By the time the average automobile clocks 100,000 miles on itsodometer, a lot of things can start to go wrong _ from rust, rubberand brakes to transmission, timing belt, carburetor, cylinders _whatever.
Likewise, by the time a person approaches retirement age, the ills andailments of aging begin to kick in. In this respect, diabetes is rightlydescribed as a process of accelerated aging.
Even diabetics who control their insulin levels as tightly as possibleeventually suffer pathologies such as kidney failure, creepingblindness, atherosclerosis, joint stiffness, lower-limb ulcers thatwon't heal. These complications coming on in the prime of life mimicthe disabilities of very old age.
"We believe," said biochemist John Egan, "the actual causative linkto the development of diabetic complications is due to the cross-linksbetween proteins that are formed due to the hyperglycemia ofdiabetes." Egan is director of biochemistry at Alteon Inc., in Ramsey,N.J.
"Cross-linking is the glucose-derived link between proteins," heexplained. "A cross-link is an AGE [no pun intended] _ an`advanced glycation end-product' on one protein that has reactedwith another protein to form a protein-AGE-protein complex. It's theglucose-derived link-up between proteins."
Cross-linking causes proteins that are normally flexible and separateto become stiff and attached. This makes cells, tissues and bloodvessels increasingly dysfunctional.
"We don't know of any normal function that AGE products have,"Egan told BioWorld Today. "We believe that their accumulation isthe first sign of aging, and we presume they are in generalpathological.
"Look at the kidney," he continued. "You'll see thickening ofbasement membrane, and a large build-up of immunoglobulin G,collagen and proteins."
Alteon was founded a decade ago as Geritech Inc. by the PicowerInstitute of Medical Research, of Manhasset, N.Y. Scientists fromboth entities are co-authors of an article in the current Nature, datedJuly 18, 1996, titled: "An agent cleaving glucose-derived proteincrosslinks in vitro and in vivo."
"Picower did the theory in the paper," Egan observed. "Alteon all therest of the science."
The company's proprietary compounds, he said, "have the ability tobreak what were previously believed to be permanent, glucose-derived bonds between proteins." The firm's prototype agent isknown as PTB, a thiazolium bromide prototypical breaker.
To test PTB's crosslink-cleaving ability in vitro, the co-authors tookcollagen tendons from the tails of rats that had been diabetic for 32weeks. These stiff collagen fibers resisted digestion by enzymatic orchemical means. However, tendons treated with PTB "produced apeptide pattern almost indistinguishable from untreated, non-diabeticcollagen," their paper in Nature reported.
Proceeding to a preclinical in vivo trial, the team treated those long-term diabetic rats with systemic PTB administered eitherintravenously or by tube into the intestine. The measure of efficacy,as Egan explained, "was reduction in the level of immunoglobulin Gcovalently crosslinked to the surface of red blood cells."
After four days of daily administering the compound, they saw "arapid 80 percent reduction in the IgG on the RBCs."
Alzheimer's disease (AD) has become a paradigm for late-stageaging.
The Alteon/Picower group then went on to test whether PTB coulddisaggregate b-amyloid, a prime constituent of senile neuritic plaquesin AD brains. Advanced-glycation end-products form b-amyloid.
PTB treatment in vitro produced less apparent disaggregation ofmyloid "than the decrease in crosslinking induced by PTB in tail-tendon collagen or red-blood-cell surface IgG," they reported inNature, "but were less dense, less uniformly organized, and morefilamentous in form than the untreated amyloid fibrils."
Alteon, Egan said, "is now at the stage of the game where we arelooking at the pharmacokinetics of our various PTB compounds.Then we can select a lead candidate for eventual clinical trials."
Currently he and his co-workers are "looking very avidly at anynumber of animal models to see if we can elicit efficacy in thediabetic kidney, and if we can effect a change in accommodation inthe eye."
As people age, their eyesight demands more and more light. Bifocalsfrequently become necessary around 40 years old. The eye's abilityto accommodate to changed conditions depends on a muscle at theback of the eyeball, "which is heavily proteinized with collagen asone ages," Egan observed. "What we're looking for is any ability ofthese crosslink breakers to restore the ability of the muscle torespond."
"When we've advanced the science a little more," Alteon's seniorvice-president and chief financial officer, Kenneth Moch, toldBioWorld Today, "we'll be looking for licensing partners tocommercialize these compounds, on which Alteon has composition-of-matter patents pending."
Meanwhile, the company is into the second year of a Phase III multi-center clinical trial testing the efficacy in diabetic kidney disease ofanother chemical compound, pimagedine. (See BioWorld Today,July 12, 1995, p. 2.)
"In this study, for Type-1 diabetes," Moch said, "we have alreadyenrolled 630 of the 660 patients to be tested, and the rest will followshortly. We expect to have data by mid-1998."
For a second trial, testing the drug's efficacy in Type-2 diabetes,Moch added, "we have half of the 900 subjects needed, and expect tocomplete enrollment by the first half of 1997."
The trials are taking place at 117 clinical centers in the U.S. andCanada. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.