The present momentum toward genetic testing for inherited diseases=20gives new meaning to that old saw, "A little knowledge is a=20dangerous thing."
Certainly, our knowledge of the mutant genes that underlie familial=20breast cancer, Alzheimer's disease and Huntington's disease _ to=20name only three _ is still little enough, though growing. Much=20current opinion maintains that it's too little to subject individuals at =
risk to the Catch-22 of learning their likelihood of acquiring the=20disease, while nothing can be done to prevent or treat it.
As neuropsychologist Nancy Wexler, of Columbia University=20College of Physicians and Surgeons, told BioWorld Today,=20"Huntington's is a disease for which there is no treatment, no=20remission; it's inevitably fatal, and very destructive en route." She is =
founder and president of the Hereditary Disease Foundation, in Santa=20Monica, Calif.
Huntington's disease (HD) strikes when certain neurons in the brain's=20striatum begin to die off. Neuroscientists are busy testing cerebral=20growth factors that apparently protect these vulnerable cells. One=20such front-running molecule is human ciliary neurotrophic factor=20(hCNTF), now being assayed in animal models.
A paper in the current bimonthly Journal of Neuroscience, dated=20Aug. 15, 1996, reports that "Implants of encapsulated human CNTF-producing fibroblasts prevent behavior deficits and striatal=20degeneration in a rodent model of Huntington's disease."
First author of the article is Dwaine Emerich, principal scientist in =the=20neuroscience division of CytoTherapeutics Inc. (CTI), of Providence,=20R.I.
He and his co-authors turned laboratory rats into precise cellular and=20behavioral mimics of human HD by injecting a nerve toxin,=20quinolinic acid, into their brains' striatal region.=20
Then, to have the animals imitate the bizarre bodily movements that=20torment HD patients, they dosed them with systemic apomorphine,=20which disturbs motor neurons, so that the rats turn aimlessly round=20and round in a measurable rotation pattern.
Smart Aiming System Hits Brain Target
To apply hCNTF as gene therapy, the CTI team transferred the=20cDNA gene for the factor into baby hamster kidney fibroblasts, and=20inserted this expression vector into rodent brain ventricles via a=20patented delivery device.
This takes the form of ultra-fine, (1 mm by 7 mm) perforated, hollow,=20polymer tubules, loaded with the gene packages, and consigned to the=20brain by a high-precision stereotactic frame. This guided the payload=20through a small hole in the skull to the striatal target area.
Rats thus treated underwent two types of behavioral tests, one to see=20if the gene therapy could curb or cure their abnormal rotary=20movements, the other to gauge their dexterity in grasping food=20pellets. Treated animals passed the first hurdle successfully, on a par=20with normal rodents. But they flunked the food-grabbing test.
Control rats, turned into HD models by quinolinic acid and=20apomorphine but deprived of the gene therapy vector, failed the gross=20motor trials too.
At the cellular level, Emerich told BioWorld Today, "What we've=20done in our study _ and I think it's the only study that's done that _=20is to definitely show the preservation of neurons that secrete GABA=20[gamma amino-butyric acid]. That's the cell type most susceptible to=20loss in HD." He added, "Any therapy that's going to be effective has=20to keep those cells alive, or tweak them up to a point where they're=20functioning normally."
Two years ago, CTI ran similar tests of a different brain molecule,=20neuronal growth factor (NGF). (See BioWorld Today, Jan. 11, 1995,=20p. 4.) "The two, CNTF and NGF, have remarkably similar cell-protective effects," Emerich said. "Clearly they affect different=20populations of neurons."
Based on this finding, CTI neuroscientists would now like to mix and=20match the CNTF and NGF molecules for a double dose of gene=20therapy in their HD rat models. "Combining those two factors,"=20Emerich observed, "may be an extremely promising avenue to=20investigate. So we're developing cell lines that will release both=20compounds simultaneously."
Recalling that animals treated with CNTF let the team down on food-grasping, he suggested, "Maybe combination of the two factors=20would exert a more significant behavioral effect as well."
Rodents To Primates To People `Within The Year'
Besides pursuing these lines of research, CTI has moved up its CNTF=20gene therapy studies in the last couple of months from rodents to=20primates. "We have to do them before we go into clinical trials"=20Emerich said. "This work with cynomolgus monkeys should be=20wrapped up in another month or so."
As a putative therapeutic for HD, he continued, "CNTF certainly has=20the potential to be preventive. Hopefully, we would be able to get it=20in early in the disease onset, to have some protective effect. At the=20same time, the molecules that we're now delivering to animal models=20could have therapeutic effect as well, by keeping the neural cell=20population alive and functioning."
He pointed out that CTI has "already used CNTF in the clinic, to=20evaluate safety and efficacy in patients with ALS [amyotrophic lateral=20sclerosis]. That would speed up our entry into the clinic=20considerably."
He hopes to see Phase I human studies of CNTF in HD patients=20"within the year."
Wexler, besides promoting research in HD therapy, belongs to a=20Huntington's family. "I find personally that the CNTF work is=20extremely intriguing," she said, "because it's the first time that some=20drug has proved neuroprotective in the best animal model that we=20have so far."
To Know Or Not To Know
She continued: "As far as this being an encouragement to go out and=20get tested I would still be very cautious, because we have not yet seen=20this cure. If people are going to be tested because they think=20something very promising is on the horizon, I wouldn't want them to=20be disappointed.
"It's still pretty preliminary," Wexler observed, "and offering the test =
there's not a big advantage in knowing this devastating information,=20which could be destructive psychologically, destructive to personal=20relationships, to employment, certainly destructive to insurance."
She concluded: "The majority of people at risk of HD who now=20decline to be screened are saying, `I would like to choose the timing=20of my knowing, to be closer to the time that I'm symptomatic.'" n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.