Citations

Abstract There are ~100 genes or copy number variants (CNVs) used in genetic testing for Autism Spectrum Disorder (ASD, or autism). These genes are protein-coding, and the associated phenotypes often extend beyond socio-behavioral traits seen in autism including cognitive/medical complexities, epilepsy, and ADHD. Here, we characterize 27 males with ASD through whole genome sequencing (WGS), delineating X-chromosome microdeletions that implicate the long non-coding RNA (lncRNA) PTCHD1-AS as an ASD-susceptibility gene (OR=2.56, p=0.01). Two Ptchd1-as knockout (KO) murine models, created by removing the evolutionarily conserved exon-3, show ASD-like features in males, increasing repetitive behaviors and impairing typical social behavior and communication without overt cognitive comorbidities or ADHD-like behaviors. Hippocampus-dependent synaptic function, complex learning, and locomotor activity are unaffected in KO mice. Native nuclear-enriched mouse Ptchd1-as showed sustained expression from post-natal day-7 onward in the dorsal striatum, a predominantly GABAergic brain region implicated in ASD. Multi-omics revealed transcriptomic alterations in striatal oligodendrocyte, astrocyte and neurons impacting myelination and plasticity pathways. Disrupting Ptchd1-as led to reductions in conventional Protein Kinase-C, altered Src and GSK3α/β phosphorylation, and an enhancement of synaptic plasticity (long-term potentiation and long-term depression). Together, these findings implicate striatal molecular and circuit level dysregulation via Ptchd1-as in ASD etiology.

INTRODUCTION: Patients with ulcerative colitis (UC) and prior biologic failure may have reduced or delayed efficacy with subsequent advanced therapies. This analysis evaluated the efficacy and safety of ozanimod during the True North (TN) study and its open-label extension (OLE) in biologic-exposed patients with UC. METHODS: TN was a randomized, placebo-controlled 52-week trial (10-week induction, 42-week maintenance period). Eligible patients could enter the OLE. Clinical outcomes were assessed at TN week (W) 10 and W52 and OLE W46 and W94. Symptomatic efficacy was evaluated through induction and in the OLE until W94. Safety was assessed. RESULTS: This analysis included 376 biologic-exposed patients. In the placebo-controlled cohort, more ozanimod-treated patients achieved clinical response than placebo at W10 regardless of the number or type of prior biologics; patients who used 1 vs ≥2 prior biologics achieved higher efficacy rates. Efficacy rates were higher at W52 than W10 and were similar across subgroups regardless of the number or type of prior biologics. Significantly greater proportions of ozanimod vs placebo patients achieved symptomatic response by W5 ( P = 0.0173) and symptomatic remission by W10 ( P = 0.0207). Among biologic-exposed TN W10 ozanimod nonresponders who entered the OLE, 61% achieved symptomatic response with an extra 10 weeks of ozanimod treatment. Ozanimod efficacy was durable for ∼3 years of continuous treatment in biologic-exposed W52 clinical responders who entered the OLE. No new safety signals were observed. DISCUSSION: Ozanimod was effective and safe in biologic-exposed patients with UC, but these patients may require more time to respond to treatment. Clinical trial registry website and trial numbers: ClinicalTrials.gov, numbers NCT02435992 and NCT02531126.

Abstract Background Long-term corticosteroid (CS) use is not recommended for patients (pts) with ulcerative colitis (UC). Receiving early advanced therapy (AT) may help limit CS overuse, but there is a need to identify pt populations who may benefit most from receiving early AT as monotherapy. Previous post hoc analyses of the phase 3 True North (TN) study (NCT02435992) demonstrated ozanimod (OZA) efficacy in 5-aminosalicylate (5-ASA)–exposed, AT-naive, immunomodulator (IMM)–naive pts. This analysis further assessed the efficacy of OZA induction therapy with and without concomitant CS in this pt population by baseline (BL) endoscopic disease severity. Methods In TN, pts in Cohort 1 (C1) were randomised to OZA or placebo (PBO); pts in Cohort 2 (C2) received open-label OZA through Week (W) 10. Pts were on stable doses of oral 5-ASA and/or CS for ≥2 wk before screening and continuing through W10. 5-ASA–exposed, AT-naive, IMM-naive pts were grouped as moderate (Mayo endoscopy subscore [MES]=2 at BL) or severe (MES=3 at BL). Data were analysed in all moderate and severe pts and by concomitant CS use. Clinical remission, clinical response, endoscopic improvement, mucosal healing, and histologic remission were assessed at W10. Results Of the 464 5-ASA–exposed, AT-naive, IMM-naive pts, 237 had moderate (PBO, n=47; OZA C1, n=108; OZA C2], n=82) and 227 had severe (PBO, n=54; OZA C1, n=97; OZA C2, n=76) BL endoscopic disease. BL pt characteristics were generally similar between moderate and severe pts with or without concomitant CS use. Overall, OZA was significantly more effective in moderate pts and numerically more effective in severe pts vs PBO in C1, with numerically greater treatment differences in moderate vs severe pts (Figure 1A). The moderate and severe groups each had 51 pts (~22%) on concomitant CS. In moderate pts, numerically greater OZA vs PBO C1 treatment differences were observed in those without concomitant CS use vs those with concomitant CS use for clinical remission and clinical response; treatment differences were significant for all endpoints in pts without concomitant CS use (Figure 1B). In contrast, severe pts with concomitant CS use demonstrated greater OZA vs PBO C1 treatment differences vs those without concomitant CS use for all endpoints (Figure 1C). Results in OZA C2 were generally similar to OZA C1. Conclusion OZA treatment was efficacious in 5-ASA–exposed, AT-naive, IMM-naive pts with UC, with numerically greater efficacy in moderate pts than severe pts. Additionally, the results suggest that concomitant CS may not provide additional benefit over OZA monotherapy in moderate pts. These findings support OZA positioning after 5-ASA, but before CS, in pts with moderate UC.