Antisense Oligonucleotide Therapy for ALS patients?

Amyotrophic Lateral Sclerosis is a devastating disease that claims the upper and lower motor neurons, and ultimately the lives of most patients within 3-5 years of diagnosis, usually from respiratory failure. Patients lose control of voluntary muscles as the pathways that innervate them degenerate. Lou Gehrig and Stephen Hawking are two famous ALS patients.

Now a group suggests that antisense oligonucleotide therapy may be used to effectively treat some forms of the disease.

Some forms of ALS are heritable. A subset of these cases are caused by a mutation to the enzyme superoxide dismutase 1 (SOD1). SOD1 normally cleans up free radicals in the body, but this action may be compromised or even "reversed" by mutations, leading to free radical accumulation and death of motor neurons. This particular form of ALS has been demonstrated in rodent models, and the researchers in question sought to block the disease by tying up the mRNA for SOD1 before it could be made into protein. This was done by infusing antisense oligonucleotides into the cerebrospinal fluid of rats with mutant SOD1. These antisense oligos are the equivalent of complementary DNA strands for RNA; these particular oligos match up their base pairs with SOD1 mRNA and bind to it, preventing ribosomes from making proteins with the SOD1 mRNA sequence.

The group also found something interesting.

The onset and progression of disease in inherited ALS is determined by the motor neurons and microglia, small immune cells in the spinal cord, which migrate through nerve tissue and remove damaged cells and debris. Damage to motor neurons determines timing of disease onset. Microglia -- the neighborhood, or "helper" cells -- are then activated to help nourish the motor neurons and clean out debris like a vacuum cleaner. But because these neighboring cells are also damaged, they hurt instead of help, thus speeding disease progression.

When the UCSD researchers isolated and shut off mutant SOD1genes in the motor neuron cells only, the disease onset slowed, but the course of the disease eventually caught up to the control rodents. When mutant genes in only the microglia were silenced, the scientists found almost no effect on disease onset, however the disease progression was significantly slowed.

...

"Limiting mutant damage to microglia robustly slowed the disease's course, even when all motor neurons were expressing high levels of a SOD1 mutant," said Cleveland. "Our research suggests that what starts ALS and what keeps it going are two separate phases; it also suggests that with the right therapy, ALS could become a manageable, chronic disease."

Pretty exciting stuff, especially for these forms of inherited ALS where onset can be more easily targeted as well as disease progression. I hope to see more of this technology in the future, and I look forward to the results from clinical trials.