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ALS and Genetics: What Do We Know?

Cedars-Sinai's Dr. Robert Baloh at work in his laboratory.

Each year, more than 5,000 Americans are diagnosed with amyotrophic lateral sclerosis (ALS), a degenerative condition that affects the spinal cord and brain.

Doctors don't know what causes it and there is no known cure. For the most part, ALS—also known as Lou Gehrig's disease—is a mystery to doctors and researchers.

We're hoping that the insights from genetics will eventually impact all patients with ALS.

But that's beginning to change. In the past few years more research is being done on how our genes impact ALS.

We sat down with the Dr. Robert Baloh, director of Neuromuscular Medicine, to discuss this important work.

What is currently known about the genetics of ALS?

Dr. Robert Baloh: The first thing to think about is the background of genetics in ALS and the role that it plays.

We know that about 10% of ALS patients have what's called familial ALS, meaning it runs in their family. In the other 90% of patients, ALS is sporadic, meaning there is no family history and we haven't identified the gene or genes driving that disease progression.

Collectively, the research community has studied familial ALS heavily over the last 20 years because it gives us insights into why ALS happens. We've used cells from ALS patients to create induced pluripotent stem cell models and studied what's going on in those cells.

Even though we still don't fully understand everything that happens in these models, recent research has focused on the possibility of gene therapies that might help patients who specifically carry these genetic mutations.

What is gene therapy?

Dr. Baloh: Gene therapy is a generic term, but it just means targeting the specific gene that's abnormal.

The goal of gene therapy is essentially to get rid of the gene that's doing something bad. In patients with familial ALS, we have identified 2 common mutations that make up the majority of those cases, and we are doing a lot of research targeting those 2 genes.

When we're looking at gene therapies, the goal is not always the same, but the most frequent approach is to degrade or change the gene's function. If we can do that, we could theoretically alter or stop the disease progression.

By studying gene therapy in this smaller population of patients, we want to learn more about ALS and then use that learning to look for therapies for sporadic ALS patients.

From DiscoveriesPoints of Origin

How are you testing gene therapy?

Dr. Baloh: There are different gene therapy technologies targeting those 2 genes that scientists are currently looking at.

The one that's currently in clinical trials is called antisense oligonucleotides, or ASOs.

ASOs can be made to target any particular gene by creating a small piece of sequence that is the opposite of the target gene sequence. Then it binds to the target gene and will either degrade it or change its function.

You can use them to do several different things, but primarily scientists are attempting to degrade the target gene if it's having a negative or toxic effect.

The challenge is that ASO therapy can't be given as a pill. We don't have the chemistry figured out to allow it to get from your stomach into your bloodstream and then into the brain cells.

The delivery method right now is into the spinal fluid itself, meaning that the patients have to get a lumbar puncture to get the treatment.

How is gene therapy changing the way you approach ALS?

Dr. Baloh: Almost everything we know about ALS has been driven by families who have genetic variants, and we are learning more about the genetic variants that cause the disease all the time.

We're hoping that the insights from genetics will eventually impact all patients with ALS.

These research findings have changed the way we approach genetic screening and genetic counseling in our clinic. We recently hired a full-time genetic counselor who works with all our neuromuscular patients, including ALS patients.

Also, we are now offering genetic testing for all patients who have a family history and often do testing of common genes in patients who don’t have a family history. We're primarily looking at whether they have one of these gene mutations because we could then get them into a gene therapy trial.