There is no cure for Huntington's disease; no treatment. Once thebizarre movements and mental aberration of this inherited afflictionshow up, usually around 40 to 45 years of age, it progresses slowlybut inexorably until death supervenes, often by suicide.

Woody Guthrie, the American folk singer (1912-1967), died ofHuntington's disease (HD), to which he gave its eponymous name.Besides being known as Woody Guthrie disease, HD's other name isHuntington's chorea, as if its involuntary, spasmodic and purposelessdance-like steps were surrealistically choreographed.

There are an estimated 25,000 HD patients in the U.S.

HD ravages the brains of its victims, destroying specific neuronsmainly in the striatum, a region lying below the cerebral cortex.There has been no true animal model in which to study theneurophysiology of HD, and test possible forms of medicalintervention.

First-generation gene therapy is attempting to rescue those doomedbrain cells with nerve growth factor (NGF).

"Now for the first time," says neuroscientist Dwaine Emerich ofCytoTherapeutics Inc., "a study links the preservation of thesestriatal neurons to reduction of movement abnormalities in an animalmodel of HD."

Emerich is first author of a paper in the latest issue of ExperimentalNeurology (dated November 1994, but mailed to subscribers on Jan.5, 1995). Its title encapsulates the team's experimental approach, andits results to date: "Implantation of Polymer-Encapsulated HumanNerve Growth Factor-Secreting Fibroblasts Attenuates theBehavioral and Neuropathological Consequences of Quinolinic AcidInjections into Rodent Striatum."

Making Rats Behave Like (HD) Humans

Emerich and his co-authors at CytoTherapeutics, of Providence, R.I.,began their experiment by inserting expression vectors containinggenes that encode high levels of human NGF into baby hamsterkidney cells. Next, they loaded several tens of thousands of thesehost cells into tiny plastic hollow-fiber cylinders a millmeter indiameter by six in length. Micropores in their walls permitted freeflow of oxygen but prevented the rats' immune systems from"seeing" the foreign protein in the carrier cylinders.

Then the researchers precisely placed these immunoisolatory devicesinto one lateral brain ventricle adjacent to the striatum ofanesthetized rats.

Three days later, to convert those somatically transgenic rodents intoworking models of HD's uncontrolled motor-neuron-choreographedmovements, the scientists injected into the striatal regions of six ratsan excitotoxic chemical, quinolinic acid, which "excites to death"cells marked for destruction by HD, Emerich explained.

At the same time, they created two cohorts of placebo controlanimals: Eight rats got only quinolinic acid; seven others, the acidplus hamster host cells devoid of NGF plasmids.

Finally, to induce a quantifiable equivalent of HD's involuntarymovements into their striatally challenged rodents, the researchersinjected the animals with apomorphine, an HD-simulating chemicalthat incited them to walk round and round in a tight rotatary motion,inside their computer-controlled test chambers.

As Emerich told BioWorld Today, the apomorphine-triggeredhyperactive contortions of the rats that received the NGF genes wereabout 75 percent less than those in the placebo cohorts. "Thisfinding," he said, "has not previously been reported," and he added,"The treatment prevented cell loss and behavioral defects."

Previously similar gene-delivering host cells in such PVC capsulescontinued to release therapeutic amounts of NGF for up to sixmonths after implantation in rats.

Under the microscope, targeted brain cells showed that the genetherapy "attenuated the extent of host neural damage produced by thequinolinic acid."

Model Also Tackling Alzheimer's, Parkinson's

Since completing these experiments last summer, Emerich said, heand his team have been optimizing dosages and refining striatal sitelocation of their HD treatment approach, "prior to scaling up intolarger animals," presumably non-human primates. Just what kind ofanimals, and what prospects there are for eventual human trials, saidElizabeth Razee, manager of corporate communications, "cannot bespecified at present, as the company has a public offering on hold,during which it maintains silence as to detailed future plans."

What can be said, she and Emerich added, is that the experimentaldesign just reported for HD is being actively adapted to treat otherneurodegenerative diseases, specifically, Parkinson's andAlzheimer's, in cooperation with the firm's research and developmentpartner, Genentech, Inc., of South San Francisco. (See BioWorldToday, March 14, 1994, p. 2.)

The striatum, Emerich pointed out, "is involved in the motorfunctioning of Parkinson's disease," where it causes rigidity asopposed to the unrestrained movements of HD.

CytoTherapeutics holds 10 U.S. patents covering its capsule deliverysystem for neuroactive substances, Razee said.

One of its inherent advantages as therapy for disorders of the centralnervous system, Emerich pointed out, is that the hollow-fiberpolymer capsules, implanted at the precise site of the brain lesion,avoid the blood-brain barrier and evade immune rejection. n

-- David N. Leff Science Editor

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