Therapies designed to decrease SOD1 are currently in clinical trial for patients with superoxide dismutase (SOD1)-linked Familial Amyotrophic Lateral Sclerosis (ALS),
To determine whether SOD1 protein in cerebral spinal fluid (CSF) may be a pharmacodynamic marker and whether SOD1 protein in CSF is a disease marker for ALS.
Antisense oligonucleotides targeting human SOD1 (hSOD1) were administered to SOD1G93A rats. hSOD1 protein levels were measured in rat brain and CSF. In human CSF, the following proteins were measured: SOD1, tau, p-tau, VILIP-1, and YKL-40. was measured in human CSF.
SOD1G93A ALS model rats. ALS subject CSF (N=93), healthy controls (N=880 and neurological disease controls (NDC, N=89), including subjects with Dementia of the Alzheimer’s Type (DAT) (55), multiple sclerosis (19), and peripheral neuropathy (15).
Antisense oligonucleotide-treated SOD1G93A rats had decreased hSOD1 mRNA (69%+/−4%) and protein levels (48%+/ −14%) in brain. Importantly, rat CSF showed a similar 42+/−14% decrease in hSOD1. In human CSF, SOD1 varied 7.1+/−5.7 % on repeat measurements separated by months. SOD1 CSF levels were higher in ALS (172+/−8ng/ml, p<0.05) and NDC (172+/−6 ng/ml, p<0.05) compared with healthy controls (134+/−4ng/ml). Elevated CSF SOD1 did not correlate with disease characteristics in ALS or DAT subjects, but did correlate with tau, p-tau, VILIP-1 and YKL-40 in DAT subjects and controls.
CSF SOD1 may be an excellent pharmacodynamic marker for SOD1-lowering therapies since antisense oligonucleotide therapy lowers protein levels in both rat brain and rat CSF and since SOD1 CSF in humans is stable upon repeat measurements.