Gene therapy and gene-targeted treatment for ALS

Gene therapy for amyotrophic lateral sclerosis (ALS) and gene-targeted treatments are expanding how researchers approach ALS care. This research focuses on altering specific genes or modifying the biological processes they control.

An approved medication called Qalsody (tofersen) demonstrates that scientists can successfully target an ALS-linked gene. Other therapies, such as true viral-vector and gene-editing therapies, remain experimental.

Ongoing studies are working to determine whether these emerging approaches can safely produce biological changes that translate into meaningful everyday benefits for people living with ALS.

What is gene therapy for ALS?

Recent research indicates that while the root causes of ALS remain complex, approximately 20% of cases stem from genetic factors.

In ALS gene therapy, researchers evaluate whether novel techniques can reduce the activity of faulty genes that trigger damage to motor neurons, the specialized nerve cells that control voluntary muscle movement.

How is gene therapy different from gene-targeted treatment?

Gene-targeted treatments focus on the body’s genetic material rather than other biochemical or cellular abnormalities to manage disease. Gene therapy represents one specific category of gene-targeted treatment. It delivers new genetic instructions directly into cells, typically using modified viral vectors, to correct how an existing gene functions or supply a healthy working copy.

Other gene-targeted options act on ribonucleic acid (RNA). These therapies suppress the creation of toxic proteins without altering a person’s underlying DNA. In contrast, experimental gene-editing technologies like CRISPR aim to modify DNA directly.

Gene therapy is especially promising for familial forms of ALS tied to identified genetic variants, since these mutations offer clear molecular targets. At the same time, scientists are working on broader RNA-based strategies that could eventually help individuals with sporadic ALS who lack an identified mutation.

Which ALS gene-targeted therapies are approved?

Qalsody (tofersen) is an approved gene-targeted therapy for ALS in the U.S. for adults carrying mutations in the SOD1 gene.

It belongs to a class of medications called antisense oligonucleotides (ASOs). ASOs do not rewrite DNA. Instead, they alter how cells process messenger RNA (mRNA), the molecular messenger that carries instructions from genes to build proteins.

By binding directly to flawed SOD1 mRNA, Qalsody reduces the production of misfolded, toxic SOD1 proteins. Because ASOs break down naturally over time, patients must receive regular maintenance doses to sustain their therapeutic effect.

In 2023, Qalsody was granted accelerated approval as a SOD1 gene-targeted therapy for ALS because it significantly lowers neurofilament light chain, a key biomarker of ongoing nerve cell damage. Ongoing full approval depends on the confirmation of long-term clinical benefits in follow-up trials.

ASO therapies targeting additional ALS-related genetic material, along with other gene-targeted approaches, are under active investigation but have not yet been approved to treat ALS.

Which ALS genes are being targeted?

SOD1

Modifying SOD1-related behavior is the focus of the most advanced genetic ALS treatment research.

SOD1 mutations account for roughly 10% to 20% of familial ALS cases and 1% to 2% of sporadic cases. Specific mutations cause the resulting SOD1 protein to misfold and become toxic to motor neurons.

Multiple strategies for SOD1 gene therapy and gene-targeted care aim to curb SOD1 production. These include the approved ASO Qalsody as well as experimental treatments utilizing viral vectors.

C9orf72 and FUS

Mutations in the C9orf72 gene represent another significant genetic driver of ALS. Researchers have tested methods to reduce the accumulation of toxic RNA and proteins associated with this mutation, though C9orf72 gene therapy remains experimental. An earlier trial assessing the C9orf72-targeted ASO BIIB078 was discontinued after study results showed no clear patient benefit.

Another experimental ASO, jacifusen, is designed to reduce production of FUS protein in people with FUS-associated ALS. While initial findings have encouraged further study, definitive clinical benefits are still unproven.

Which viral-vector gene therapies are in trials?

