Gene Therapy Delays Death In Mouse With Symptoms Of Lou Gehrig's Disease

In experiments with mice destined to develop the condition, injection of the gene for insulin-like growth factor-1 (IGF-1) into muscles protected nerve cells, extended survival and improved strength, say the scientists, who are planning a clinical trial they hope to be able to begin in the next year.

The most beneficial treatment ever seen in the mice, it is also the first to extend animals' survival when given after symptoms develop, the researchers say. In the experimental mice and in people with the disease, known as amyotrophic lateral sclerosis or ALS, nerves that control muscles gradually die, leading to paralysis and death.

"ALS is a terrible disease and patients have few treatment options today. We're very excited about this," says Jeffrey Rothstein, M.D., Ph.D., professor of neurology and neuroscience and director of the Packard Center for ALS Research at Johns Hopkins. "Even in mice, progression of the disease is so rapid that we only test possible treatments before the mice get sick. It is amazing that this gene therapy can slow progression even after symptoms develop."

Gene therapies use a virus to deliver specific genetic instructions to cells and usually have to be delivered directly to where the gene is needed. But instead of injecting this "adeno-associated" virus into specific nerves in the brain and spinal cord -- a feat that is likely impossible -- researchers at the Salk discovered and took advantage of the virus's ability to migrate from muscle into the nerves that control them. The nerve cells then made the IGF-1 protein.

"IGF-1 protein has been used in clinical trials, but with marginal results," said Fred H. Gage, Ph.D., professor of genetics at the Salk Institute. "The biggest challenge has been to deliver the protein across the blood-brain barrier into the central nervous system."

Studying a fluorescent version of the adeno-associated virus, Salk research fellow Brian Kaspar discovered that it could travel from muscles into nerves. Once in the nerves' nuclei, the cells' machinery pumped out the glowing protein.

The virus's ability to migrate (known as "retrograde delivery") into nerves from muscle gets the therapeutic IGF-1 protein where it appears to be needed most -- the brain and spinal cord. The researchers showed that when IGF-1 is only produced in muscle, the benefit is minimal.

Key to the work is a mouse model of ALS, developed in part at Johns Hopkins. Without any treatment, these mice, engineered to make extra superoxide dismutase-1 (SOD-1), develop the first symptoms of weakness at 90 days of age and succumb to the paralysis within the next 45 days.

Injection of the IGF-1 gene therapy into both quadriceps (upper hindlimb) muscles and into muscles between the ribs that help control breathing maintained strength and lengthened survival.

Mice that received IGF-1 gene therapy at 60 days of age developed symptoms 31 days later than untreated mice (i.e., at 121 days) and lived, on average, 40 days longer. The treated mouse that survived the longest lived 265 days, while the longest-lived control mouse lived just 140 days. Mice that received injections of IGF-1 gene therapy at 90 days of age lived an average of 22 days longer than their untreated counterparts.

In addition to planning a clinical trial, the researchers will also continue to investigate how IGF-1 protects nerves to improve understanding of the disease and increase the therapeutic potential of IGF-1.

About 30,000 people in the United States have ALS, and about 5,000 new cases are diagnosed each year. Most will die within five years of their diagnosis. While excessive SOD-1 in mice simulates the effects of the human disease, the cause of ALS in people is not known.

The Johns Hopkins researchers were funded by Project ALS. The Salk researchers were funded by Project ALS, Christopher Reeve Foundation, the National Institute on Aging and the National Institute of Neurological Diseases and Stroke.

Authors on the paper are Kaspar, Gage and Nushin Sherkat of the Salk Institute for Biological Studies, and Rothstein and Jeronia Llado of The Johns Hopkins University School of Medicine.