All About Multiple Sclerosis

More MS news articles for November 2002

Gene therapy works late, in lysosomal storage

Wednesday 6 November 2002
SFN 2002 - Day 4
Investigator: Beverly Davidson
by Apoorva Mandavilli

Delivering missing genes to the brain can reverse the symptoms of some neurological diseases, even much after disease onset, according to new results presented today.

In a mouse model of lysosomal storage disease, enzymes delivered by an adenovirus vector restored both behavioral and electrophysiological deficits, said lead researcher Beverly Davidson, associate director of The Iowa Center for Gene Therapy.

There are more than 40 lysosomal storage disorders, including Tay-Sachs and Gaucher's disease. Lysosomes degrade proteins, nucleic acids, polysaccharides, and lipids and either recycle the fragments or digest the debris. A defect in lysosomal enzymes can therefore cause debris to aggregate in the brain.

The researchers worked in a mouse model of Sly syndrome, characterized by a deficiency in the enzyme beta-glucuronidase. The syndrome is particularly easy to study because a sensitive stain for beta-glucoronidase leaves a brilliant red precipitate wherever the enzyme is expressed.

In addition to cognitive deficits, mice lacking beta-glucoronidase also have significant electrophysiological problems - specifically, they are deficient in long-term potentiation, or the increase in synaptic strength.

Davidson and her colleagues have shown previously that when the beta-glucuronidase gene is delivered by a viral vector, the enzyme spreads from the site of injection and clears storage granules in the brain.

Because lysosomal diseases affect the entire brain, the researchers wanted to improve the enzyme's reach. Many vectors commonly used for gene therapy, such as adenovirus, lentivirus and adeno-associated virus 2 (AAV2), are not well-distributed in the central nervous system, so the researchers chose AAV5 to deliver the gene. Davidson now has unpublished data showing that when the gene is delivered via the AAV5 vector, it restores LTP in the mice to a normal profile.

"The results corroborate our [earlier] studies and both together suggest you can reverse the behavioral defects in this model," Davidson said. "That's very exciting because it proves that it's real, and that we can reverse the underlying electrophysiological problems."

It is also important, Davidson added, that gene therapy succeeded well after the mice displayed symptoms. Traditionally, researchers have given gene therapy to animals at birth and prevented the appearance of behavioral deficits. "But patients don't show up at the clinic before they're sick," she told BioMedNet News.

The technique is very promising because it reverses effects of the disease after they appear, agreed Mark Tuzynski, director of the Center for Neural Repair at the University of California in San Diego. "That's part of the promise of these therapies," he told BioMedNet News. "It's what makes them clinically relevant."

Tuzynski developed a method to deliver nerve growth factor to prevent degeneration of cholinergic neurons. The first human clinical trial of gene therapy in Alzheimer's patients is based on his findings.

© Elsevier Science Limited 2002