With much appreciation, we read the letter to the editor by Khan and Khan1 with respect to our manuscript describing the identification of therapy-responsive biomarkers in patients with SOD1-amyotrophic lateral sclerosis (ALS) treated with tofersen.2 The authors surely highlight interesting aspects regarding the interpretation of our study. First, the true origin of the pro-inflammatory proteins detected in the cerebrospinal fluid (CSF) samples 12 months after treatment initiation cannot be determined with ultimate certainty. As mentioned by Khan and Khan, the intrathecal application of the antisense oligonucleotide repetitively every 4 weeks is indeed leading to inflammatory signatures in the CSF, which in most cases remain clinically silent.3 In fact, the patients and samples used for our study were partly included in the 12-month observation study from Wiesenfarth et al, hence basic CSF reports about cell count, protein, and oligoclonal bands were already investigated and described.3 Although the involvement of microglia and neuronal inflammation is suggested to play an important role in the ALS pathogenesis,4, 5 there is still no direct evidence of tofersen exerting a direct effect on the inflammatory response of patients. Thus, a combination of inflammatory reaction, due to the invasive treatment, and of disease progression (although slowed down by the treatment) is probably responsible for the increased pro-inflammatory response. Second, the influence of sex hormones on the gender-dependent response of Aβ-peptides to the treatment with tofersen is a very important aspect. Unfortunately, at least for our patient cohort, we did not have information about hormone levels at the timepoint of sampling. Just by filtering the epidemiological data with regard to age at lumbar puncture, we could speculate whether the female patients were rather pre- or post-menopausal. There, we did not see any pattern of responder or non-responder female patients depending on the hypothetical menopausal state. Collecting anamnestic as well as analytical data in follow-up studies would definitely help gain more insight into the physiological sex-dependent response of Aβ-peptides to the treatment with tofersen. Third, the role of neuronal pentraxins (NPTX1, NPTX2, and NPTXR) in neurodegenerative diseases has been significantly growing in the latest time. Not only are the proteins altered between patients with Alzheimer's disease and healthy controls,6 but also seem to represent a proxy for neuroprotection in patients suffering from spinal muscular atrophy and treated with the antisense oligonucleotide Nusinersen.7 In ALS, serum neuronal pentraxin 2 levels have been found to be associated with shorter survival.8 Nevertheless, we have to point out that, in our study, there was no significant change between ALS at baseline and healthy controls. In addition, the interplay between TDP-43 pathology and NPTX29 is unlikely to represent a major pathological factor in patients with SOD1-ALS, who lack this canonical ALS-hallmark. Still, we agree that neuronal pentraxins represent a promising biomarker especially with regard to drug trials and therapy-responsiveness, because their dynamics upon treatment seem to be very consistent and mirror the clinical state of patients on a molecular level. Christina Steffke: Writing – original draft; writing – review and editing. David Brenner: Writing – original draft; writing – review and editing. Alberto Catanese: Writing – original draft; writing – review and editing; resources. The data that support the findings of this study are openly available in https://doi.org/10.1002/ana.70025 (reference 2)
Steffke et al. (Sat,) studied this question.