By David N. Leff
Six French patients with active Huntington's disease (HD) are standing by in Paris to become the first subjects to try a treatment aimed at alleviating their physical and mental symptoms.
This seems like an oxymoron: Everyone knows that HD is incurable. Yet the gene therapy planned for these volunteers has proven successful in a preclinical trial featuring half a dozen cynomolgus monkeys. It's reported in today's Nature (dated March 27, 1997), under the title: "Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington's disease."
Its lead author is neuroscientist Dwaine Emrich, who until recently led development of the approach at CytoTherapeutics Inc. (CTI), of Providence, R.I. (See BioWorld Today, Aug. 22, 1996, p. 1.) Emrich now directs neuroscience at Alkermes Inc., in Cambridge, Mass.
The trial, awaiting approval by French health and medical authorities, is being sponsored by CTI. The company's chairman and CEO, Seth Rudnick, told BioWorld Today: "Going from an animal model — whether primate or not doesn't matter — to testing in humans is a big big leap."
Rudnick went on: "But at least what our monkey trial shows is that if the human disease has some behavior that's analogous in the animal, we'll be able to protect more than just the motor abnormalities of HD."
HD's Double Threat: Motor And Mental
The disease was originally called Huntington's chorea — after the Greek word for a choral dance. In this sense, its salient symptoms include irregular, spasmodic, involuntary movements of the limbs or facial muscles. But progressive dementia is also a hallmark of HD.
This failure of cognition is attributed to the slow but relentless dysfunction of neurons in the brain's cerebral cortex. Similar neuronal losses in the striatal region, below the cortex, are thought responsible for the aberrant physical features of HD.
Both aspects are targeted by CTI's approach, now tested in primates, and are pending in people.
Central to the therapy is human ciliary neurotrophic factor (hCNTF), a cytokine protein that protects and nourishes nerve cells. CTI expressed the hCNTF gene in baby hamster kidney cells and delivered them to the brain by polymer hollow-fiber capsules, circumventing the blood-brain barrier.
As Rudnick described the procedure in the subhuman primates: Under local anesthetic and stereotaxic head clamps, the cell-loaded capsules, a few centimeters long and less than a millimeter in diameter, were inserted by needle through a small hole in the skull directly into the striata of three monkeys. "Most of the devices," he said, "have little tethers on them leading out, so we can pull them back if necessary."
One week later, all six animals got injections to the brain of quinolinic acid, a nerve toxin that attacks the striatal region, turning its primate recipients into neuronal animal models of HD. The three that received untransfected (dummy) cells served as controls.
"The main population of striatal neurons that degenerates in HD," Rudnick explained, "causes the loss of normal inhibitory function of GABA [gamma-aminobutyric acid], one of the brain's main neurotransmitters, and thus produces HD's abnormal movements."
In two key striatal regions, the caudate and putamen, the lesioned control animals lost 89 and 94 percent of the GABA neurons, whereas the three treated primates lost only 64 percent of theirs. Similar results were obtained with smaller neuronal populations that produced two other neurotransmitters crucial to HD.
"This three fold difference in neurons spared is very significant," Rudnick observed. "The best analogy is Parkinson's disease. You don't show symptoms until you've lost somewhere in the range of 80 to 90 percent of your neurons. We get the neurons that we're going to get at birth," he continued, "and when we're still little kids, they start dying off. They die for 70 or 80 or 90 years -- however long we live -- and for the most part we pretty much function normally. That's because we have huge functional reserves in our brains. So preserving enough neurons should be able to shift HD people from being symptomatic to asymptomatic."
Dual Putative Protection: Striatal And Cortical
"I think what's different about this from anything ever shown before," Rudnick observed, "is that not only did we prevent damage to the striatal site, where that toxic blow to the brain is administered, but we protected all the projections into the cortex, which contributes to the dysfunctioning dementia you see in the true HD patient."
Armed with this data, CTI is now in end-stage negotiation with France's various regulatory agencies that govern genetic engineering science, products and clinical trials.
"The six patients are ready to go," Rudnick said, "pending French regulatory commission permission." He expects the trials to commence in the fall.
"If all the subsequent human studies showed safety and efficacy over a long span of time," Rudnick ventured, "the next step might be to go back into patients who have family members. If they carry the HD gene -- which you can actually detect — at a level where they were at high risk of developing symptoms, one might say: 'Would you like to try and see if you can be in a preventive protection trial?'"
Beyond that distant, optimistic but uncertain outlook lies assuaging the ultimate suffering inflicted by Huntington's disease. With discovery of the HD gene in March of 1993, it's become possible to test members of HD families for susceptibility. The symptoms usually kick in during the prime adult years.
Many such possible future victims prefer not to know whether they carry the mutant gene. Instead, they live with uncertainty.
Those who do learn they are marked face the opposite burden — certainty. *