Answer ALS, a large-scale resource for sporadic and familial ALS combining clinical and multi-omics data from induced pluripotent cell lines

Abstract

Answer ALS is a biological and clinical resource of patient-derived, induced pluripotent stem (iPS) cell lines, multi-omic data derived from iPS neurons and longitudinal clinical and smartphone data from over 1,000 patients with ALS. This resource provides population-level biological and clinical data that may be employed to identify clinical–molecular–biochemical subtypes of amyotrophic lateral sclerosis (ALS). A unique smartphone-based system was employed to collect deep clinical data, including fine motor activity, speech, breathing and linguistics/cognition. The iPS spinal neurons were blood derived from each patient and these cells underwent multi-omic analytics including whole-genome sequencing, RNA transcriptomics, ATAC-sequencing and proteomics. The intent of these data is for the generation of integrated clinical and biological signatures using bioinformatics, statistics and computational biology to establish patterns that may lead to a better understanding of the underlying mechanisms of disease, including subgroup identification. A web portal for open-source sharing of all data was developed for widespread community-based data analytics.

Identification of Therapeutic Targets for Amyotrophic Lateral Sclerosis Using PandaOmics – An AI-Enabled Biological Target Discovery Platform

“…For each dataset, samples could be divided into subgroups based on their clinical subtypes or other phenotypic attributes. In addition, transcriptomic and proteomic data of the diMNs, generated from ALS patients and neurologically healthy subjects in Answer ALS ( Baxi et al, 2022 ) were uploaded to PandaOmics and incorporated in our analyses.…”

“…The iPSCs underwent three major stages of differentiation for 32 days to generate the mixture of mature motor neuron populations. Detailed protocol for the diMN generation and standards of quality assurance were described by Baxi et al (2022) . The consortium generated multi-omics data comprising genomic, epigenomic, transcriptomic, proteomic, laboratory test, medical records and other data.…”

Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis

“…This combination of growth factors will be referred to as neurotrophic factors (NFs) further on. At this point the cells were frozen in vials containing handy cell numbers for future use (1x10 6 , 5x10 6 or max. 10x10 6 cells).…”

Effects of the investigational drug sodium phenylbutyrate-TUDCA (AMX0035) on the transcriptional and metabolic landscape of sporadic ALS fibroblasts

“…In addition to potential effects on methylation, PB is an HDAC inhibitor with known epigenetic effects (13, 14), and TUDCA can also modulate chromatin modifying enzymes (6). Numerous studies have linked changes in DNA methylation and histone post-translational modifications to ALS (74), including in a large collection of induced pluripotent stem cell-derived motor neurons (75). Furthermore, altered DNA methylation patterns were recently described in a large-scale study of blood samples from ALS patients compared to controls (76).…”