Potential New Targets in the Search for Therapy

In the search for therapies to slow the death of motor neurons in ALS, researchers have to look beyond the “usual suspects,” to consider new targets for drugs, new cells that may influence the disease process, and new methods for delivering drugs to the central nervous system.

That was a major focus of The ALS Association's Drug Discovery Workshop, held in Washington D.C., in March 2012. “By pursuing all the options available, we increase our understanding of the disease process, and thereby increase our chances of developing a truly effective therapy,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D.

Mitochondria

Doug Wallace, M.D., of Emory University in Atlanta, Georgia, reminded the group of the central role played by mitochondria in powering cells. Because neurons require so much energy, "a partial systemic mitochondrial defect will give you neurodegenerative diseases preferentially," he said. Mitochondria may enter the ALS picture through a number of pathways. Damage to mitochondria may arise from excitotoxicity, environmental toxins, or other insults, and damaged mitochondria can trigger neurons to die. While several clinical trials in ALS focusing on mitochondrial health have proved negative, including coenzyme Q 10 and minocycline, Dr. Wallace suggested mitochondria may yet hold important clues to understanding ALS and its treatment.

Autophagy and Protein Clearance

Another cellular component in the spotlight at the meeting was the autophagy pathway. Ana-Maria Cuervo, M.D., Ph.D., of Albert Einstein College of Medicine in New York, described autophagy as a group of processes that help the cell clear out damaged or worn-out molecules and organelles.  However, the complexity of autophagy comes with a price. “There are so many ways to make it go wrong,” Dr. Cuervo said. Defects in autophagy have been linked to another neurodegenerative disease, Huntington's disease, and several ALS-related proteins are involved in autophagy, including ubiquilin-2, one of the most recently discovered ALS genes. Ubiquilin-2 protein helps bring defective proteins already marked for destruction to the proteasome, a large structure in which proteins are broken down. Defects in this process may help explain why ALS motor neurons develop protein aggregates, which may accumulate if they cannot be properly recycled.

Oligodendrocytes

Jeff Rothstein, M.D., Ph.D., of Johns Hopkins University in Baltimore, and colleagues have begun to focus their attention on cells in the central nervous system called oligodendrocytes, and their precursor cells, called NG2 cells. “These are a major contributor to ALS,” said Dr. Rothstein. Oligodendrocytes provide metabolic support for motor neurons. They are widely distributed throughout the central nervous system, making up about eight to 10% of all brain cells.

He has found that deleting SOD1 from NG2 cells delays the onset of disease in mice and increases their survival. SOD1 is a gene that causes some forms of familial ALS. This suggests that targeting therapy to the NG2 cells directly may be more effective than therapy for motor neurons themselves.

Gene Therapy

Brian Kaspar, Ph.D., of Ohio State University, gave the group an update on gene therapy strategies for neurodegenerative diseases. A major challenge in therapy for diseases like ALS is that relatively few drugs will cross the blood-brain barrier. However, certain viruses will do this readily, including the AAV virus. This virus comes in many different forms, each of which targets a specific kind of cell. This makes it ideal for gene therapy because it could carry a gene directly to one kind of cell without infecting another kind. “There are fewer off-target effects with AAV,” Dr. Kaspar said.

The major successes so far for AAV have been in muscle diseases, but recently Dr. Kaspar has begun to work in models of spinal muscular atrophy (SMA), another degenerative disease of motor neurons. Here, he has delivered a small RNA molecule that overcomes a gene defect that causes the disease. He has had success so far in mice and is now moving on to tests in monkeys to perfect the system before human trials. In ALS, he is trying the same strategy to reduce mutant SOD1 in the mouse and has reported promising initial results.

Much work remains to be done to fully exploit each of these targets and strategies. “We are committed to pursuing these and other promising ideas fully in our search for effective treatments for ALS,” said Dr. Bruijn.