failing heart and boost kidney function to help clear the body of excess salt (natriuresis) and water. Heart failure leads to more than one million hospitalizations annually, and subsequent kidney failure hampers recovery.

"That's the beauty of CD-NP," Dr. Burnett said. "It really covers both of those things."

Proteins that scientists engineer by splicing together different genes, or parts of them, are called chimeric proteins. CD-NP is a chimeric protein that Burnett calls "a super-natriuretic peptide." CD-NP is the acronym for the two hormones that Burnett and Lisy combined by fusing a portion of DNP's genetic sequence to a specific gene location in C-type natriuretic peptide (CNP).

CNP is a naturally occurring hormone produced in cells that line blood vessels and in heart muscle cells. It is a 22-amino-acid molecule first discovered in the brains of pigs. In humans it works like nitroglycerin, dilating blood vessels.

Discovering the Healing Properties of Snake Venom

The second molecule, called Dendroaspis natriuretic peptide (DNP), comes from the venom of the African green mamba snake (Dendroaspis angusticeps), a fast-moving, tree-dweller that eat birds, rodents, frogs and lizards. Relatives include cobras and coral snakes. The green mamba is highly venomous.

"A constant review of the world's research literature on natriuretic peptide biology led to intense study of the version found in the green mamba, " says Dr.Burnett who "decided to push that field" after it was not pursued by the French research team that discovered it in 1992.

Dr. Burnett has been studying cardio-renal peptides, including four natriuretic peptides, since 1982, when he was a research fellow in the lab of his mentor Franklyn Knox, M.D., an internationally recognized kidney researcher at the National Institutes of Health, who has since retired At the time, Knox's lab was among a handful worldwide that studied cardio-renal peptides.

DNP got Dr. Burnett's attention after it was isolated in 1992. DNP is genetically different from other natriuretic peptides, which act in concert with receptors in the cardiovascular system to keep fluids and toxins moving when the heart is under pressure. When the kidney fails, however, these fluids and toxins are unable to be cleared from the body. DNP appears to offer stronger support for the kidneys.

In 1999, Dr. Burnett and his colleagues documented a DNP-like immune response in human plasma and the myocardium in Mayo Clinic Proceedings. The same year, Dr. Lisy was lead author of an animal study published in Kidney International detailing DNP's ability to flush sodium from the body. In the subsequent studies in animal heart failure, he has shown that the new protein, originally isolated from snake venom, has a cardiac "unloading effect," by enhancing the glomerular filtration rate, a measurement of kidney function and clearing both salt and water.

"This unique peptide has also renin-inhibiting properties and activates the second messenger cyclic GMP system," Dr. Lisy said.

Renin is an enzyme in the kidney. It triggers a cascade of undesired molecular interactions that lead to increased blood pressure. The cyclic GMP system involves intracellular reactions that reduce renin production.

Therapeutic Potential of CD-NP

"Compared with B-type natriuretic protein (BNP), our potential new drug is less likely to lower the blood pressure to dangerous levels and is more likely to increase the kidney's filtration rate," Dr. Lisy adds.

"The real elegance of our work is the idea of exploiting the desirable properties of two peptides," Burnett said. "People come to the emergency room acutely short of breath due to fluid accumulation in the lungs. You want a safe drug that can decrease the pressure in the heart being caused by fluid overload, but at the same time boost renal function so that you can get rid of the salt and water."

The therapeutic potential of CD-NP -- which Mayo Clinic has licensed to Nile Therapeutics -- is for treating both acute and chronic congestive heart failure. It also could be used to improve renal function in patients undergoing heart surgery.

Burnett's Mayo colleague Horng Chen, M.D., is particularly pleased with its potential. Chen has been focusing on BNP, which does well in reducing pressure on the heart walls but doesn't sufficiently boost the renal system in human patients as it had in animal studies. Mayo Clinic researcher Andrew Stingo, M.D., was one of the first to show that CNP is synthesized and released by epithelial cells, a discovery that prompted scrutiny of CNP's potential.

The recombinant version of BNP, nesiritide, which carries the Scios Inc. brand name Natrecor, was approved by the FDA in 2001 for treating acute heart failure in patients experiencing shortness of breath. It was the first new heart-failure drug in almost 15 years.

"The use of the new CD-NP during the recovery of BNP-treated heart-failure patients is an intriguing future application,"says Dr. Burnett. "Long term, we envision new technologies where we can turn this into a product that can be taken orally, like any other pill. You could get in the hospital treatment through IV then go home and follow up with a pill. This could, over time, enhance the elasticity of the heart by the drug's anti-fibrotic properties."

Burnett's lab was the first to create a synthetic chimeric natriuretic peptide. In 1993, he and colleagues reported in the Journal of Clinical Investigation that they had fused genetic sequences of CNP and BNP to create a vasoactive peptide they called VNP. Again, the renal-enhancing action they desired was insufficient.

Clinical Trials

Dr. Chen is helping to plan and implement clinical trials for CD-NP. The trials will go through three stages in the next year with long-time Burnett collaborators both inside and outside Mayo Clinic.

In the first part of 2008, researchers will begin testing CD-NP in heart failure patients at a clinical research center affiliated with the University of Minnesota. The focus on general safety and dosage levels repeats an earlier study conducted with healthy individuals. This time patients with heart disease will be tested to identify safe dosage levels that don't trigger undesired drops in blood pressure.

At Mayo Clinic, Burnett's team will perform in-depth studies on the effects of CD-NP on the kidney to fully gage its impact on kidney function. Next will be an important, small but in-depth study in which heart-failure patients at the University of Southern California will be monitored to assure that CD-NP safely unloads fluid buildup and reduces pressure on heart walls.

"We are exploring whether CD-NP is beneficial not only as a renal protective agent but also whether it may be used in some forms of kidney insufficiency or failure," Dr. Lisy says. "We also are actively exploring its use in patients experiencing heart attack."

The studies to test CD-NP as an investigational new drug were approved on a fast track in January 2007, soon after Dr. Burnett's team applied to the FDA's Center for Drug Evaluation and Research. However, it is being closely watched in light of safety concerns, mostly excessive blood-pressure lowering properties, raised by clinical trials to test a promising natriuretic peptide, urodilatin (URO).

"We are very excited by this combination drug," Chen says of CD-NP. "It has a lot of potential."

- Jim Barlow