Amyotrophic Lateral Sclerosis (ALS), commonly called Lou Gehrig’s disease, is a neurodegenerative disorder of the motor neurons that causes progressive muscle weakness and respiratory failure (1). ALS is the most common motor disease among adults (2), affecting around 60,000 people in the U.S. and Europe. Life expectancy for those with the fatal disease is typically 2-5 years after diagnosis (1), and onset is usually in late middle life (3). While 90-95% of ALS cases are sporadic, meaning there’s no family history of the disease, familial ALS arises in about 5-10% of cases. Genetic testing — a personal choice that comes with both benefits and risks — is the only way to know if you carry a gene mutation associated with ALS.

Mary Johnson’s life journey with ALS began when her mom started falling in 1974. After the diagnosis was made, 20-year-old Mary moved back home to help her dad take care of her mom. The rapid progression of the disease saw her mom going from walking to walking with a walker to being wheelchair dependent within weeks. After losing the ability to speak, eat, and breathe on her own, she died that same year at the age of 44.

Mary refers to this as the beginning of her journey with the beast known as ALS, an appropriate name for a condition with no cure. The disease had killed her grandmother and likely her great-grandmother and would ultimately take the lives of Mary’s mother, sister, brother, cousin, two young nieces, and nephew. A few weeks after her mom’s passing, Mary’s dad encouraged his kids to get tested to find out if they had the genetic mutation, but Mary decided against being tested, not wanting her entire life to be plagued by wondering if a simple twitch or fall was the start of the disease.

After Mary lost her brother, she started to have issues with her left hip. “Was this the start?” she wondered. It was finally time to see if she had the genetic mutation that had unleashed so much pain on Mary’s family. In August 2017, 43 years after her mom’s death, Mary got the news she did not have the mutation. “After finding out I didn’t have the gene, I was, of course, relieved and yet survivors’ guilt would come,” Mary wrote. “Today, I know I was spared so that I could fight for a cure and put an end to the worst disease.”

Genetic Complexity Hinders Drug Development

Despite decades of research and more than 40 ALS-causing genes identified, effective treatments remain limited. Current treatment options provide symptom management and respiratory support (2), with the only approved medications commonly used, Riluzole and Edaravone, providing modest benefits in only some patients (3). While a large number of ALS-causing genes have been discovered, many still remain unknown, adding to the slow progress in creating an effective ALS treatment (3). The complex nature of ALS and the large genetic and phenotypic diversity among patients make it difficult for genetically similar animal models to translate into successful human trials (3).

However, the success and approval of antisense oligonucleotides (ASO) for treating spinal muscular atrophy (SMA), another motor neuron disease, has brought hope of developing therapies for similar diseases (2). With the many ALS-linked genetic mutations, researchers are looking at a variety of potential solutions, including targeting the mutated gene, mRNA, or toxic proteins to reduce, block, or eliminate the damage caused by ALS gene mutations.

Of the identified genes, four — C9orf72, SOD1, TARDBP, and FUS — cause the disease in up to 70% of people with familial ALS in European populations. The most common consequence of mutations in the genes causing ALS is the production of a defective protein that becomes toxic.

C9orf72 mutation

Mutations in C9orf72 were identified in 2011 as the most common genetic causes of ALS, found in 25 to 40% of familial ALS cases and 6% of sporadic cases. The frequency of the C9orf72 mutation is higher in Europe and the United States, pointing to a founder effect of northern European origin (2).

The healthy function of the gene is still being researched, so its name indicates the gene’s open reading frame position on chromosome 9. The mutation in the C9orf72 gene that triggers ALS is a six-letter repeated segment known as a hexanucleotide repeat. While a healthy version of the gene only has about six of these hexanucleotide repeat units, the mutation has hundreds to thousands of them.

Interestingly, the same gene causes around 25% of the neurodegenerative disease called frontotemporal dementia (FTD). Some people with the mutation will only develop ALS, some only FTD, and some will develop both diseases, but it’s not understood which or if both will develop for someone carrying the mutation.

In a preclinical “proof-of-concept” study, researchers showed that CRISPR-Cas9 was able to remove the repeat expansion in the C9orf72 gene without upsetting the parts of the gene that give instructions for making healthy C9orf72 proteins.

