As a groundbreaking clinical trial examining the use of gene therapy in treating Canavan disease winds to a close, the country’s leading researcher into the hereditary brain disorder is now looking to stem-cell therapy to treat the disease.
Dr. Paola Leone, director of the Cell & Gene Therapy Center at the Robert Wood Johnson Medical School, located in New Jersey, has dedicated more than 10 years to studying the rare disease. She is hoping to use stem cells to replace missing or damaged brain cells in Canavan patients.
“Cell loss is so dramatic among Canavan patients that we had to start thinking about cell replacement,” Leone said. “It’s a question of reprogramming the brain.”
Patients suffering from Canavan disease face a host of often debilitating symptoms that can affect movement, cognitive ability and social behavior. Seizures, poor vision, and difficulty breathing and eating are common, and the disease is often fatal. About one in 35 Ashkenazic Jews carries the disease, and one in 6,400 Ashkenzic Jewish children is born with it.
In the gene-therapy treatments, which clinical investigators first began exploring more than a decade ago, Leone and her team delivered healthy genes directly into the brain.
“In the youngest patients we slowed down the onset of the disease,” she said. “But there is dramatic brain atrophy in the first four years of life, and the damage really starts from day one.”
Canavan symptoms are brought about by an enzyme deficiency in the brain, which leaves N-acetylaspartic acid (NAA) unmetabolized, preventing nerves in the brain from functioning properly. The goal of the gene-therapy clinical trials was “to decrease NAA concentration in the brain,” Leone said.
“But with stem cells, the hope is to both supply this normal enzyme and to allow for cell regeneration,” she said. Leone’s current project will end next year, and she is in the process of preparing grant applications for a new round of clinical trials with stem-cell therapy, which she hopes to begin 18 months from now. The proposed project calls for the use of “adult” stem cells, from aborted fetuses rather than from the embryonic lines that have been largely outlawed in federally funded research.
While Leone noted that scientists have learned a great deal about the disease from years of study with animal models, some key questions remain surrounding the logistics of using stem-cell therapy in children with Canavan.
“It sounds nice, but it’s really a huge biological undertaking,” said Dr. Darryl De Vivo, chairman of the Canavan Foundation’s scientific and medical advisory board. “It’s a complicated process — getting the stem cells to the right place in the body affected by the disease, and having the stem cells take cues from the environment to determine how they will develop.”
The “environmental” question is a significant one, as researchers must concern themselves not only with identifying and implanting the proper stem cell to treat the disease but also ensuring that the brain’s environment is sufficiently nurturing for the new cells.
“Think of it like a lawn,” said Helene Karlin, who founded the Canavan Research Foundation with her husband after their daughter Lindsay was diagnosed with the disease 12 years ago. “If the soil is too acidic or too alkaline, you will have a hard time planting grass that will thrive.”
Dr. Evan Snyder, who as director of the Stem Cell Biology and Regeneration Program at the Burnham Institute for Medical Research has worked with stem cells since the mid 1980s, put it more bluntly: “Is the cell dying by suicide or murder? If it’s suicide” — if Canavan prompts essential brain cells to self-destruct — “then we need to replace the cell.”
“But if it’s murder,” he said — if the disease is the product of environmental causes — “then our concern should be with protecting the new cell.”
Heightened levels of NAA, found especially in older Canavan patients, can produce a toxic environment that could make it difficult for stem cells to take hold and properly mature.
“Lowering NAA would be an ideal environment for cells to differentiate and proliferate,” Leone explained. She and other researchers studying Canavan have theorized that using gene therapy in combination with stem cell-treatments could create a more hospitable setting in which the cells could develop.
Some investigators, however, would like to see more advanced studies of the “essence” of the disease before the start of clinical trials. “We may be a couple years off until we have a better sense of what exactly we want the stem cells to do,” Snyder said.
According to De Vivo, “scientifically, no time is more exciting than today” — a statement echoed by most in the close-knit world of Canavan researchers.
“As we originally knew Canavan years ago, as the terrible disease that took the life of an infant — that’s only 1% of what we know now,” he said.