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

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.

Analyzing progression of motor and speech impairment in ALS.

Amyotrophic lateral sclerosis (ALS) is a degenerative disease which causes death of neurons controlling voluntary muscles. It is currently assessed with subjective clinical measurements, but it would benefit from alternative surrogate biomarkers that can better estimate disease progression. This work analyzes speech and fine motor coordination of subjects recruited by the Answer ALS foundation using data from a mobile app. In addition, clinical variables such as speech, writing and total ALSFRS-R scores are also acquired along with forced and slow vital capacity. Cross-sectional and longitudinal analyses were performed using speech and fine motor features. Results show that both types of features are useful to infer clinical variables especially for males (R2=0.79 for ALSFRS-R total score), but their initial values are not helpful to predict speech and motor decline. However, we found that longitudinal progression for bulbar and spinal ALS onset are different and they can be identified with high accuracy by the extracted features.

Olfactory dysfunction in amyotrophic lateral sclerosis.

We utilized the well-validated University of Pennsylvania Smell Identification Test (UPSIT) to examine whether olfactory dysfunction occurs in ALS participants. After adjusting for relevant confounders in a multiple linear regression model, ALS participants scored significantly lower on the UPSIT compared with control participants, with an estimated mean difference of 2.31 points (P = 0.015). ALS participants also had twice the rate of olfactory dysfunction (microsmia or anosmia). This study suggests that olfactory dysfunction exists in ALS patients, which expands our understanding of the extramotor findings in ALS. Future investigations could determine whether there are correlations between olfactory dysfunction and specific ALS phenotypes.

A comprehensive library of familial human amyotrophic lateral sclerosis induced pluripotent stem cells.

Amyotrophic lateral sclerosis is a progressive disease characterized by the loss of upper and lower motor neurons, leading to paralysis of voluntary muscles. About 10% of all ALS cases are familial (fALS), among which 15-20% are linked to Cu/Zn superoxide dismutase (SOD1) mutations, usually inherited in an autosomal dominant manner. To date only one FDA approved drug is available which increases survival moderately. Our understanding of ALS disease mechanisms is largely derived from rodent model studies, however due to the differences between rodents and humans, it is necessary to have humanized models for studies of disease pathogenesis as well as drug development. Therefore, we generated a comprehensive library of a total 22 of fALS patient-specific induced pluripotent stem cell (iPSC) lines. These cells were thoroughly characterized before being deposited into the library. The library of cells includes a variety of C9orf72 mutations, sod1 mutations, FUS, ANG and FIG4 mutations. Certain mutations are represented with more than one line, which allows for studies of variable genetic backgrounds. In addition, these iPSCs can be successfully differentiated to astroglia, a cell type known to play a critical role in ALS disease progression. This library represents a comprehensive resource that can be used for ALS disease modeling and the development of novel therapeutics.