SOD1 mutation

The SOD1 gene was the first to be associated with ALS in 1993 (3). Mutations in the SOD1 gene are the second-most common cause of familial ALS, found in about 10-20% of cases and 1-2% of sporadic ALS cases. When healthy, SOD1 proteins attach to copper and zinc molecules to break down toxic byproducts made during normal cell processes. These byproducts need to be broken down regularly to prevent cell damage. If the protein is mutated, it misfolds and clumps within motor neurons and astrocytes — cells associated with ALS development and progression. These clumps may interfere with healthy cell functions or trigger other needed proteins to misfold and lose their function.

Over 150 different mutations in the SOD1 gene have been found and linked to ALS. Each mutation affects the disease and how quickly it progresses differently. In North America, the most common SOD1 mutation is A4V — a mutation changing the fourth amino acid in the protein from an alanine to a valine — which typically causes a rapid disease progression. Most ALS cases caused by SOD1 start in the lower motor neurons and limbs (2).

Biogen and Ionis’ ALS drug, Qalsody (tofersen, BIIB067), was designed to target the RNA produced from mutated SOD1 genes to halt the production of toxic SOD1 proteins. The ASO drug received accelerated approval in the U.S. last April based on preliminary data showing a reduction in plasma neurofilament light chain, a marker of neurodegeneration. Qalsody was also approved by the European Commission in May.

A phase 1/2 clinical trial of 50 people showed that tofersen was generally safe and reduced SOD1 protein levels in cerebral spinal fluid. While the drug pioneered ASO therapies for ALS, the results of its larger phase 3 clinical trial, known as the VALOR trial, showed the drug did not meet its primary endpoint of slowing the rate of disease progression. However, a follow-up study using 12 months of data from the VALOR trial and open-label extension revealed that earlier initiation of the drug did slow the decline in clinical and respiratory function, strength, and quality of life.

Biogen is currently testing tofersen in a different phase 3 study, called the ATLAS trial, with 150 participants with the SOD1 gene mutation but no signs of ALS symptoms. ATLAS is the first trial for pre-symptomatic ALS, attempting to find if it is possible to treat people before significant and irreversible neuron damage occurs. The trial is expected to be completed in 2027.

AL-S PHARMA AG is also working on a therapy with its drug AP-101, a lab-made monoclonal antibody designed to seek out and destroy misfolded SOD1 proteins. Produced by AL-S PHARMA AG, early mouse model studies of the drug showed it reduced motor symptoms and increased survival, while its subsequent phase 1 study demonstrated it was well-tolerated by people with ALS at all tested doses. It’s currently in its Phase 2 trials.

AMT-162, an investigational gene therapy that expresses a microribonucleic acid (miRNA), was designed to target the SOD1 gene and prevent the production and accumulation of misfolded SOD1 proteins. The drug — acquired from Apic Bio by uniQure — is currently in its Phase 1/2 trial.

FUS (fused in sarcoma) mutation

Discovered in 2009, FUS is the fourth most common gene causing familial ALS in the U.S. and Europe. It is especially pervasive in sporadic, early-onset, and juvenile patients (2). FUS mutations often occur in patients in their 30s or 40s, with an upper extremity onset and rapid disease progression (2).

The FUS gene provides directions for making a protein called fused in sarcoma (FUS), found within most tissues’ cell nuclei. Like TDP-43, the FUS protein plays several roles in protein production, including transcription, pre-mRNA splicing, RNA transport, and translation regulation (3).

Ionis developed another ASO drug, ION-363 (known as Ulefnersen and jacifusen), for treating ALS caused by an FUS mutation, which is currently in its Phase 3 trial. ION-363 was designed to reduce the production of a mutated, neurotoxic form of the FUS protein.

TARDBP mutation

In 2008, TARDBP was discovered as a causative gene of ALS. Familial ALS with TARDBP mutation commonly starts in the limbs and has a broader range of onset age (2).

The TARDBP gene contains instructions for creating a transactive response DNA binding protein 43 kDA (TDP-43), which helps keep cells healthy. The gene is linked to about 4% of familial ALS cases and 1% of sporadic cases. TDP-43 works as a regulator of gene expression and contributes to several RNA processing steps, including pre-mRNA splicing, regulation of mRNA stability, mRNA transport, translation, and the regulation of non-coding RNAs (3).

Targeting ATXN2 to reduce TDP-43 toxicity

TDP-43 may play a crucial role in many forms of the disease, as clumps of the abnormal TDP-43 protein are found in the nerve cells of about 95% of ALS patients, even those without a TARDBP mutation. Studies of yeast and flies suggest that targeting the ataxin-2 protein could reduce TDP-43 toxicity, and preclinical mouse models demonstrated that blocking the ataxin-2 protein prolonged their survival and slowed ALS progression.

