For the first time ever, infants with Tay-Sachs disease may have a fighting chance at prolonging their lives.
In July, the pharmaceutical company Actelion approved a contract for clinical trials of the drug Zavesca for treatment of infants with Tay-Sachs disease. The proposal marks the first clinical trial ever to involve infants suffering from the disease. Zavesca, also known as miglustat or OGT918, has for some years been in clinical trials for Late Onset Tay-Sachs, a milder, adult variation of the disease.
Tay-Sachs is a recessive genetic disease, the gene for which is carried by one in 27 Ashkenazic Jews. In recent years, screening for carrier status has reduced the disease’s prevalence dramatically in the Jewish community. Where Jewish infants once made up a majority among Tay-Sachs patients, today only one third of infants born with the disease are Jewish.
Dr. Cynthia Tifft, chief of Genetics and Metabolism at Children’s National Medical Center in Washington, D.C., will oversee the drug trial, which is expected to begin within the next few weeks, aimed at monitoring how the drug is metabolized in the infants’ bodies to determine its potential efficacy.
Unlike patients afflicted with the adult or juvenile variations of the disease, infants with Tay-Sachs have none of the Hex-A enzyme necessary to control the buildup of the waste material GM2 ganglioside, which causes the disease. For this reason, Zavesca, which works as a substrate inhibitor to slow down the lipid buildup of the waste material, will not be able to reverse or stop the patients’ regression, but according to Tifft, “the thinking is that this drug may stabilize” the disease.
To have any meaningful effect on infant patients, the drug will have to be used in conjunction with “another therapeutic modality,” whether stem-cell or bone marrow transplant, gene therapy or neural stem-cell transplant, Tifft said.
Research into the use of stem-cell transplants in mice with Sandhoff’s disease, the closest animal model to the human Tay-Sachs patient, by Dr. Evan Snyder, program director and professor at the Burnham Institute for Medical Research in La Jolla, Calif., is showing promising signs. In the past year, Snyder reported, “we’ve been able to extend their life span significantly, doubling it” while prolonging motor function. The cells function to replace the missing enzyme, thus significantly reducing the amount of storage material and decreasing the brain inflammation that results from the lipid buildup. Combining stem cells with drugs that reduce the amount of substrate the enzyme has to metabolize has an even more beneficial effect than any modality alone.
Tifft’s trial will use 10 subjects, all of whom must meet specific criteria, including onset before 9 months of age and being within one year of initial diagnosis at the time of trial. The trial will include patients with Tay-Sachs and the similar Sandhoff’s disease (which, unlike Tay-Sachs, has no ethnic predilection). The Zavesca pill will be ground to a powder and administered to the infants either orally or through feeding tubes, three times daily, in dosages scaled to match the body-surface area of the infants. The patients will receive the drug for a six-month period, with a possible two-month extension.
“Statistically we’re not going to be able to draw major conclusions,” Tifft said. One major difficulty in assessing the drug’s efficacy, she said, is the fact that the disease hits infants fairly early, often before they are old enough to even sit up on their own. Still, Tifft feels that Zavesca brings real hope to parents of children with the disease. In the past, when parents were given the fatal diagnosis, they were told to “take their babies home and make them comfortable” until they died, Tifft said.
Zavesca also is being used in clinical trials for the treatment of juvenile onset Tay-Sachs, also known as chronic GM2, under Dr. Joe Clarke at the Hospital for Sick Children in Toronto. The trials already have been under way for a year. Unlike both the adult and infantile variations of the disease, Chronic GM2 is not a Jewish genetic disease, and none of Clarke’s five subjects are Jewish. But Tay-Sachs, said Jayne Gershkowitz, executive director of the National Tay-Sachs and Allied Diseases Association, runs along a continuum and while the genetic mutation for chronic GM2 is completely different from the mutations present in patients with classic Tay-Sachs or LOTS, the symptoms are similar and the severity, while varied, lies somewhere between that of its two sister diseases. Like infants with Tay-Sachs, patients with juvenile onset Tay-Sachs often are too severely affected to be able to self-evaluate, so that Clarke is relying heavily on brain imaging by magnetic resonance imaging and magnetic resonance spectroscopy, while subjecting patients to extensive neuropsychological testing.
“What we’re looking at is development,” and measuring whether the infants are progressing, regressing or staying the same, Tifft said. One method she plans to use in the infant trials will involve observing changes in the cherry-red spot visible at the back of the eyes of infants with lysosomal storage diseases. The red spot, often used to diagnose such diseases, results from an accumulation of GM2 in the ganglion cells in the retina, which turns to a yellowish color, so that the center, where ganglion cells are not present, looks red against the yellow background. Eventually, the ganglion cells die and in advanced stages of the disease infants lose the cherry red spot, along with their sense of vision. One possible marker of stabilizing effects of the drug would be a cherry red spot that remains constant over time, Tifft said.
The trial also will make use of spinal fluid from the infants at predetermined points throughout the trial’s duration, to determine how much of the drug has crossed the blood-brain barrier, and to measure the amount of GM2 ganglioside. The spinal taps also will help determine whether the drug has helped decrease the inflammation in the brain that results from the lipid buildup.
“Parents are enthusiastic,” about the drug, Tifft said. While “they know it is not the whole answer, they feel like they’ve got to try something, at least to give their children a chance.”