Until Tofersen from Biogen, ALS drugs were only slightly slowing the disease. Tofersen aims to lower the levels of a specific mutation of SOD1. This therapy is probably a lifeboat for the patients with the matching SOD1 mutation. It's certainly slowing the disease progression, but only for a tiny portion of ALS patients less than 2%.
Not all patients with the right SOD1 mutation react to Tofersen similarly.
People have two SOD1 genes in their cells and sometimes only one allele is mutated and the other can make up for the defective one. There are also other proteins named SOD2 and SOD3 that can assume partly the functions of SOD1.
In the worst case with ASO medications, ALS patients are merely exchanging a defective protein with a lower production of the same protein. This is not a great perspective, a genetic therapy that makes cells produce the correct version of SOD1 would be better. Yet genetic therapies have their share of problems, including low efficiency and increased cancer risk.
All members of this protein family, transform a byproduct of the mitochondrial electron transport chain, into hydrogen peroxide and diatomic oxygen. Yet those two chemical species are themselves quite reactive. SOD1 is located in the cytoplasm of cells, SOD2 in their mitochondria, and SOD3 is extracellular.
In that case, where there is still one functional allele, it would be nice to check SOD1 levels in the body of patients treated with Tofersen. If it's too low (because of Tofersen) the therapy renders itself ineffective. This could be done by analyzing blood, but scientists reckon that checking SOD1 in CSF would be a better idea.
The discovery of children developing SOD1 Deficiency Syndrome (ISODDES) which is characterized by injury to the motor system, suggests that a too-low SOD1 antioxidant activity may be deleterious in humans. Measuring SOD1 activity in cerebrospinal fluid (CSF) in Tofersen-treated patients is recommended but difficult due to low concentration and the presence of the isoenzyme SOD3.
To assess SOD1 activity, the scientists propose to remove SOD3 from CSF samples with antibodies and subsequently measure the SOD1 activity.
To propose this as a standard procedure for human beings is a bit weird. Repeatedly piercing the membranes that protect the spinal cord sounds like an unhealthy proposal, particularly if it's done to patients having motor neuron disease.