A drug long used to treat a rare genetic disease also has the potential to treat a form of Batten disease, a fatal group of hereditary disorders that gradually robs its victims of their eyesight and mental abilities before claiming their lives.
The laboratory study, appearing in the April 1, 2001 Nature Medicine, was conducted by researchers at the National Institute of Child Health and Human Development (NICHD) and the Institute for Basic Research in Developmental Disabilities in Staten Island, New York. The researchers are now seeking patients with this form of Batten disease to test whether the drug phosphocysteamine will be an effective treatment for them.
"This is an extremely promising lead," said Duane Alexander, M.D. Director of the NICHD. "The NICHD team has shown in laboratory studies that phosphocysteamine breaks down the toxic compound responsible for a Batten disease variation which leaves its victims without higher brain function by the time they reach their fourth birthday."
Batten disease is a relatively common (one in 12,500 births worldwide) group of genetic disorders of the nervous system that begin in early childhood. These disorders result from the buildup of substances called lipopigments in the body. The NICHD researchers found that phosphocysteamine breaks the lipopigments apart, into the lipids (fats) and proteins that comprise them. The NICHD researchers concentrated their efforts on the form of Batten Disease known as infantile neuronal ceroid lipofuscinosis (INCL), which claims the lives of its victims much earlier than do the other forms of the disease. Estimates of INCL's frequency in the United States do not exist, but researchers believe it is uncommon.
Phosphocysteamine has been approved for use in patients by the U.S. Food and Drug Administration. Another team of NICHD scientists pioneered the drug as a treatment for cystinosis, a rare hereditary disorder that, if untreated, results in blindness, kidney failure, and death by about age nine. The authors of the current study noted that cystinosis patients have used phosphocysteamine safely for more than 20 years.
Also called Santavuori-Haltia disease, INCL strikes between six months and two years of age. Children who have the disorder lose their eyesight by age two, experience frequent seizures, and deteriorate mentally until their brain has no cortical activity at three to four years of age. They live in this vegetative state until about eight to twelve years of age, when they die.
INCL is caused by a defect in the gene that provides the information for palmitoyl-protein thioesterase (PPT), according to the study's senior author, Anil B. Mukherjee, head of the NICHD's Section on Developmental Genetics. As a result of normal chemical reactions in the cell, any number of different kinds of proteins bind chemically with lipid molecules. These protein and lipid molecules are then transported inside lysosomes-minute, balloon-like sacs within the cell.
Ordinarily, PPT breaks the bonds that hold the proteins and lipids together, which allows the newly separated molecules to be broken down and transported to other parts of the cell. Because children with INCL lack PPT, the protein-lipid complexes accumulate within their lysosomes. Eventually, the lysosomes grow so large they eventually kill the cell.
Dr. Mukherjee and his coworkers tested laboratory cultures of cells taken from patients with INCL. The researchers found that phosphocysteamine reduced the amount of protein-lipid complexes within the lysosomes to minimal levels. Additional doses of the drug prevented the complexes from reaching toxic levels.
Dr. Zhongjian Zhang, the first author of the study, said, "We're extremely excited by the possibility that this drug might improve the lives of patients." This study was supported by a "bench-to-bedside" award from the Clinical Center of the National Institutes of Health (NIH) and a clinical trial has been approved for patients with the most severe form of INCL. The first patient for the study has been enrolled and is now receiving phosphocysteamine. The researchers will not know for some time whether the drug is effective in patients.