Shneider, Neil A.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease of motor neurons for which therapeutics are limited. Improved biomarkers are imperative to improve patient care and therapeutic development. Here, we employed 35-plex isobaric tandem mass tag labeling based on isobutyl-proline reporter group (TMTpro) to perform unbiased proteomic analysis of cerebrospinal fluid (CSF) and plasma from control (n= 28, n= 31) and sporadic ALS (sALS) (n= 39, n= 41), from the Target ALS Global Natural History Study (TALS GNHS). We identified 2,875 proteins in CSF and 1,118 proteins in plasma and identified known and novel differentially expressed proteins (DEPs) between controls and sALS, some of which were orthogonally validated using immunoassay. Comparison of TMTpro-MS and Olink proximity extension assay proteomics revealed common and non-overlapping differentially expressed proteins illustrating strengths unique to each platform. This initial cross-sectional proteomic study of biofluids from the TALS GNHS, with unrestricted availability of study results to the research community, highlights the potential of this resource as a potent platform for ALS biomarker discovery.

Abstract Patients with extremely rare pathogenic variants pose unique challenges to current healthcare systems. Nano-rare mutations have been defined as mutations with a known prevalence of <30 patients worldwide, but because of the small fraction of humans who have undergone genetic testing, neither the precise prevalence of individual mutations nor the total prevalence of patients with nano-rare mutations is known. n-Lorem is a non-profit founded in 2020 with the mission of equitably discovering, developing, and providing bespoke experimental antisense oligonucleotides (ASOs) for free, for life, to patients with nano-rare mutations that are amenable to ASO treatment. In this perspective, we provide an overview of the n-Lorem processes and systems, the characteristics of the first 329 patients who have applied for treatment for whom initial assessment was completed and suitability for ASO treatment determined, and a summary of the results of ASO treatment for patients treated to date. Detailed data on individual patients and the overall clinical safety and tolerability profiles of the ASOs for which there are clinical data are the subjects of other manuscripts.