Treating Familial ALS at the Source: The Introduction of Gene Therapies


As scientific researchers continue to uncover new genetic links to amyotrophic lateral sclerosis, the rise of gene therapies to treat the neuromuscular disease will remain a development to watch in the coming years.

Kuldip Dave, PhD, senior vice president of Research, The ALS Association

Kuldip Dave, PhD

Amyotrophic lateral sclerosis (ALS), a progressive disease that affects nerve cells in the brain and spinal cord, is characterized by generation of upper and lower motor neurons, leading to paralysis, respiratory failure, and death—typically in 2 to 5 years from onset. For approximately 90% of all cases, there is no known family history of the disease or presence of a genetic mutation linked to ALS. Although, for the remaining 5% to 10%, there is a known family history of the disease, which has opened the door for gene therapy, a targeted approach that can potentially fix or block the negative effects of coding errors.1

Gene therapy involves the delivery of genetic material to cells and introduction of functional copies of dysfunctional genes, trophic factors, and other disease-modifying genes, or the silencing of harmful gene expression. Some of the most promising gene-therapy–based approaches for ALS to date include antisense oligonucleotides (ASOs), RNA interference (RNAi), or gene editing technology such as CRISPR. Although a gene-targeted therapy for ALS could potentially fix the genetic mutations causing the disease, most of those in development do not target DNA directly.

The State of Therapeutics

With only 4 FDA-approved medications to treat the disease, industry leaders have been willing to explore all options. To date, researchers have discovered close to 40 different genes linked to the disease; however, a large majority are not fully validated.2 "Not all of them are validated to the same extent. Some are validated, some need more validation, and some are linked to other diseases. The pipeline is robust because we have a huge number to pick from," Kuldip Dave, PhD, senior vice president of Research, The ALS Association, told NeurologyLive®.

For years, Dave and The ALS Association have been supporting gene therapy projects, genetic testing, and genetic counseling in ALS. In 2014, the organization announced the US arm of Project MinE, an international, large-scale research initiative devoted to discovering genetic causes of ALS. That project was supported by the Center for Genomics of Neurodegenerative Disease (CGND) at the New York Genome Center.3 To gain insights into the relationship between mutations, gene expression, and disease mechanisms, the CGND utilizes whole-genome sequencing data with other genomic-scale data such as RNA sequencing, RNA-protein interactions, and DNA methylation proteins.

Mathew B. Harms, MD, associate professor of neurology, Columbia University, and medical consultant and care center director, Muscular Dystrophy Association

Mathew B. Harms, MD

"That’s where big science is ALS has recognized a need—the prospective collection of longitudinal clinical information to be paired with biofluids that can be studied for biomarkers, and genetic information that can be studied for genetic implications," Mathew B. Harms, MD, associate professor of neurology, Columbia University, and medical consultant and care center director, Muscular Dystrophy Association, said in a conversation with NeurologyLive®.

He added, “You can go back and forth. Does this gene increase the likelihood of a good or bad prognosis? Does this genetic mutation increase the likelihood that you’ll have dementia associated with your ALS or bulbar onset of your ALS? We’re going to learn a lot from studying these databases."


Among the handful of validated targets, the SOD1 mutation—which affects roughly 12% to 20% of people with familial ALS and 1% to 2% of those with sporadic ALS—represents one of the more intriguing and promising areas of therapeutic exploitation.4 One notable agent, Biogen and Ionis’ tofersen, has shown the capability to reduce SOD1 protein in a phase 3 study (NCT02623699), but failed to show improvements on functional capacity. In the early- and delayed-start tofersen groups, patients demonstrated reductions of 33% and 21% in SOD1 protein and 51% and 41% in plasma neurofilament light, a marker of neuronal injury, respectively, at the 12-month time point. Despite reaching the intended target, there was no statistically significant change observed on the Revised ALS Functional Rating Scale (ALSFRS-R; difference, 1.2 points; P = .97).5

Apic Bio’s APB-102 represents another hopeful SOD1-targetedcandidate. The agent is a recombinant AAVrh10 vector that expresses an anti-SOD1 artificial microRNA, thereby reducing production of the mutant protein and hopefully improving survival or motor function. After the FDA cleared an investigational new drug application, the company proceeded with a phase 1/2b multicenter, 3-part trial to assess APB-102 in patients with SOD1 ALS. It includes a single-ascending dose portion; a randomized, double-blind, placebo-controlled part; and an extended follow-up.6

Dave expressed that these promising signs still come with caution, and further validation. “You need to take that gene and start to understand what the validation is in the disease,” he said. “How much do you need to knock down or increase the activity of that gene? Where does it happen? Does it happen centrally, peripherally, or all over? Can you do it in a safe way? Is there is a particular amount you need to reduce or increase before getting on-target side effects of that drug?”

