ALS Gene Targeted Therapies

Many diseases, including ALS, are linked to errors, or mutations, in our genetic code. Genes provide the instructions to build proteins, the workhorses of the body, and an error in a gene can lead to a missing or damaged protein and threaten our health. Gene targeted therapy can potentially fix or block the negative effects of this error and help the body function in a healthy way.

Today, doctors treat patients with genetic illnesses using drugs that temporarily replace, repair, or stop the body from producing faulty proteins. These drugs usually consist of small molecules (like aspirin) or other proteins. People must take these drugs often and for the rest of their lives. This is because as a long as one or more of their genes provides the wrong instructions, their body will always struggle to produce healthy proteins.

Gene targeted therapies, in contrast, bring relief to people with genetic diseases using genetic material such as DNA as the treatment. Gene targeted therapies do not merely cover for missing or damaged proteins, like other drugs do. Rather, some gene targeted therapies correct or compensate for the genetic mutations that are causing the problem in the first place.

A gene targeted therapy for ALS could potentially fix the genetic mutations that are causing the disease. But most gene targeted therapies for ALS in development today do not target DNA directly.

DNA holds the instructions on how to build proteins, but instead of instructing your protein factories directly, DNA sends a molecule called messenger RNA (mRNA) to communicate the steps. Some gene therapies in development today block these mRNA messengers from reaching your protein factories. While this doesn’t fix one’s DNA, it prevents a damaged protein from being made.

Read below to learn about a few of the gene targeted therapies undergoing clinical trials for ALS and how you can get involved in clinical trials:

Gene Targeted Therapies For ALS

Researchers are currently developing several gene targeted therapies for people with ALS. For example, Apic Bio received permission from the Food and Drug Administration (FDA) to start a phase I/II clinical trial for an ALS gene therapy called APB-102. This gene therapy is intended to treat people with a mutation in the SOD1 gene, which affects about 12-20 percent of people with familial ALS and 1-2 percent of people with sporadic, or singleton, ALS. Click here to learn more about the genes linked to ALS.

Apic Bio is just starting its journey, but the gene therapy that is closest to reaching people with ALS is tofersen. This therapy also treats people who have ALS with a SOD1 mutation. The therapy was developed by Biogen in partnership with Ionis Pharmaceuticals and and the phase 3 clinical trial has closed. A phase I/II clinical trial showed that, in a group of 50 people, the treatment was safe and lowered SOD1 levels in the cerebral spinal fluid. Now, researchers are testing a larger group of 150 people to confirm the therapy’s safety and whether it can impact disease. The trial has enrolled all of their participants. Biogen announced the top-line results of the VALOR trial in mid-October 2021. Learn more about tofersen here.

Ionis is developing another gene therapy called ION363. This therapy treats people with FUS mutations. Mutations in this gene are found in about five percent of people with familial ALS and about one percent of people with sporadic or singleton ALS. People with FUS mutations tend to develop ALS earlier and live shorter lives than people with mutations in other genes. Ionis is currently recruiting people with ALS symptoms for a phase III clinical trial.

Meanwhile, Helixmith is testing a gene therapy called Engensis that could potentially help all people with ALS. This therapy is currently undergoing a phase II clinical trial to see if it makes an impact in people with ALS.

Gene Targeted Therapies in the Pipeline





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    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:

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