Many of the 15,000 registrants expected to attend the 24th annualmeeting of the Society for Neuroscience next week in Miami will seea poster telling how elderly monkeys, converted into animal modelsof Alzheimer's disease, responded to a form of slow-release genetherapy.
The Nov. 8 Proceedings of the National Academy of Sciences(PNAS) provides greater detail about the unique experiment,described by its authors as "the first demonstration that NGF [nervegrowth factor] can provide trophic and tropic influences todegenerate cholinergic . . . neurons in the aged primate brain."
The PNAS paper's full title is, "The aged monkey basal forebrain:rescue and sprouting of axotomized basal forebrain neurons aftergrafts of encapsulated cells secreting human nerve growth factor."Behavioral neuroscientist Dwaine Emerich, who heads theNeuroscience Group at CytoTherapeutics Inc., in Providence, R.I., issenior co-author of both the PNAS report and the Miami meetingposter.
Choline acetyltransferase is a key neurotransmitter in the brain. Thecholinergic neurons that secrete it, Emerich told BioWorld Today,"have been shown consistently to be involved in the cognitiveprocess." It's that process that fades away in Alzheimer's diseasepatients, as advancing old age diminishes their cholinergic system."
He noted that "the extent of cholinergic cell loss in an Alzheimer'spatient correlates with the severity, as well as the onset, of thedementia." And Emerich added that the reason the anti-Alzheimer'sdrug Tacrin works at all is because it acts on the cholinergic system.
Subhuman primates, such as rhesus and cynomolgus monkeys,Emerich said, "have many of the same molecular landmarks in theirbrain cells that human Alzheimer's patients have, such as senileneuritic plaques and neurofibrillary tangles." (See BioWorld Today,Nov. 3, 1994, p. 1).
Recombinant human nerve growth factor (hNGF), for which SouthSan Francisco-based Genentech Inc. presumably holds patent rights,Emerich said, has been pumped or infused into the brains of many anelderly rodent, and a few youthful primates, that simulateAlzheimer's because a bundle of their cholinergic neurons has beensurgically severed.
Rhesus monkeys reach a ripe old age at 20, he observed; the oldestone in the colony at his disposal is 31 years old. To test the effect ofhNGF on such superannuated animals, CytoTherapeutics joined upwith brain surgeon Jeffrey Kordower (first author of the PNASpaper) at the Alzheimer's Center of Rush-Presbyterian-St. Luke'sMedical Center, in Chicago.To begin with, the two teams opened 1.5-by-4-centimeter bone flapsin the skulls of six rhesus monkeys 24 to 29 years of age. Then theysevered the fornix neurons on the cholinergic pathway. Into the gapbetween the nerve cell stumps in one of the two brain hemispheres ofthree monkeys they implanted a row of five PVC cylinders, each acentimeter long by a millimeter thick.
CRIBs Loaded With Baby Hamster Cells
These proprietary microporous, slow-release devices, called CRIB(cellular replacement by immunoisolatory biocapsule) byCytoTherapeutics, had been loaded with tens of thousands of babyhamster kidney cells genetically engineered to secrete hNGF.Theother three animals, acting as controls, got similar CRIBs, butwithout their recombinant payload.
As all six Alzheimer's model primates had their cholinergic neuronscut only in one hemisphere, they also served as their own internalcontrols, for comparing the fates of those severed neurons with theirintact contralateral counterparts.
Those five slender microcapsules, Emerich explained, were walledwith semi-permeable membranes, which allowed the nerve growthfactor to bypass the blood-brain barrier. They admitted nutrients forthe cells, but kept out components of the body's immune system,which would have destroyed them.
A month later, the researchers sacrificed the Alzheimer's animalmodels, and measured the effect of the recombinant growth factor.Monkeys that had received the encapsulated, hNGF-secreting cells"displayed only a modest loss of choline acetyltransferase [0 to 36percent]," whereas their control partners experienced reductions of57 to 75 percent. These percents, Emerich explained, relate to the"1,000 to 2,000 cholinergic neurons in the [Alzheimer's-specific]septum of an elderly primate."
Moreover, the active-ingredient trio "displayed robust sprouting ofcholinergic fibers" on the side where the CRIBs had been implanted.And capsules retrieved just prior to the autopsy showed viable cells"releasing biologically relevant levels of hNGF." Emerich concludedthat "those neurons, which normally die following that surgicallesion, are rescued with the addition of hNGF."
Emerich and Kordower concluded that their experiment "supportsthe concept that grafts of genetically modified cells sequestered in apolymer capsule may be a viable method of administering hNGF tothe human brain for the treatment of the cholinergic deficit seen indementing illnesses such as Alzheimer's."
Before that day dawns, several more studies must be conducted inelderly Alzheimer's primate models, Emerich said. Among these,determining optimal dosage required for clinical benefit, and theability of hNGF to provide long-term support to degeneratingneurons.
However, demonstrating that the slow-release gene therapy canimprove cognitive performance, such as memory, in primates is not aprerequisite to eventual trials in humans.
Treatment Will Be Less Invasive
Actual clinical treatment, Emerich pointed out, will involve a far lessinvasive mode of delivering the capsules to Alzheimer's-relevantareas of the brain. Instead of bone-flap surgery, an aperture in theskull only big enough to admit a needle will be required, under localanesthesia.
To date, only one known human Alzheimer's patient has receivedNGF. This individual, treated at the Karolinska Institute inStockholm, got infusions of mouse nerve growth factor, with modestimprovement in memory, but no changes in other cognitive tasks,PNAS reported. Emerich noted that that therapy "delivered verymuch higher doses than we used in our study."
If and when CytoTherapeutics undertakes human trials, thecompany's CEO, Seth Rudnick, told BioWorld Today, it will be inconcert with Genentech. "The ultimate strategy will be determinedby a joint nerve growth factor research committee," he said, "onwhich Emerich sits. It's now doing a series of preclinicalexperiments, leading up to initial clinical trials," Rudnick said. n110894
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.