How ALS Targeted Gene Therapy Works
ALS targeted gene therapies are emerging in multiple identified ALS genes, such as SOD1, C9orf72, and FUS. Below we provide information about current targeted gene therapies in development starting with SOD1, which is furthest along on the drug development pipeline.
The SOD1 gene encodes a protein that is also called SOD1. This protein normally helps clear out toxins from the brain, but when the SOD1 gene harbors certain mutations, it creates a defective SOD1 protein. The malformed protein not only fails to do its normal job, but it also creates its own problems. In people with SOD1 mutations, the SOD1 protein clumps together with other copies of itself and these clumps damage the nervous system, leading to the symptoms of ALS.
Tofersen works by blocking the production of the SOD1 protein using a molecule called an antisense oligonucleotide (ASO). An antisense oligonucleotide is a small string of synthetic DNA that, in this case, blocks your cells’ protein factories from reading your mRNA. Ultimately, no SOD1 protein gets made. Doctors inject tofersen straight into peoples’ spinal fluid, so it can reach the neurons that control their muscles.
Biogen also has gene targeted therapies focusing on the C9orf72 gene and others that are earlier in their drug development pipeline.
Ionis’ therapy also uses an antisense oligonucleotide, but instead of blocking SOD1 mRNA, it blocks FUS mRNA.
Apic Bio’s therapy works in a similar way, but instead of using an antisense oligonucleotide to block mRNA from being read, it uses a similar molecule called microRNA to silence the messenger. In contrast, Helixmith’s therapy is DNA-based. People get injected with the instructions to create proteins that helps neurons grow.
Many gene therapies in development today use a virus called adeno-associated virus (AAV) to help the therapy get inside our cells. Scientists use viruses for this purpose because of their unique ability to infect cells. Viruses work by latching onto a cell, injecting its genetic code, and hijacking your cell’s machinery to make more copies of itself. In several therapies in development, such as the Apic Bio gene therapy, AAV still injects a genetic code – but not its own. Before the virus enters the body, scientists gut it of its own genetic material and replace it with the DNA that encodes the microRNA. In effect, the virus is tricked into injecting a therapy into someone’s cells. Scientists often use AAV, because it is safe. It generally does not cause a significant immune response on its own.
Pre-Symptomatic ALS Clinical Trials
The most effective way to slow the progression of ALS is to treat people early. Ideally, if FDA approved, people would start taking tofersen before they even show symptoms. Because of this, the current phase III clinical trial (called ATLAS) for tofersen is testing the treatment in people who are pre-symptomatic, meaning they do not have any ALS symptoms but are likely to start developing them later.
Having a strong family history (two or more individuals with ALS in your family) increases your chance of developing ALS yourself, so researchers are finding people to participate by looking at family members of people who already show symptoms. Genetic testing will help you find out if you carry mutations in SOD1 and other ALS-associated genes and whether you are eligible for a clinical trial like ATLAS. But getting a genetic test is a personal choice, and one that requires thoughtful consideration
Is Genetic Testing the Right Path for You?
Since tofersen and APB-102 act on SOD1 mRNA, they only work in people who harbor mutations in the SOD1 gene. Learn more about getting a genetic test for mutations in this gene and others here.
You may find it difficult to decide whether to get a genetic test, especially before you show any symptoms of ALS. Finding out that you have mutations in SOD1 or another ALS-associated gene could affect you in several ways. It is important to work through the benefits and risks of getting tested with an expert in genetic testing. A genetic counselor can help you; these experts work with healthcare providers, caregivers, and people with ALS to arrange genetic testing, interpret the results, and plan out next steps. They, along with your physician, can help you make sense of the process and help you decide if genetic testing is right for you. Click here to learn more about genetic counseling.
The ALS Association believes that upon diagnosis, people living with ALS/MND and their families must have the right to access genetic counseling and testing, current education about clinical genetics in ALS/MND, and safeguards against genetic discrimination.
More Information about Clinical Trials for ALS
Discovering a SOD1 mutation in your genome might mean that you are eligible for a clinical trial. Talk to your doctor about genetic testing and counseling and how to find out if you are eligible for a clinical trial. Here are some resources where you can learn more about clinical trials for ALS:
- Find a clinical trial in your area
- Overview of clinical trials
- More information about tofersen
- More information about genetic counseling and about how to find a counselor in your area from the National Society of Genetic Counselors at www.nsgc.org.