La Jolla scientists help develop drug approved to treat genetic ALS

A team including La Jolla-based scientists has developed a drug for people with familial, or genetic, ALS that obtained approval April 25 from the U.S. Food and Drug Administration.

ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease) is a progressive neurodegenerative disorder affecting nerve cells in the brain and spinal cord.

It causes the brain to lose the ability to initiate and control muscle movement, and patients may lose the ability to speak, eat, move and breathe.

Generally occurring more in men than women, ALS carries a life expectancy of two to five years once symptoms appear. There is no cure.

Dr. Richard Smith, director of the La Jolla-based Center for Neurologic Study, has been researching ALS for about 60 years. He said 10 percent of cases are genetic.

The new drug, called Qalsody (tofersen), was developed by Smith in collaboration with Frank Bennett of Ionis Pharmaceuticals in Carlsbad and Don Cleveland at UC San Diego in La Jolla. It works to reduce production of a mutated protein called superoxide dismutase 1, or SOD1.

SOD1, first identified in 1993, is “in every cell in our bodies, involved in stabilizing the cell against the threat of free radicals,” Smith said.

When SOD1 was discovered, “it was thought the protein isn’t working,” he said. His first efforts were to replace the enzyme.

Scientists later discovered that the protein is working but mutation has shifted its functions. “Nobody really knows” what the mutated protein does, Smith said.

In the 10 percent of patients with genetic ALS, the mutation is coded into the body from birth, Smith said. Its effects don’t emerge until the patient is 40 or 50.

Qalsody targets the mRNA of the affected protein to “downregulate the expression of the gene,” Smith said.

Qalsody uses antisense technology — a tool for controlling gene expression — administered through spinal injection to bypass the blood-brain barrier that often prevents drugs from getting into the brain.

Developing therapies for ALS “has pretty much been considered almost an impossible task,” Smith said. The therapies currently approved by the FDA to treat the disease are Qalsody, Nuedexta (which Smith also developed), Relyvrio, Radicava, Rilutek, Tiglutik and Exservan.

Though Qalsody only helps ALS patients with familial cases — about 500 people in the United States — there are exciting implications for the future, Smith said.

“There are other neurologic diseases that may be amenable to treatment with this strategy,” he said. ◆