Blood SOD1 Activity in ALS Patients Receiving Tofersen Treatment.

SOD1 variants lower blood superoxide dismutase 1 enzymatic activity in a variant-type-dependent manner, already at the asymptomatic stage; tofersen lowers SOD1 protein levels without changing this residual activity.

Tofersen, an antisense oligonucleotide, is the first disease-modifying drug for SOD1-related ALS, approved on its ability to lower SOD1 protein and neurofilament levels, but its effect on SOD1 enzymatic activity was unknown. The authors measured blood SOD1 activity in a discovery cohort (n = 120) and a validation cohort (n = 208) including controls, sporadic ALS, C9orf72 carriers, and asymptomatic then symptomatic SOD1 variant carriers. Activity was significantly lower in asymptomatic (median 7.5 U/mg, IQR 7.0-9.0) and symptomatic carriers (7.9 U/mg, IQR 7.1-9.1) than in controls (9.2 U/mg), C9orf72 carriers (9.4 U/mg) and sporadic ALS (9.5 U/mg; p < 0.0001), and lower for deleterious than for neutral variants. In 18 tofersen-treated patients, SOD1 protein and neurofilaments decreased whereas enzymatic activity remained stable. The authors conclude that the tofersen benefit is independent of SOD1 activity and call for studies of cerebrospinal fluid SOD1 activity.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The reassuring message is clear: under tofersen, residual enzymatic activity does not collapse, ruling out the feared scenario of added loss-of-function toxicity in already deficient carriers. The most usable observation for the clinic lies elsewhere — activity is reduced from the asymptomatic phase and varies with variant type, making it a useful functional argument when facing a SOD1 variant of uncertain significance. Two limits remain: the assay is blood-based whereas the therapeutic target is intrathecal, and 18 treated patients allow no conclusion at the individual level.

Analysis by Dr Thibaut Benquey