Perhaps it’s the urgency of Tay-Sachs that brought parents to action when a pharmaceutical company allowed a promising clinical trial to languish.
Two years ago, drug company ExSar proposed a trial that would test the chemical pyrimethamine’s ability to restore a vital enzyme in Late Onset Tay-Sachs and Juvenile Tay-Sachs patients. ExSar had three medical centers on board — and the hopes of many at stake.
In Late Onset Tay-Sachs, a genetic mutation depletes the patient’s amount of the enzyme Hex A, leaving enough to clean up only some lipid buildup in the brain — as opposed to classical Tay-Sachs, in which infants die from having no Hex A at all. LOTS symptoms emerge later in life. LOTS is usually non-fatal, and patients face slower neurological degeneration in the form of muscle loss, unsteady gait and, sometimes, mental afflictions. As is the case with other forms of the disease, there is no effective treatment to stop or reverse the effects of LOTS.
Upon hearing about the pyrimethamine trial, parents rejoiced over the rare glimmer of hope. Never before had a treatment seemed within grasp. “This is the first time we’re really onto something,” said Sophie Pesotchinsky, a medical device professional and mother of a LOTS patient.
“The LOTS community was thrilled at a chance for a therapy to slow or even stop the progression of this relentless disease,” said Susan Kahn, executive director of the National Tay-Sachs and Allied Diseases Association. “As a rare form of a rare disease, the LOTS community often feels overlooked and neglected.”
Since pyrimethamine is already available on the market for malaria and toxoplasmosis, the trial could be expedited, and its potential excited researchers, too.
But then the company suspended the trial in November. ExSar President Bijan Almassian said the decision was made “due to financial reasons.” He said that the company diverted resources toward potential treatments for Gaucher disease.
Dr. Edwin Kolodny, a New York University Medical Center neurologist and geneticist, suggested that since pyrimethamine is already marketed cheaply, ExSar might have realized that financial gains would not overcome the gargantuan price tag of the trial.
The hang-up enraged families who stood to benefit from the trial. “We were waiting and waiting and waiting for them to go ahead with it,” said mother Bonnie Pastor of the Late-Onset Tay-Sachs Research and Education Foundation. “And then at the end, they changed their minds. It was very, very unfortunate for the people that were waiting. We’re talking about a progressive disease here, and time is of the essence.”
Parents, however, quickly turned from frustration to action. “Those that did know this major news were understandably disappointed and frustrated, but ultimately channeled their energies into doing anything necessary to make the trial a reality,” Kahn said.
Determined to test pyrimethamine, parents approached medical investigators and drafted a less costly testing plan. Pesotchinsky — who was familiar with the grant-writing world — worked with physicians and other medical professionals on a revised plan for a clinical test. Parents spearheaded letter-writing campaigns to potential donors. Small foundations consolidated their donations through the National Tay-Sachs and Allied Diseases Association, and eventually accumulated the necessary sum.
Slated to run the trial for ExSar, NYU’s Kolodny and Dr. Joe Clarke of Toronto’s Hospital for Sick Kids signed on to the revived effort.
The original trial cost more than $1 million dollars. The revamped version — phases I and II — costs under $200,000. But the scope of the trial narrowed along with the cost. There will be fewer tests and no hospital stay. “We cut it down to bare bones so we can get it off the ground,” Pastor said. By May, NYU had approved the new version of the trial.
The idea that pyrimethamine might slow the brain’s degeneration derives from the theory of chaperone therapy: Certain molecules can attach to misshapen enzymes, restoring them to the proper structures that can effectively clean up neural gunk. Test tube experiments have shown that pyrimethamine stabilizes the mutant enzymes and increases the proportion of active Hex A.
Chaperone therapy seems simple enough. But a major stumbling block for treatment has been the blood-brain barrier, which often renders lab results irrelevant: Large chaperone molecules often fail to penetrate the brain, and can never cure neurological disorders. Pyrimethamine dazzled researchers: Since toxoplasmosis patients currently use the drug, it is known to be small enough to enter the nervous system.
“I’m excited about the prospect of being able to orally administer a drug that has a good likelihood of actually entering the nervous system,” Kolodny said.
The trial will begin in September with 20 patients in New York and Toronto. In its I-II phase, researchers will test the treatment’s safety and tolerability. Researchers will monitor blood components that indicate the presence of Hex A. If this segment is successful and the trial receives more funding, the next step would be to increase the number of patients involved and test for efficacy.
But pyrimethamine is only one piece of the Tay-Sachs puzzle. Researchers predict that a comprehensive treatment will eventually involve a combination of drugs, gene therapy and stem cell therapy. Regardless of the trial’s outcome, families have shown resilience by reviving a potential treatment suspended for commercial reasons.
“I have devoted my life to trying to find a cure,” Pesotchinsky said. “That’s how you have to look at it — it’s my life, entirely.”