SOD1 Mutations in ALS — From 1993 Discovery to Tofersen
The history of ALS genetic research begins in 1993 with a single paper in Science. Daniel Rosen and colleagues identified mutations in the gene encoding superoxide dismutase 1 as a cause of familial ALS — the first time a specific inherited change in DNA had been linked to motor neuron degeneration. That discovery opened three decades of research that eventually led, in 2023, to the approval of tofersen: the first drug that works by targeting a defined genetic cause of ALS. Understanding the SOD1 story is foundational to understanding where motor neuron disease drug development has come from, and where it is going.
What they did
In the early 1990s, a collaborative effort involving multiple research groups undertook genetic linkage analysis in families with autosomal dominant familial ALS. The approach was systematic: study large pedigrees with multiple affected members across generations, track genetic markers through the family, and identify chromosomal regions that co-segregate with disease. The chromosome 21 region near the SOD1 gene emerged as a candidate locus.
Rosen and colleagues then sequenced the SOD1 gene in affected family members and identified missense mutations — single amino acid changes in the encoded protein — that were present in affected individuals and absent in unaffected controls. Their 1993 paper in Science reported 11 different mutations across 13 kindreds, establishing that SOD1 mutations were a cause of familial ALS.
What followed over the next three decades was an intensive effort to understand how SOD1 mutations cause motor neurons to die, to build animal models replicating the disease, and to develop therapies that could intervene in the identified mechanism. The SOD1 mutant mouse, developed in 1994, became the most widely used animal model in ALS research — used to test hundreds of compounds before tofersen.
What they found
SOD1 (superoxide dismutase 1) is an antioxidant enzyme that normally converts harmful superoxide radicals into oxygen and hydrogen peroxide. Rosen's initial hypothesis — that the mutations caused ALS by reducing this enzymatic activity — turned out to be wrong, and the correction of that hypothesis was one of the field's most important early lessons.
Subsequent research established that SOD1 mutations cause ALS through a toxic gain of function, not loss of the enzyme's normal activity. The mutant protein misfolds into an abnormal conformation, acquires new toxic properties, and causes damage through those toxic properties rather than through deficient antioxidant function. This was demonstrated most directly by the observation that mice with increased copies of mutant SOD1 develop motor neuron disease, while mice lacking SOD1 entirely do not — the disease is caused by the presence of the abnormal protein, not the absence of the normal one.
Over 200 different SOD1 mutations have now been identified, accounting for approximately 20% of familial ALS and about 2% of all ALS cases. Different mutations produce different disease trajectories — some (like A4V, common in North America) cause rapid progression, others cause a slower course that can span many years.
Misfolded SOD1 protein — detectable with antibodies specific to the abnormal conformation — is found not only in patients with SOD1 mutations but in a subset of sporadic ALS patients as well. This observation raised the question of whether SOD1 misfolding might contribute to some sporadic ALS cases, and it motivated AP-101, a monoclonal antibody targeting misfolded SOD1 that showed preliminary signal in a Phase 2 trial in both SOD1-mutant and sporadic ALS patients.
The toxic gain-of-function mechanism was precisely what made SOD1-ALS amenable to an antisense oligonucleotide (ASO) approach. If the disease is caused by the presence of a toxic protein, then reducing production of that protein should slow or stop the disease. An ASO targeting the SOD1 messenger RNA can reduce its translation into protein, lowering the burden of misfolded toxic SOD1 in motor neurons. This was the mechanism of tofersen.
The VALOR Phase 3 trial of tofersen demonstrated that intrathecal administration reduced CSF SOD1 protein concentration and plasma neurofilament light chain (NfL) — a biomarker of neurodegeneration — in patients with SOD1 mutations. The primary functional endpoint did not achieve statistical significance in the main trial, but extension data and presymptomatic use in the ATLAS trial showed functional benefits. The FDA approved tofersen (Qalsody) in April 2023 under the accelerated approval pathway, based on reduction of NfL as a reasonably likely surrogate endpoint.
Why it matters
Tofersen is the first approved drug that works by targeting a defined genetic cause of ALS. Its approval, thirty years after the Rosen 1993 discovery, is the proof of concept that the strategy works: identify the causal gene, understand the mechanism, suppress the toxic product. The same strategic logic — gene identification, mechanism clarification, targeted suppression — is now being applied to C9orf72 and FUS.
The SOD1 story also established several things that have broader implications for MND research. It demonstrated that animal models built on human genetic causes can support drug development over decades. It established NfL as a pharmacodynamic biomarker for motor neuron degeneration, now used across ALS and PLS trials. And it showed that genetic subtyping of ALS patients — identifying the specific mutation before enrolling them in a trial — is both feasible and necessary for precision medicine in motor neuron disease.
For PLS specifically, the SOD1 story is important context, but the direct relevance is limited. PLS is almost never caused by SOD1 mutations. PLS patients, as a clinical population, are unlikely to carry SOD1 mutations, and tofersen is not a therapy for PLS absent such a mutation. The relevance is structural: tofersen demonstrates that once a causal genetic target is identified in a motor neuron disease, the pathway from discovery to therapy — while long — is navigable. If a genetic basis for a subset of adult PLS is ever clearly identified, the SOD1 experience provides the template.
Limitations and caveats
SOD1-ALS is in some respects the most tractable form of ALS — a single dominant gene, a well-defined toxic mechanism, an available mouse model, a clear therapeutic target. The lessons it has taught may not generalize to C9orf72-ALS, sporadic ALS, or PLS, where the biology is more complex or less well understood. Many compounds that extended survival in SOD1 mice failed completely in human trials — a sobering reminder that model-to-patient translation is not guaranteed. The SOD1 story is a proof of concept for precision genetic therapy in MND, but it does not promise that a similar drug will work for every form of the disease.
How this connects
Tofersen's ASO mechanism is the same class of drug being developed against C9orf72, and the pharmacodynamic biomarker it validated — plasma NfL — is now a standard outcome measure in motor neuron disease trials including PLS. TDP-43 pathology appears in SOD1-ALS patients despite the distinct genetic cause, illustrating how multiple genetic routes converge on overlapping downstream processes. For a summary of where gene-targeted therapies stand now, including tofersen and the ASOs in development, see the Investigational Treatments page. For how the genetics research framework applies to PLS patients, including the question of who should consider genetic testing, see the Genetics patient guide and the Genetics Research hub.
Citation
Rosen DR, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362(6415):59–62. doi:10.1038/362059a0
Miller TM, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. New England Journal of Medicine. 2022;387(12):1099–1110. doi:10.1056/NEJMoa2204705