Therapies Targeting ALS-Linked Genetic Mutations
The discovery of ALS-linked genetic mutations has opened the door to the development of genetically targeted therapies. These therapies are designed to precisely identify and interact with mutated DNA or the RNA or proteins it produces to help slow, stop, or reverse the progression of ALS. As researchers learn more about the DNA changes and toxic proteins that drive ALS, they will be better able to develop new therapies to treat the underlying causes of the disease.
How Mutations Cause Disease
A mutation changes the letters in a person’s DNA (also known as a genetic sequence) that spell out the instructions for making a specific protein. When a cell needs to make this protein, these genetic “typos” are copied from the DNA into shorter related molecules called RNA during a process called transcription. The RNA then serves as a messenger, taking the instructions from the nucleus to structures called ribosomes, which serve as the protein-making factories of cells. In the ribosome, this information is translated from the language of genetic code into the language of amino acids, which are the building blocks of proteins.
If this information includes any mistakes (mutations), it changes the protein that is produced. In the case of SOD1, for example, the gene contains the instructions for producing a protein called superoxide dismutase type 1 (SOD1). This protein normally helps clear out toxins from the brain, but when the SOD1 gene is mutated, it creates a defective SOD1 protein. The abnormal protein not only fails to do its normal job, but it also clumps together to form aggregates. Over time, these aggregates build up, damaging the nervous system and leading to the development of ALS.
How Gene-Targeted Therapies Work
To stop the damage caused by mutations in ALS-linked genes, researchers are leveraging a number of different technologies that reduce, block, or eliminate toxic proteins and their aggregates. They do this by specifically targeting mutated genes (DNA), messenger RNA (mRNA), or the toxic protein itself.
Targeting DNA
The most obvious place to target would be the source of the issue—the mutated gene (DNA)—but until recently, that wasn’t easy to do. With the development of CRISPR/Cas9 gene editing technology, researchers have more efficient tools to target and correct specific mutations. Essentially, researchers can program CRISPR/Cas9 gene editing tools to “cut out” a specific region of DNA. For example, in a preclinical “proof-of-concept" study in mouse models of ALS and human cells, researchers were able to remove the repeat expansion in C9orf72 the most common genetic cause of ALS, without affecting the parts of the gene that provide instructions for making healthy proteins.
Targeting RNA
An approach much further along in development is targeting mutated messenger RNA (mRNA). This type of therapy is called gene silencing because, instead of repairing or interacting with the mutated gene (DNA), it aims to “silence” the gene’s messengers before they are translated into toxic proteins.
One drug that leverages this approach is Qalsody, also known as tofersen, which was approved by the Food and Drug Administration (FDA) in 2023 for the treatment of ALS connected to mutations in the SOD1 gene. Qalsody is an antisense oligonucleotide (ASO), a small string of DNA letters that specifically target the mRNA produced from a mutated SOD1 gene to stop toxic SOD1 proteins from being made. Other gene silencing technologies include microRNA (miRNA) and short interfering RNA (siRNA).
Despite the promise of being able to stop the production of toxic proteins, these therapies will probably not be able to simply turn off ALS like a light switch. Research is showing that it takes time for these therapies to reduce protein levels and even more time after that for this reduction to be translated into a clinically meaningful benefit, such as slowing disease progression, improving physical function, or living longer.
Targeting Toxic Proteins
A third approach is to target the toxic protein after it has been produced. An example of this approach is the investigational treatment AP-101, which is being tested in a phase 2 clinical trial. AP-101 is a human monoclonal antibody. Monoclonal antibodies are proteins made in laboratories that act like the antibodies produced by the immune system. Antibodies made by the immune system seek out a wide range of foreign and toxic substances, like bacteria and viruses, and then stick to them so the body can destroy them. Laboratory-made monoclonal antibodies are created to seek out and destroy one specific thing. In the case of AP-101, it was designed to selectively target and reduce toxic clumps of misfolded SOD1 proteins. .
Opportunities for Sporadic ALS
Treatment approaches using ASOs and monoclonal antibodies are not just being developed for people with ALS-linked gene mutations. Researchers are also interested in using these technologies to treat sporadic ALS. One of the most promising targets for sporadic ALS is a protein called TDP-43, which clumps up and accumulates in the brains and spinal cords of about 97% of people with ALS. Learn more about this research.
Focusing on Prevention
Because toxic proteins build up and cause damage over time, researchers are interested in finding out whether targeted therapies could benefit people with ALS-linked gene mutations but no signs or symptoms of ALS. The thought is that by treating people with these mutations before significant and irreversible neuron damage occurs, it could delay or even prevent the onset of ALS.
The first clinical trial for pre-symptomatic ALS, the phase 3 Atlas Study, is testing Qalsody in approximately 150 participants who have specific SOD1 gene mutations but do not have any signs or symptoms of ALS. Through this study, the researchers are trying to determine whether Qalsody can delay the onset of signs or symptoms of ALS and slow declines in function once signs or symptoms appear. The trial is projected to be completed in 2027.
Therapies in Clinical Trials
Last updated August 2024
| Drug Name | Therapy Type | Target | Phase | Estimated Completion |
|---|---|---|---|---|
| AIT-101 (LAM-002A) |
Small molecule | Toxic proteins produced from C9orf72 repeat expansion (PIKfyve inhibitor) | Phase 2 | Completed |
| AMT-162 | miRNA | SOD1 mRNA | Phase 1/2 | 2032 |
| AP-101 | Monoclonal antibody | Misfolded and aggregated SOD1 protein | Phase 2* | 2025 |
| ION-363 (jacifusen) | ASO |
FUS mRNA |
Phase 3 | 2028 |
| Metformin | Small molecule | Toxic proteins produced from C9orf72 repeat expansion | Phase 2 |
2024 |
| Qalsody (tofersen) | ASO | SOD1 mRNA | Phase 3 (pre-symptomatic gene carriers) |
2027 |
* Also being tested for people with sporadic ALS
Importance of Genetic Testing
Because of the targeted nature of these therapies, they only work for people who have mutations in the specific gene the therapy was developed for. The only way to know if you have a mutation in an ALS-linked gene is to get a genetic test.
The decision whether to get tested or not is very personal. Genetic testing comes with benefits, but also with risks, and may not be right for you. A genetic counselor can help you weigh the pros and cons as you decide whether or not to get tested. Click here to learn more about the benefits and risks of genetic testing for people currently living with ALS. If you haven’t been diagnosed with ALS but have family members with the disease, click here to explore the potential benefits and risks of genetic testing.
ALS Association Support
We have made significant investments over the years into identifying the underlying genetic causes of ALS. This support led to the landmark discoveries of the SOD1 gene mutations in 1993 and C9orf72, the most common gene associated with ALS, in 2011. Since then, multiple large, global “big data” initiatives we’ve supported, such as the New York Genome Center and Project MinE, have undertaken large sequencing and gene identification efforts. This work has led to the discovery of additional genes thought to cause or increase the risk of developing ALS, and therefore increasing the number of potential targets for genetically targeted therapies.
We were the first to fund research of ALS-specific ASOs back in 2004 when it was an emerging technology, despite the high risk of the technology not coming to fruition. Thanks to the generosity of our donors, we continue to fund numerous research groups that are exploring the use of antisense and other DNA- and RNA-based therapies to target a diverse array of ALS-linked genes and proteins. We continue to be excited by the potential of these therapies to improve the lives of people with both familial and sporadic ALS as well as other neurodegenerative diseases.
