Genetic disease, nervous system damage reversed in feline model

PHILADELPHIA — Drs. John Wolfe and Charles Vite of the University of Pennsylvania discovered a way to treat naturally occurring genetic disease of the central nervous system in cats.

The procedure, which injects the therapeutic gene feline alpha-mannosidase directly into 8-week-old kitten's brains born with the abnormality, prolongs the animal's life and reduces tremors caused by the disease.

Researchers performed weekly neurological exams on effected cats as well as uneffected animals as a control group. Magnetic resonance imaging was performed on the kittens at 16 weeks and followed by post-mortem analysis, including the animal's history and biochemistry. The treated animals showed significant improvement, with marked improvement on tremors and functionality.

This procedure is the first that successfully treated an animal larger than a mouse or rat, suggesting the therapy could be used in humans because brain sizes are more similar to children. The procedure could treat a list of lysosomal storage disorders. In addition, helping cats that are born with the disorder live, on average, twice as long as cats that do not receive treatment.

"A mouse brain is more than 2,000 times smaller than that of a child, while a cat brain is about 10-20 times smaller, making the scale much closer," says Wolfe, professor of pathology and medical genetics at the University of Pennsylvania School of Veterinary Medicine and a neurology researcher at Philadelphia's Children's Hospital.

Animals with the disorder have difficulty eating and using their paws. After living with the disease for several months the animal's head constantly bobs making it difficult for it to walk or function. There is no clear-cut cause of death in these cases, many organs begin to deteriorate and the heart often malfunctions.

"This is a progressive disease, one of the more common, yet still rare diseases in humans is Tay-Sachs. There are however more than 50 lysosomal storage diseases in humans, 45 of which are also found in cats," Wolfe adds.

Through the gene therapy, the damaged gene responsible for alpha-mannosidase is replaced with a functioning copy. Shortly after birth, brain tissue matures, and there is a window to treat infants and animals with gene therapy.

"In our study, we found that gene therapy used during a particular time led to restoration of damaged neurons, although lesions on the brain that represent the disease are extensive," Wolfe says.

Animals and children with lysosomal disorders have an accumulation of cellular debris within the storage areas of the cells called lysosomes.

The study demonstrated that a limited number of injections were needed to induce the working gene, which is transported via a neutralized virus that infects cells with the functional gene.

The blood-brain barrier would block the virus carrying the gene if it were circulating in the bloodstream.

The university's center is dedicated to finding and characterizing diseases in domestic animals. Many of the diseases are the same or similar to those found in humans, Wolfe says. Because the same gene is defective in cats as in children, the center is hoping to help animals and humans with the research.

Children with the disease generally die within their first decade of life, whereas cats live about six months.

The study was published in the March issue of Annals of Neurology. Funding for the study was provided by the National Institutes of Health.