On this election day, citizens might be interested in one effort to cuttaxes that escaped the candidates' notice.

It involves an annual expenditure of some $10 billion dollars incurredby Medicare to maintain chronic kidney failure patients onhemodialysis, according to the U.S. Renal Data System at theUniversity of Michigan.

"There are 300,000 patients on dialysis with end-stage chronic renaldisease," observed molecular biologist Charles Cohen. "They haveon average five years to live. Of another 700,000 pre-end-stagepatients, some haven't been diagnosed yet because they'represymptomatic."

Cohen is chief scientific officer of Creative BioMolecules Inc.(CBM), in Hopkinton, Mass. That company's premier preclinicalproduct is osteogenic protein 1 (OP-1). This molecule, despite itsbone-boosting name, is under wide academic investigation forrestoring function to other tissues besides bone, among them thekidney.

If human trials of OP-1, expected in 1997, bear out results in rats,presumably that $10 billion dialysis tax could be cut considerably.

Today in New Orleans, at the 29th annual meeting of the AmericanSociety of Nephrology, pediatric nephrologist Anna Paredes willreport recent rodent experiments that imitate chronic kidney failure inpeople.

"The classic animal model for studying this disease," Cohen toldBioWorld Today, "is to remove five-sixths of a rat's two kidneys.That is, take out one kidney, then 10 days later ablate two-thirds ofthe other. This animal, over time, will develop chronic renal failurethat is very similar to the same clinical manifestation that we see in ahuman. That is, decreased capacity for clearing waste products fromthe blood."

Paredes, who is at the University of Miami, Florida will report twoexperiments, one gauging the effect of CBM's recombinant OP-1therapy on restoration of failing function, the other, preventingfunction from failing.

As for the first goal, her experiments, Cohen said, "suggest in factthat OP-1 treatment started in the restoration model six months afterremoval of all but one-sixth kidney tissue, improved renal function ina statistically significant way, and reduced mortality."

When treatment began only two weeks after that ablation, "Verypositive data showed that biochemical markers of function, andhistological preservation of renal organ architecture, displayed amuch healthier outlook, as compared with control animals. So didsurvival of rats treated with OP-1."

Cohen continued: "These mortality studies were taken out as long asfour months, when survival of the OP-1 group was about 85 percent;of untreated rodents, in the 35-percent range."

Getting By On 10 Percent

The primary diseases that contribute to progressive chronic failure ofrenal function are high blood pressure and diabetes. By the time thatfunction drops to only 10 percent of normal, Cohen pointed out, "it'stime for renal replacement therapy, whether an organ transplant ordialysis. If we could use OP-1 treatment to delay or halt theprogression of this decline, that would really be a quite spectacularresult clinically. It would make a tremendous impact on health care."

But chronic kidney failure is only the half of it. The other half isacute.

"The primary insult that produces acute renal failure," Cohencontinued, "is cessation of blood flow to the kidneys. Say you'rehaving major surgery, and the surgeon needs to interrupt the bloodflow. If the kidney is downstream of that ligated blood vessel, it'sgoing to be starved for nutrition. And this is not something that thekidney handles well."

That ischemia damages the renal tubules so that the kidney is unableto filter and excrete nitrogenous wastes. "This creates a toxicity,"Cohen added, "which will probably precipitate multiple organcollapse and contribute to the patient's death. "

Here too rodents pinch-hit for people. Paredes described to thenephrology meeting that she created acute ischemia by clamping offblood supply to rat kidneys for varying periods of time.

"At 40 minutes," Cohen observed, "the animals sustain severe acuterenal failure. At 60 to 70 minutes, it's life-threatening, and many ofthem will die. Here, again, survival of rodents in the OP-1 group wassuperior to that in controls." None of the rats that received multipledoses of the recombinant protein died, while two of the seven that gotdummy drugs did.

From Bone To Kidney To Brain

Later this month in Washington, neuroscientist Seth Finkelstein ofMassachusetts General Hospital will tell the 26th annual meeting ofthe Society for Neuroscience that OP-1 injections into the brains ofrats with simulated stroke produced "marked enhancement of limbfunction" and "a less pronounced behavioral recovery."

CBM will next test the safety of its multi-purpose protein (seeBioWorld Today, May 10, 1996, p. 1) in a primate model. "With anyluck," Cohen said, "we can hope to begin clinical trials before theend of 1997."

OP-1, which the company isolated and cloned in 1987, belongs to thetransforming growth factor-b (TGF-b) superfamily. Early ingestation, the signaling molecule helps induce uncommittedembryonic cells to take the path of differentiation _ forming specificcells, tissues and organs.

In adults, OP-1, along with other TGF-b factors, helps trigger theformation of new tissue. Grown-ups are essentially revisiting thescene of their embryonic development process. "Used locally,"Cohen said, "OP-1 can stimulate growth of new bone and cartilage,"as well, apparently, of kidney (in which the protein is primarilysynthesized) and brain cells.

With 15 issued U.S. patents, CBM last June entered into a broadcross-licensing agreement with Genetics Institute Inc., of Cambridge,Mass., "which had independently developed an intellectual propertyposition on many members of this growth factor family," Cohen. n

-- David N.. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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