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C286 an orally available retinoic acid receptor Beta agonist drug regulates multiple pathways to achieve SCI repair

ABSTRACT: Retinoic acid receptor beta (RARbeta) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal mode of action. We have developed a first in class RARbeta agonist drug, C286, with demonstrated safety in a Phase 1 trial and proven efficacy in a sensory root avulsion rat model. Using genome-wide and pathway enrichment analysis in spinal cords of avulsed rats we show that C286 modulates regenerative pathways amongst which extracellular matrix (ECM) and adhesion molecules were of note. Protein expression analysis showed that C286 upregulates tenascin-C, integrin alpha9 and osteopontin in the injured cord. We further demonstrate the drug's efficacy in a rodent model of spinal cord contusion where it remodulates ECM molecules, hampers inflammation and prevents tissue loss. Treatment with the agonist induced upregulation of RARbeta in dorsal root and spinal neurons. In the single ascending dose (SAD) cohorts in white blood cells from healthy human participants RARbeta2 expression increases with dose and at the highest dose administered the pharmacokinetics are similar to doses used in rat proof of concept (POC) studies. We also show plasma S100B in nerve injured rats as a correlative measure of axonal regeneration. Finally, comparison with other clinically available retinoids which are non RARbeta selective showed these were ineffective in aiding regain of function in avulsed rats. Taken together our data suggests that further clinical testing of C286 in POC trials is justifiable for a broad spectrum of SCIs

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE268237 | GEO | 2024/08/08

REPOSITORIES: GEO

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Project description:Purpose: The goal of this study was to determine the gene expression changes that occur over 7 days in parralyzed muscle in response to isometric contraction elicited by electrical stimulation initiated 4 months after spinal cord injury and to compare such changes to those observed in a normal muscle subjected to overload. Methods: Electrical stimulation of the soleus and plantaris muscle was stimulated in female rats with complete transection of the spinal cord at the interspace between the 9th and 10th thoracic vertebrae. Stimulation was begun 16 weeks after spinal cord transection and produced near-isometric contraction of soleus, plantaris and tibialis anterior. Muscle was analyzed at 1, 2 and 7 days after starting exercise with electrical stimulation. To provide a baseline reference for gene expression at 16 weeks after spinal cord injury, muscle was also analysed from an additional group of spinal cord transected animals. One additional group of animals with a sham-spinal cord injury was included to provide information about gene expression in neurologically intact animals of similar age. In parallel studies, rats underwent bilateral gastrocnemius ablation to overload soleus and plantaris, or a sham ablation as a control. Muscle was analyzed at 1, 3 and 7 days after gastrocnemius ablation or sham-ablation. Gene expression was determined using Affymetrix Rat Exon microarrays. For each group of animals, microarray analysis was performed for soleus muscle for each of 3 separate animals, using one array per animal. Control sammples for the spinal cord injured groups included a group of animals with a Sham-spinal cord injury, and a group of spinal cord injured animals that did not get electrical stimulation. The comparator for determining fold-change expression values was the spinal cord injured group that did not receive electrical stimulation. For each day after gastrocnemius ablation, a control was included that received all procedures needed for this ablation except cutting the distal insertion of the gastrocnemius into the Achilles tendon to control for effects of the surgery on gene expression.

Project description:We have investigated the process of disease-induced functional perturbation and the related transcriptional changes occurring in thoraco-lumbar spinal cord extracted from Sprague-Dawley rats heterozygous for the G93A SOD1 gene mutation (Emerging Model 2148 Het Male, Taconic USA; Wyeth and Amyotrophic Lateral Sclerosis Association 2002) using spinal cord from wild type females littermates as reference tissues. Rats were obtained from a breeding project at Taconic Breeding Services (USA). We have applied large-scale gene expression analysis to define the pattern or transcriptional changes occurring in spinal cord from the G93A SOD1 rat model from a pre-symptomatic stage, at disease onset and at end-stage disease, using Bead Array analysis (Illumina, San Diego, USA). We have pooled spinal cord from N:5 transgenic rats for each of the time points considered, using the same pools of spinal cord from sex and age-matched WT rats as reference. In this specific project, the aim was to obtain a gene ontology (GO) pathway analysis of the transcriptional changes induced by the G93A SOD1 mutation in rat spinal cord. Hence, we have opted for a sample pooling strategy, well aware that in so doing, we would not obtaineed information about individuals genes variation across the samples in study but an overall view of the activation of multi-genes molecular signals. Total RNA was isolated from the spinal cords of mutant (G93A SOD1 gene mutation) female rats sacrificed at a pre-symptomatic stage (10-week old), at disease onset and at end stage disease and from age and sex-matched wild type (WT) littermates. RNA samples obtained from spinal cord extracted from rats of the same genetic types and sacrificed at the same time points (e.g. 5 RNA samples from mutant spinal cord from end-stage rats; 5 RNA samples from mutant spinal cord from rats at disease onset; 5 RNA samples from mutant pre-symptomatic rats and 5 RNA samples from spinal cord obtained from age-matched WT rats sacrificed at each of the 3 time points) were pooled and used for gene expression analysis and Ontology analysis of the expression profiles.

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C286 an orally available retinoic acid receptor Beta agonist drug regulates multiple pathways to achieve SCI repair

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