Hybridon Inc. has signed a five-year agreement with Medtronic, Inc.,the Fortune-500 medical-device company, for a joint attack onAlzheimer's disease. Medtronic has taken an initial $4 million equityposition in the Worcester, Mass.-based firm.This investment amounts to somewhat less than 5 percent of thecompany's capitalization, said E. Andrews Grinstead III, Hybridon'schairman and CEO. He noted that an initial $4 million stake fromHoffmann-La Roche early last year netted Roche nearly 8 percentequity because the stock was less expensive.Medtronic's investment, he said, does not involve a seat on Hybridon'sboard, but rather "visitation rights, to keep them abreast of our researchprogress.""The Hybridon collaboration is one of several in which Medtronicseeks to address unmet medical needs with its implantable druginfusion system," said John A. Meslow, president of Medtronic'sNeurological Business, who signed the accord for the Minneapolis-based company.Meslow added, "The delivery of antisense compounds to the brain mayprovide a promising therapeutic approach for the treatment ofAlzheimer's disease and other neurodegenerative disorders."Hybridon has been conducting preclinical research for over three yearson unleashing its antisense molecules against the genes encodingproteins implicated in Alzheimer's, Grinstead told BioWorld.`"We are looking at multiple targets," he said, "including the obviousones _ "beta-amyloid protein, amyloid precursor protein and ApoE4_ employing proprietary animal models of AD."Medtronic's SynchroMed device for programmed pumping ofmedications to sites within the body, Grinstead said, may lend itself to"delivering specifically adapted antisense compounds to the centralnervous system via access to the cranial cavity." He pointed out that,"We don't know yet to what extent our Alzheimer's drugs willpenetrate the blood-brain barrier. Even if they do, there might becertain clinical circumstances where using Medtronic's deliverytechnology would be the optimum approach."`No Better Partner Then Medtronic'He added, "If Hybridon's animal studies indicate that the optimal routeof administration is via direct delivery of antisense oligonucleotides totreat Alzheimer's, we could find no better partner than Medtronic, Inc.He noted that it manufactures about half the cardiac pacemakers in theworld.Hybridon and Medtronic will each retain exclusive rights to thecompounds and device, respectively, arising from their collaboration.If a joint management committee decides to proceed with such anantisense delivery system, Grinstead explained, "each party willcooperate in developing specifications that adapt the compound to theSynchroMed system."At present, SynchroMed is used primarily for dispensing intraspinalmorphine to relieve patients from intractable pain. It has recently beenapproved as an alternative to destructive neurosurgery for severespasticity caused by spinal cord injury or multiple sclerosis.Next Monday at Brown University in Providence, Rhode Island,"hundreds, if not thousands," of rats will begin preclinical testing ofHybridon's anti-Alzheimer's antisense molecules.Charles Marotta, who directs psychiatric neuroscience at Brown, willenroll the lab animals for the five-year research program under acontract with the company. He will measure levels of presumptivepathological Alzheimer's proteins in the rodents' brains, beginningwith beta-amyloid, and also observe any behavioral changes.Meanwhile, Hybridon's timetable is to compile enough experimentaldata by mid-1995 to file an investigational new drug application forclinical trials "well before mid-1996," Grinstead said. He points outthat the experience acquired in Hybridon's GEM 91 antisensecompound against AIDS can extrapolate to laying the groundwork forvalidating other antisense medical targets, such as Alzheimer's.

-- David N. Leff Science Editor

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