Lou Gehrig's disease, also known as amyotrophic lateral sclerosis (ALS), is marked by the degradation of nerve cells that control muscle movement. It quickly attacks these motor nerve cells in the brain and spinal cord, resulting eventually in total paralysis and death. Cause unknown.

While the disease was first identified in the 19th century, it gained international attention in 1939. In that year, baseball great Lou Gehrig announced that he had ALS, and retired from the New York Yankees. He died two years later. About 30,000 people in the U.S. have ALS, and some 5,000 new cases are diagnosed each year. Most will die within five years of being diagnosed. The worldwide ALS body count amounts to around 70,000.

"ALS is a terrible disease, and patients have few choices for therapy today," observed neuroscientist Jeffrey Rothstein, co-author of a paper in today's issue of Science, dated Aug. 8, 2003. Its title: "Retrograde viral delivery of IGF-1 [insulin-like growth factor] prolongs survival in a mouse ALS model." Its senior author is neuroscientist Fred Gage at the Salk Institute for Biological Studies in La Jolla, Calif.

ALS is a fatal neuromuscular disease characterized by the degeneration of spinal and brainstem motor neurons, leading to atrophy of limb, head and neck, and respiratory muscles. "Our findings," Gage noted in a press statement, "are the first to show this degree of recovery after the paralyzing and ultimately fatal nervous system disorder begins. They may eventually lead to a new gene-based treatment for the disease. Injecting a gene that expresses IGF-1 into muscles resulted in longer life spans, preserved nerve cells and reduced muscle wasting."

How to make mice mimic the symptoms and disease course of little-understood ALS was solved by Gage and his co-authors with the help of IGF-1. This insulin-like growth factor is an important protein for potential growth. It is produced in the liver, kidney, muscle, pituitary, gastrointestinal tract and cartilage cells.

The team injected an adeno-associated viral vector (AAV) to express the IGF, which promotes the survival of neurons, into the limb and between rib muscles of their mice. The authors report that their results demonstrated "substantial behavioral, functional and pathological improvements in a clinically relevant mouse model of the motor neuron disease."

Crucial Key: Retrograde Gene Transport

"Adeno-associated viruses," Gage explained, anent the novel retrograde treatment, "are retrogradely transported from the synapses in the muscle to the nucleus of the motor neuron inside the spinal cord." This, he added, "emphasizes the importance of basic science in developing rational therapies for disease."

The retrograde ability of the viral vector's capacity to migrate into nerves from muscle gets the therapeutic IGF-1 protein where it appears to be needed most - the brain and spinal cord. "When IGF-1 is produced only in muscle," Gage observed, "the benefit is minimal. We report that insulin-like growth factor-1 prolongs life and delays disease progression even when delivered at the time of overt disease symptoms."

"Retrograde transport from motor neurons that innervate muscles requires the virus to bind to viral receptors on the axon terminal," the article noted, "with subsequent transport over a long distance to the motor neuron nucleus, allowing sustained gene expression. We investigated the ability of AAV to target specific subsets of those neurons that project to defined muscles in 90-day-old transgenic mice that express the SODI (superoxide dismutase) transgene - the high-expressing mutant mouse that displays disease onset at 90 days and dies, 30 days later.

"Overexpression of superoxide dismutase 1 gene mutations in mice and rats recapitulates the clinical and pathological characteristics of ALS in humans," the article went on, "in which motor neurons degenerate and animals die shortly after onset of symptoms."

"Our unique gene therapy method," Gage pointed out, "is not a cure, but it postpones the symptoms, and nearly doubles the life span in the ALS mouse model."

Gage and his co-authors report in Science that "delivery of a nontoxic gene therapy, using an AAV vector that carried IGF-1 into muscle - with subsequent transfer of IGF-1 to neurons dying in ALS - delayed disease onset by 31 days and expanded the mice's life span to a maximum of 265 days. This compared to 140 days for the untreated control animals. IGF-1 was also able to extend the life spans by 22 days when injected after symptoms appeared, indicating the method's potential treatment for different stages of disease. In addition to extending survival, the gene therapy maintained physical movement for a significantly longer time than in untreated mice, and provided 20 percent more muscle mass.

"The biggest challenge," Gage continued, "has been to deliver the protein across the blood-brain barrier into the central nervous system. By injecting our viral vectors into muscles, the gene could then deliver the protein into nerve cells that controlled the muscle. This resulted in the preservation of those nerve cells that would otherwise succumb more quickly to ALS."

Human Clinical Trials On Both Burners

The researchers demonstrated that IGF-1 triggers a molecular pathway that also appears to preserve nerve function. "When IGF's receptor is activated, an enzyme called Akt has a phosphate molecule added to it (by phosphorylation). The actions of IGF-1 occur at least in part through an anti-apoptotic mechanism."

"When Akt is activated," Gage noted, "it helps block the process of apoptosis. IGF-1 has been known to increase the number of phosphorylated Akt molecules, which inhibits apoptosis by directly inhibiting different pro-apoptotic signals. We found that IGF-1 decreased levels of a specific protein involved in apoptosis by more than 63 percent compared to untreated mice. Understanding the pathway led us to experiment with IGF-1 in the first place."

Sidestepping the usual in vivo preclinical suspects, such as guinea pigs, dogs and monkeys, the Salk staff is moving toward initial human clinical trials. "While this research is still in the experimental animal stage," Gage pointed out, "and a number of steps need to be taken before any possible therapy is deemed safe and effective enough for use, we are in the planning stages of human trials for this gene therapy method. Plans for the first ALS patient trial utilizing this approach," he concluded, "are under way and in the design stage."