C9orf72-associated ALS

Another target for drug development has been C9orf72-associated ALS. Some of the more notable agents in the pipeline include Alector’s AL001 antibody, TPN-101 (Transposon), and ASOs such as BIIB078 (Biogen/Ionis) and WVE-004 (Wave Life Sciences). More disappointing news came in March 2022, as Biogen announced that it was discontinuing their program of BIIB078 in response to an unsuccessful phase 1 study.7 As for WVE-004, in FOCUS-C9, a phase 1/2a trial (NCT04931862), the drug was found to durably reduce poly-GP dipeptide repeat proteins, a key biomarker of C9or72-associated ALS.8

Furthermore, all active WVE-004 treatment groups (10 mg: n = 2; 30 mg: n = 4; 60 mg: n = 3) had reductions of poly-GP, with the 30-mg group showing a statistically significant 34% reduction in poly-GP at day 85 (= .11) compared with placebo. In addition to FOCUS-C9, there is an ongoing study of a multidose cohort at 10 mg, with additional single and multidose data expected to be announced sometime in 2022.8

FUS Targeting in ALS

Mutant Fused in Sarcoma (FUS) protein, a genetic cause of motor neuron degeneration, is another pathway that has become prominent in recent years. In 2019, Ionis and Columbia University Medical Center sought permission from the FDA for the compassionate use of ION363, an investigational ASO, to treat Jaci Hermstad, a 26-year-old woman with P525L FUS-ALS whose identical twin had earlier died of the disease. That led the US House of Representatives to pass Jaci’s Bill (HR 2855), which allowed the doctors to administer the agent before completing toxicology testing in rodents.

Although Hermstad died, the drug continued on with her name, as jacifusen. Most recently, in April 2021, Ionis began their phase 3 FUSION trial (NCT04768972), a large-scale study to evaluate the efficacy and safety of the agent in patients with P525L FUS-ALS.9 Previous mouse models have indicated that antisense-mediated reduction of mutant FUS protein prevents motor neuron loss, which is the hypothesis for researching it in ALS.

"This [ION363] is sort of the next tofersen," Dave said. "That’s the next one we will learn from. It’s targeting a gene that’s very aggressive, happens mostly in young onset ALS, and people who have it pass away very quickly from the gene. It’s an acute need in the community, even though it’s ultra-rare." FUS is the most commonly mutated gene in juvenile and pediatric ALS, but it only causes about 5% of cases in adults. It remains unclear why younger patients with FUS mutations exhibit a more aggressive disease course than adults.10

Stathmin-2 Targeting in ALS

Stathmin-2, encoded by STMN2, has recently been reported as a potential contributor to the pathogenesis of ALS.11,12 STMN2, a member of the stathmin family of proteins, encodes a phosphorprotein that has an important role in microtubule dynamics, which play a factor in neuronal growth and cell division. One critical study published in March 2021 found noncoding CA repeat in stathmin-2 to be significantly associated with disease risk (P = .042). Additionally, the study showed that longer CA allele length was associated with earlier age-of-onset (P = .039), and shorter survival duration in bulbar-onset cases (P = .006). Of note, in an Australian longitudinal subcohort (n = 67), ALSFRS-R scores were significantly lower in carriers of the long/long genotype (P = .034).13 

"Both stathmin and ataxin-2 are genes that may not be just linked with the familial part of the disease, they may be linked with sporadic forms as well," Dave said. "Stathmin is so much closer. Now, we have a linked pathology to TDP-43 which makes even more sense to go after. You’re not going after TDP-43, which is the culprit in ALS, you’re going after the protein that regulates it. That type of thinking makes sense."