While these four main gene mutations account for most familial cases of ALS, more than 40 other known mutations can cause the disease, making a treatment that’s effective for all ALS patients difficult. The idea of targeting TDP-43 — found in 95% of all cases — via reducing the ataxin-2 protein could be a potential target; however, recently an investigational drug attempting to do just that was dropped.

Investigational ALS drug to be dropped after Phase 1/2 trial

On May 16, Biogen Inc. and Ionis Pharmaceuticals announced they would discontinue BIIB105, an investigational antisense oligonucleotide (ASO) drug for ALS. The decision was based on data from the Phase 1/2 ALSpire study.

The ASO drug was designed to reduce the expression of ataxin-2 (ATXN2) protein. As ataxin-2 has been found to modify the buildup of TDP-43 proteins, BIIB105 was expected to prevent TDP-43 from forming the abnormal protein clumps that cause nerve cell toxicity in ALS, thus slowing the disease progression. While it successfully did reduce ATXN2 in patients’ cerebrospinal fluid, they did not seem to benefit from this. Notably, patients’ neurofilament levels, a marker of dying neurons, didn’t drop.

“While BIIB105 lowered ATXN2 protein, it did not reduce neurofilament, which gives us confidence that BIIB105 did not slow the disease process,” Stephanie Fradette, Pharm.D., Head of the Neuromuscular Development Unit at Biogen said in the press release.

Additionally, it did not succeed in significantly reducing neurodegeneration or improving functional measures like breathing, function, and strength. There was also no evidence the drug benefited any subgroup evaluated in the 99-patient study.

During the six-month randomized, placebo-controlled trial evaluating BIIB105, patients’ most common adverse events were procedural pain, headache, and falls. Adverse events that led to the study discontinuation were higher in the BIIB105 group (8.3%) than in the placebo group (3.6%).

While the trial may not have achieved its desired results, this doesn’t necessarily mean ATXN2 is a bad drug target. Questions of whether patients were treated early enough and whether the drug reached all the correct neurons often afflict ALS trials. Meanwhile, other companies, including Maze Therapeutics, Affinia Therapeutics, Aviado Bio, and HuidaGene, are working on therapies aimed at lowering ATXN2.

The termination of BIIB105 comes not long after Amylyx Pharmaceuticals said it was withdrawing its ALS drug Relyvrio from the U.S. and Canada after the treatment failed in a critical late-stage trial.

The future of ALS treatment

Will a cure for this beast of a disease come to fruition? The termination of investigational drug BIIB105 and withdrawal of Relyvrio seem like setbacks in the process of finding an effective treatment for a disease that can have so many genetic causes. However, researchers, pharmaceutical companies, and advocates continue to work toward treatments, with ASOs, monoclonal antibodies, gene therapies, and even CRISPR-Cas9 technologies being potential candidates for effective treatments. We have already seen one candidate approved in Qalsody, the ASO used for the treatment of SOD1 ALS, and other ASOs are also in clinical trials to address various causes of ALS. Beyond ASOs, two other approaches are in clinical trials: a monoclonal antibody and a gene therapy that expresses a microribonucleic acid. These advances, along with the successful preclinical proof of concept study showing that CRISPR could remove the repeat expansion in the C9orf72 gene, are encouraging, as they provide multiple avenues of potential treatment for the many different causes of ALS.

References:

1. Van Damme P, Veldink JH, van Blitterswijk M, Corveleyn A, van Vught PW, Thijs V, Dubois B, Matthijs G, van den Berg LH, Robberecht W. Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2. Neurology. 2011 Jun 14;76(24):2066-72. doi: 10.1212/WNL.0b013e31821f445b. Epub 2011 May 11. PMID: 21562247.
2. Suzuki N, Nishiyama A, Warita H, Aoki M. Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy. J Hum Genet. 2023 Mar;68(3):131-152. doi: 10.1038/s10038-022-01055-8. Epub 2022 Jun 13. PMID: 35691950; PMCID: PMC9968660.
3. Mejzini R, Flynn LL, Pitout IL, Fletcher S, Wilton SD, Akkari PA. ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now? Front Neurosci. 2019 Dec 6;13:1310. doi: 10.3389/fnins.2019.01310. PMID: 31866818; PMCID: PMC6909825.

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