August 8, 2003

GROWTH FACTOR GENE TRANSFER
PROLONGS LIFE, FUNCTION IN MICE WITH ALS

Jeffrey Rothstein, director of the MDA/ALS Center at Johns Hopkins University in Baltimore, was part of a team of scientists that achieved encouraging results with an experimental gene therapy approach in mice with amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). The findings are in the Aug. 8 issue of Science.

Researchers injected the gene for the protein insulin-like growth factor 1 (IGF-1), inside a molecular “transport vehicle” known as an adeno-associated virus (AAV), into limb and respiratory muscles of mice genetically bred to develop ALS.

These mice, born with an ALS-causing mutation in a gene known as SOD1, usually develop ALS at about 90 days of age and die about 30 days later.

“We’re cautiously optimistic about this result,” said Sharon Hesterlee, MDA’s director of Research Development. “The results in mice are striking, but extending them to humans will be complicated by the need to deliver the IGF-1 gene to a much larger mass of muscle.”

When these mice received the IGF-1 gene injections prior to the start of ALS symptoms, disease onset was delayed by 31 days. They survived a median of 37 days longer than untreated animals with the same disease (160 days compared to 123 days, a 30 percent difference).

The researchers also found that the AAV transported the IGF-1 genes from the muscle cells, where they were injected, up nerve fibers to the cell bodies of motor neurons, the muscle-controlling nerve cells that are destroyed in ALS.

However, doctors rarely have the opportunity to treat ALS patients before symptoms develop. Therefore, finding treatments that work after the development of weakness is crucial.

To explore this aspect, investigators injected IGF-1 genes when the animals had reached 90 days of age, when symptoms began to appear.

The IGF-1 treatment in these mice extended life by a median of 22 days compared to the life span of the untreated animals (146 days compared to 124 days, an increase of 18 percent).

Equally important, the IGF-1 gene treatment sustained the animals’ strength even as they aged with ALS. While the untreated mice displayed significant loss of grip strength and the ability to stay on a rotating rod when they were 100 to 110 days old, the treated mice didn’t show significant deficits in these skills until about 20 days later.

The muscle mass of the IGF-gene-treated animals was 20 percent higher at 115 days of age than that of the untreated mice.

The number of surviving motor neurons in 110-day-old mice that received IGF-1 gene injections at 90 days was similar to the number in normal mice, although this number eventually declined as the mice approached the end stages of the disease.

The investigators say that the ability of the AAV transport vehicle to move the IGF-1 genes from the muscle cells to the nerve cell bodies, and the genes’ ability to produce sustained levels of the IGF-1 protein to act on motor neurons and surrounding cells, are crucial factors in the beneficial effects seen in these experiments.

One large-scale trial in human ALS patients using the IGF-1 protein (Myotrophin) instead of the gene and delivering it through injections under the skin instead of into muscle showed marginal benefits, while another failed to show any benefit. Myotrophin is still being tested.

When the researchers on today’s study tried other gene transport vehicles, such as one made from a lentivirus, results weren’t as good.

Findings were also disappointing with the gene for a protein called glial-derived neurotrophic factor, or GDNF.

The investigators say they think the right combination of nerve-preserving protein, delivery method and gene transporter are needed to make gene transfer effective in ALS.