Selection and Prioritization of Candidate Drug Targets for Amyotrophic Lateral Sclerosis Through a Meta-Analysis Approach

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. Although several compounds have shown promising results in preclinical studies, their translation into clinical trials has failed. This clinical failure is likely due to the inadequacy of the animal models that do not sufficiently reflect the human disease. Therefore, it is important to optimize drug target selection by identifying those that overlap in human and mouse pathology. We have recently characterized the transcriptional profiles of motor cortex samples from sporadic ALS (SALS) patients and differentiated these into two subgroups based on differentially expressed genes, which encode 70 potential therapeutic targets. To prioritize drug target selection, we investigated their degree of conservation in superoxide dismutase 1 (SOD1) G93A transgenic mice, the most widely used ALS animal model. Interspecies comparison of our human expression data with those of eight different SOD1G93A datasets present in public repositories revealed the presence of commonly deregulated targets and related biological processes. Moreover, deregulated expression of the majority of our candidate targets occurred at the onset of the disease, offering the possibility to use them for an early and more effective diagnosis and therapy. In addition to highlighting the existence of common key drivers in human and mouse pathology, our study represents the basis for a rational preclinical drug development.Electronic supplementary materialThe online version of this article (doi:10.1007/s12031-017-0898-9) contains supplementary material, which is available to authorized users.

PACAP and PAC1R are differentially expressed in motor cortex of amyotrophic lateral sclerosis patients and support survival of iPSC‐derived motor neurons

“…In order to investigate the potential contribution of PACAP/PAC1R axis in motor neuron viability, we generated an in vitro model of human motor neurons by reprogramming PBMC through iPSC technology. Despite the beneficial role of endogenous PACAP has been already demonstrated in visceromotor neurons of SOD1(G93A) mice (Ringer et al, ), animal models often do not sufficiently reflect the more complex human disease (Morello, Spampinato, Conforti, D'Agata, & Cavallaro, ). Therefore, motor neurons‐derived from human iPSC offer a unique opportunity to obtain with a non‐invasive procedure an optimal culture of patient's specific motor neurons, opening the way to in vitro disease models suitable for drug test and/or cell therapy studies as well (Veyrat‐Durebex et al, ).…”

Splicing Players Are Differently Expressed in Sporadic Amyotrophic Lateral Sclerosis Molecular Clusters and Brain Regions

“…The existence of transcriptional differences separating SALS patients in two (or more) distinct sub-clusters might explain why several compounds showing promising results in preclinical studies failed to translate into successful clinical trials [27,88]. Indeed, the lack of therapeutic progress may mainly due to an insufficient understanding of the complexity and heterogeneity underlying ALS [89,90].…”

PACAP Modulates the Autophagy Process in an In Vitro Model of Amyotrophic Lateral Sclerosis

“…In recent years, the wide genomic expression analysis performed by DNA microarrays has allowed for the identification of deregulated genes in ALS and new potential drug targets for the treatment of the disease [21]. The analysis of the genomic profiles of 41 motor cortex samples identified the deregulation of the pituitary adenylate cyclase-activating polypeptide (PACAP) gene in a subgroup of sporadic ALS patients [21].…”

“…In recent years, the wide genomic expression analysis performed by DNA microarrays has allowed for the identification of deregulated genes in ALS and new potential drug targets for the treatment of the disease [21]. The analysis of the genomic profiles of 41 motor cortex samples identified the deregulation of the pituitary adenylate cyclase-activating polypeptide (PACAP) gene in a subgroup of sporadic ALS patients [21]. This peptide has neuroprotective and neurotrophic effects in different models of neurodegeneration through binding to three different G protein-coupled receptors known as PAC1, VPAC1 and VPAC2 [22][23][24][25][26][27][28].…”