By Jacob Ahlstrom | Posted - Oct 29th, 2020





What is Gene Therapy and How is it Changing the Future for ALS?

Amyotrophic lateral sclerosis, or ALS, is a neurological disease that causes the death of motor neurons. More commonly known as Lou Gehrig’s disease, ALS robs patients of their ability to speak, eat, move, and breathe. Few treatments are currently available, but many different therapies are under investigation. One of these treatments under investigation is called Gene therapy. Gene therapy works with the idea that one can treat ALS by regulating the mutated genes in motor neurons.  

Gene therapy or gene silencing is a technique used to “silence” mutated genes known to affect ALS. This is commonly done by inserting a small strand of genetic material capable of regulating the toxic effects of mutated genes known to trigger ALS.  

The potential of regulating genes was first theorized in the ’90s when scientists across the globe started mapping the DNA sequences that make up human DNA. Known as the Human Genome Project, this international effort has led to the discovery of specific gene sequences known to be directly associated with ALS. One of the first genes identified is called the SOD1 gene. It is strongly associated with about 10% of familial ALS cases.  

There are two general classifications of ALS; familial ALS and sporadic ALS. Familial ALS (fALS) or genetic ALS make up 15% of the ALS population. 

Now with over 25 years of research in the pocket, technology has finally caught up with the science behind gene therapy. This past summer 2 articles were published in the New England Journal of Medicine, both with promising data on the topic of Gene therapy for ALS cases with mutations in the SOD1 gene. 

“Many cool things are happening in ALS therapeutics.”  

-Dr. John Ravits

The two teams administered spinal injections designed to target the SOD1 gene. The more effective method, published by Miller et al., treated 48 participants with a drug called tofersen. The injections of this drug into the spinal cord are meant to allow a small strand of genetic material into the motor neurons. This strand of genetic material is called an antisense oligonucleotide, which is just science talk for a molecule engineered to attack specific genetic material inside the cell. This molecule goes and erases the blueprints for the toxic SOD1 protein.  

When we asked Dr. John Ravits, one of the co-publishers of this study, about his work with gene therapy he encouraged us that, “many cool things are happening in ALS therapeutics.”  

This last summer Ravits’ team investigated the potential therapeutic benefits of suppressing SOD1 gene expression in patients with ALS and SOD1 mutations. 48 patients were randomly assigned to receive 1 of 4 doses of the drug, tofersen, or a placebo. The primary outcome of this early phase trial is safety with drug function being a secondary outcome. The research team measured this secondary outcome by measuring the SOD1 concentration in the brain and spinal cord. The results show that the highest doses of the drug tofersen lead to a 33% reduction of SOD1 concentration levels after day 85 of treatment.  

As for the second method, which used viral injections, their results were not as clear as the first. The second study only treated 2 patents and did not record any changes in SOD1 concentrations. But a postmortem evaluation did show evidence of suppressed SOD1 levels in spinal cord tissue. This could be evidence of the efficacy of viral injections as a potential treatment for ALS.  

Although this treatment only affects about 2% of the ALS population, there is a possibility that misfolded SOD1 may contribute to disease progression in patients with sporadic ALS. There is not yet any research to back these theories, but if such connections are made then the effects of gene therapy could be expanded to sporadic ALS as well.  

Meanwhile, additional therapies for the other genetic forms of ALS are currently underway outlining the future of ALS treatment. This includes therapies for ALS and Frontotemporal dementia associated with the gene C9orf72 and groundbreaking genetic therapies that treat sporadic ALS. 

“These advances signal a new beginning for ALS therapeutics in which some forms of the disease may become treatable. By starting with subgroups with specific genomic features,2 investigators are providing new hope for patients at genetic risk for this devastating fatal disease.” 

“The Beginning of Genomic Therapies for ALS” Hardiman et al. 

Jacob Ahlstrom
About the Author

Jacob Ahlstrom - Jacob is a Neuroscience undergraduate at Brigham Young University. Jacob's interest in researching and writing about ALS is fueled by his hope to make the process easier for everyone else. Over the last year he has worked alongside Seth Christensen to find ways to educate and connect ALS patients.