Previous literature has identified that ALS and frontotemporal dementia are associated with nuclear transactive response DNA-binding protein 43 (TDP-43). Findings from Melamed et al showed that reduced stathmin-2 expression was found in neurons transdifferentiated from patient fibroblasts expressing an ALS-causing TDP-43 mutation, in motor cortex and spinal motor neurons from patients with sporadic ALS and familial ALS with GGGGCC repeat expansion in the C9orf72 gene, and in induced pluripotent stem cell (iPSC)-derived motor neurons depleted of TDP-43.12 Notably, while reduction in TDP-32 was shown to inhibit axonal regeneration of iPSC-derived motor neurons, rescue of stathmin-2 expression restored axonal regenerative capacity.12

Additionally, a study in mice published in 2017 showed that decreases in ataxin-2 reduced aggregation of TDP-43 markedly increased survival, and improved motor function. When ASOs were administered in the central nervous system to target ataxin-2, survival was extended, suggesting a potential disease-modifying therapeutic strategy.14

The Future for ALS Gene Therapy

There are several promising routes of gene therapy in ALS, with the potential to change the treatment landscape over the coming years. It has already made its way in other neuromuscular diseases, most notably in spinal muscular atrophy (SMA). In 2019, the FDA approved onasemnogene abeparvovec-xioi (Zolgensma; Novartis), the first gene therapy for children with SMA, the most severe form of SMA and a leading cause of infant mortality.15

"We need to get people aware of genetic testing and counseling," Dave said. "It’s not something people think of when they’re diagnosed. It’s a hard thing, when you’re diagnosed, and you know you have a terminal disease. You’re not thinking about genetic testing unless it runs in your family, and even then, you may not be thinking about it. If they get tested and they have a particular gene, and there’s a gene therapy [trial] going on, they can enlist."

He continued, "That trial doesn’t have to spend 5 years recruiting their cohort, they can do it in 5 or 6 or 8 months. The more people know about their genetic status, the better recruitment will be in the trials. Additionally, if we’re fortunate for one of these therapies to get to the market and they know they have a particular gene mutation, they can then take advantage of what’s approved."

Looking for more gene therapy content? Check out our sister site, CGTLive™.

1. Genetic testing in ALS? The ALS Association. Accessed July 19, 2022.
2. Amado DA, Davidson BL. Gene therapy for ALS: a review. Mol Ther. 2021;29(12):3345-3358. doi:10.1016/j.ymthe.2021.04.008
3. Project MinE. The ALS Association. Accessed July 19, 2022.
4. ALS Gene Targeted Therapies. The ALS Association. Accessed July 19, 2022.
5. Ionis partner Biogen announces that results from phase 3 VALOR study and open-label extension of tofersen showed clinical benefit in SOD1-ALS patients. News release. Ionis. June 3, 2022. Accessed July 19, 2022.
6. Epic Bio announces FDA clearance of IND application for lead gene therapy candidate APB-102 for the treatment of SOD1 ALS. News release. Epic Bio. April 21, 2021. Accessed July 19, 2022.
7. Biogen and Ionis Announce Topline Phase 1 Study Results of Investigational Drug in C9orf72 Amyotrophic Lateral Sclerosis. News release. Biogen, Ionis. March 28, 2022. Accessed July 19, 2022.
8. Wave Life Sciences announces positive update to ongoing phase 1b/2a FOCUS-C9 study driven by potent, durable reductions of poly(GP) with low, single doses of WVE-004. News release. Wave Life Sciences. April 4, 2022. Accessed July 19, 2022.
9. Ionis initiates phase 3 trial of novel antisense medicine to treat leading cause of juvenile-onset ALS. News release. Ionis. April 5, 2021. Accessed July 19, 2022.
10. Picher-Martel V, Brunet F, Dupre N, et al. The occurrence of FUS mutations in pediatric amyotrophic lateral sclerosis: a case report and review of the literature. J Child Neurol. 2020;35(8):556-562. doi:10.1177/0883073820915099
11. Klim JR, Williams LA, Limone F, et al. ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nat Neurosci. 2019;22:167-179. doi:10.1038/s41593-018-0300-4
12. Melamed ZE, Lopez-Erauskin J, Baughn MW, et al. Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nat Neurosci. 2019;22:180. doi:10.1038/s41593-018-0293-z
13. Theunissen F, Anderton RS, Mastaglia FL, et al. Novel STMN2 variant linked to amyotrophic lateral sclerosis risk and clinical phenotype. Front Aging Neurosci. 2021;13:658226. doi:10.3389/fnagi.2021.658226
14. Becker LA, Huang B, Bieri G, et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature. 2017;544:367-371. doi:10.1038/nature22038
15. FDA Approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. News release. FDA. May 24, 2019. Accessed July 19, 2022.
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