Two notable gene therapy clinical trials for ALS are currently in early human testing:

• AMT-162 uses an adeno-associated virus (AAV) vector to deliver instructions for an artificial microRNA designed to lower SOD1 production. It is being tested as a one-time intrathecal injection in the Phase 1/2 EPISOD1 study (NCT06100276). The trial primarily focuses on evaluating safety and tolerability, while also examining potential effects on ALS.

• INS1202 also employs an AAV vector to deliver genetic code that lowers SOD1 protein production. The Phase 1 ARMOR study (NCT07290062) evaluates a single intrathecal dose in participants with SOD1 mutations, as well as select participants without known genetic variants.

These Phase 1 and 2 studies mark a crucial step forward, but evaluating viral vector therapy for ALS requires caution. Their primary goal is to assess safety, dosage tolerance, and biological activity, rather than proving that the treatments slow functional decline.

Who might qualify for an ALS gene therapy trial?

Eligibility criteria vary across studies. For example, a trial testing a SOD1-targeted therapy may require comprehensive genetic testing to confirm an eligible mutation.

Protocols also evaluate age, disease duration, breathing capacity, overall functional score, prior ALS treatments, and a candidate’s ability to undergo lumbar punctures safely. In viral-vector trials, investigators check for pre-existing antibodies against the delivery vector, which could neutralize the therapy.

Speaking with a certified genetic counselor can help an individual and their family understand how specific test results shape their eligibility for targeted clinical trials.

How are gene therapies administered?

Experimental ALS gene therapies and approved ASOs are usually given intrathecally through a routine lumbar puncture directly into the cerebrospinal fluid. This allows the medication to reach motor neurons throughout the spinal cord and brain. Other experimental methods explore intravenous infusions or targeted direct delivery into muscle or brain tissue.

Qalsody requires repeated dosing: three initial doses two weeks apart followed by a maintenance dose every four weeks.

In contrast, viral-vector therapies such as AMT-162 and INS1202 are being studied as single-dose treatments. However, while this reduces the burden of repeated procedures, the effects can be irreversible.

What are the possible risks of gene therapy?

Risks depend heavily on the specific approach used. Intrathecal injections carry procedural side effects common to lumbar punctures, including post-procedure headaches, localized back soreness, fluid leakage, bleeding, or infection.

Viral-vector therapies can trigger immune or inflammatory reactions that may require steroids or immunosuppressants. Participants may need blood tests and monitoring for liver abnormalities and other signs of toxicity.

Scientists must also ensure that silencing a mutated gene does not inadvertently compromise the protein’s normal functions elsewhere in the body. Some gene therapies may have long-lasting effects, and an immune response to a viral vector could make redosing difficult.

For these reasons, participants in gene therapy trials may require long-term monitoring.

How should early trial findings be interpreted?

A treatment can successfully decrease targeted protein levels or change biomarker values without necessarily slowing the clinical progression of ALS.

Researchers refer to verified biological activity at the molecular site as “target engagement.” While hitting a biological target is an essential milestone, researchers must ultimately assess clinical benefit through measures such as daily function, muscle strength, breathing function, disease progression, and survival.

Animal models provide crucial early safety data before human testing begins, but positive outcomes in laboratory models do not always translate to benefits in human patients.

What should I consider before joining a trial?

People considering participation in a gene-targeted therapy trial should speak with their healthcare provider and the trial coordinator to understand potential medical and practical considerations.

Questions to ask about a gene therapy trial

Questions to ask the healthcare team and trial coordinator before joining a gene-targeted therapy trial include:

• Which specific gene or mutation does this investigational therapy target?
• Does this treatment alter my existing DNA, or does it work on RNA?
• What functional evidence exists showing patient benefit beyond biomarker reductions?
• Can this therapy be paused, discontinued, or reversed?
• What are the most common short-term side effects and potential long-term safety concerns?
• Will receiving this experimental therapy disqualify me from joining future gene therapy studies?