RESUMEN
Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated. Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events. Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported. Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction. Funding: No funding was received towards this study.
RESUMEN
The loss-of-function mechanism in progranulin (PGRN) mutation carriers makes PGRN an interesting target for upregulation as a therapeutic approach in neurodegenerative diseases like frontotemporal lobar degeneration. This gives rise to several questions: (1) how stable are PGRN levels in blood and cerebrospinal fluid (CSF) in follow-up? (2) Is it necessary to measure PGRN levels in CSF to monitor a therapeutic effect? Therefore, concentrations of PGRN were measured in paired CSF and serum samples of 22 patients with behavioural variant frontotemporal dementia, including one GRN mutation carrier (c.349+1G>C), 16 patients with amyotrophic lateral sclerosis and 17 non-neurodegenerative patients, which included 22 follow-up levels. PGRN levels of 14 patients with isolated dysfunction of the blood-CSF barrier were measured and PGRN was correlated with albumin quotients as a marker for blood-CSF barrier function. The intrathecal fraction of PGRN was calculated on the basis of CSF-to-serum ratios and hydrodynamic properties. Follow-up measurements of CSF and serum PGRN levels did not show any significant change in diagnostic groups. Mean PGRN levels are 35 times higher in blood than in CSF. However, the CSF-to-serum PGRN ratio does not correlate with the albumin quotient even in patients with severe impairment of the blood-CSF barrier. The calculated intrathecal fraction of CSF PGRN levels ranged between 80 and 90 %. Assuming that CSF PGRN is either brain-derived or transported from the vascular compartment via receptor mediated mechanisms, we propose that monitoring CNS specific effects of PGRN modulating drugs should be done in CSF.
