Researchers use gene therapy in mouse models of fatal childhood disease to stop brain degeneration
GAINESVILLE, Fla. — Scientists from the University of Florida and the University of Texas Medical Branch at Galveston have used gene therapy to hinder destruction of brain tissue in mouse models of Canavan disease, a rare genetic disorder that is fatal in children.
Researchers gave a single injection of a corrective gene into the brains of mice to stop healthy tissue from developing pockets of fluid and air that render it spongy and nonfunctional, said Ronald J. Mandel, a neuroscientist with the UF Genetics Institute and UF’s Evelyn F. and William L. McKnight Brain Institute.
“The results in the mice are absolutely remarkable,” Mandel said. “Tissue that would otherwise be damaged looks normal. We have not determined matters of how the brain would function, but the structure of the brain improved.”
Canavan disease is an inherited brain disorder that can occur in any ethnic group, but it primarily affects children of Eastern and Central European Jewish – specifically Ashkenazi – origin, according to the National Institute of Neurological Disorders and Stroke. About 90 percent of Jews in the United States are of Ashkenazi descent; one in 40 carries the Canavan gene.
The findings, reported in the current online issue of Molecular Therapy, indicate the potential value of gene therapy for children with Canavan disease, as well as for patients with other fatal genetic brain diseases.
Children with Canavan disease have a deficiency of the enzyme aspartoacylase, which causes the chemical compound N-acetyl-L-aspartic acid, or NAA, to accumulate in the brain, Mandel said. The accumulation of NAA erodes myelin, the brain’s protective white matter and an essential part of the nervous system. The buildup of NAA causes mental retardation, blindness and tremors.
“The results give tremendous hope not just for helping children with the disease, but for the method of treating it,” said Dr. Reuben Matalon, a professor of pediatrics and genetics at the University of Texas Medical Branch at Galveston and the discoverer of the genetic defect in Canavan disease. “This is the first gene therapy data ever regarding Canavan disease collected from an animal model. Further, the strategy to deliver the corrective gene via the adeno-associated virus may be used to correct many other diseases.”
Currently, there is no cure for Canavan disease, which usually becomes apparent when infants are 3 to 9 months old. Symptoms often include rapidly increasing head circumference, lack of head control and abnormal muscle tone, such as stiffness or floppiness. Most children with Canavan disease do not reach 10.
Matalon produced the mice used in the study. In all, 30 mice were divided into three groups of 10 – one group of normal mice and two groups of mice with the single-gene defect that causes Canavan’s disease. Of the 20 mice with the disease, 10 were randomly selected to receive the corrective gene.
Researchers encoded DNA with the missing enzyme and loaded it into the harmless adeno-associated virus, which had been stripped of its own genetic information. Then they injected it into the thalamus of the mouse brains – an area that is severely affected by the disease. Images taken of the brains of the live mice that received gene therapy showed a remarkable lack of spongy degeneration of the thalamus and reduced levels of NAA, researchers said.
Three to five months later, the corrective material kept the mice brains clear of NAA at the injection site and in a small area surrounding it, suggesting that an encouraging “bystander effect” took place within the cells, researchers said.
“The good news is it’s not just the cells that receive the gene that remain clear, but the cells in the small, immediate area surrounding those cells,” said Nicholas Muzyczka, the American Cancer Society Edward R. Koger eminent scholar at UF and the interim director of the UF Genetics Institute. “You can picture it as injecting food coloring into a bowl of gelatin. Canavan’s disease is extremely challenging because you have to fix the problem in the whole brain, unlike Parkinson’s disease, where only a small region of the brain is affected. The questions are how far the corrective genes can travel and how many injections would be necessary to clear the whole brain.”
Continued improvements observed in the brain for as many as five months after the mice were treated suggest the destructive nature of the disease was reversed; however, further study will be needed to determine whether the corrective gene continues to express itself for a year or longer, researchers said.
“Lots of technical details regarding the gene vectors and where to inject them have to be worked out, and it’s preferable to do those basic studies in animals,” said Dr. Hugo W. Moser, director of the Neurogenetics Research Center at the Baltimore-based Kennedy Krieger Institute. “This is a good step in a long series of steps toward human treatment.”