Faculty Bibliography

The presence of an extra copy of human chromosome 21 (Hsa21) leads to a constellation of phenotypic manifestations in Down syndrome (DS), including prominent effects on the brain and immune system. Intensive efforts to unravel the molecular mechanisms underlying these phenotypes may help developing effective therapies, both in DS and in the general population. Here we review recent progress in genetic and epigenetic analysis of trisomy 21 (Ts21). New mouse models of DS based on syntenic conservation of segments of the mouse and human chromosomes are starting to clarify the contributions of chromosomal subregions and orthologous genes to specific phenotypes in DS. The expression of genes on Hsa21 is regulated by epigenetic mechanisms, and with recent findings of highly recurrent gene-specific changes in DNA methylation patterns in brain and immune system cells with Ts21, the epigenomics of DS has become an active research area. Here we highlight the value of combining human studies with mouse models for defining DS critical genes and understanding the trans-acting effects of a simple chromosomal aneuploidy on genome-wide epigenetic patterning. These genetic and epigenetic studies are starting to uncover fundamental biological mechanisms, leading to insights that may soon become therapeutically relevant.

Purpose Patients who overuse acute medicationsfor migraine generally experience more migraine days, greater disability, and more severe pain intensity. The FOCUS study of fremanezumab, a fully-humanized monoclonal antibody (IgG2DELTAa) that selectively targets calcitonin gene-related peptide (CGRP), was the first and largest study of a migraine preventive treatment in adults with both chronic migraine (CM) and episodic migraine (EM) and documented inadequate response to 2 to 4 classes of migraine preventive medications.This subgroup analysis of the FOCUS study evaluated the efficacy of fremanezumab in patients with baseline medication overuse (use of any acute medication on >=15 days/month or use of triptans, ergots, or combination medications on >=10 days/month). Methods In the randomized, double-blind, placebo-controlled period of the phase 3b FOCUS study, patients were randomized (1:1:1) to quarterly fremanezumab (month 1: 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: CM, 675 mg; EM, 225 mg; months 2 and 3: 225 mg), or matched monthly placebo for 12 weeks. Changes from baseline in the monthly average number of migraine days and monthly average number of headache days of at least moderate severity at 4 weeks and during 12 weeks of treatment were compared using a mixed-effect model for repeated measures. Results Of 838 randomized patients, 435 had baseline medication overuse. Reductions from baseline in the monthly averagenumber of migraine days were significantly greater with quarterly fremanezumab (least-squares mean [standard error (SE)] change, -3.3 [0.61]) and monthly fremanezumab (-4.6 [0.55]) versus placebo (-0.5 [0.62]; both P <= 0.0001) during 12 weeks of treatment. Reductions from baseline in the monthly average number of headache days of at least moderate severity were also significantly greater with quarterly fremanezumab (least-squares mean [SE] change, -4.0 [0.61]) and monthly fremanezumab (-5.1 [0.54]) versus placebo (-0.8, [0.61]; both P < 0.0001) during 12 weeks of treatment. At 4 weeks of double-blind treatment, changes from baseline in the monthly average number of migraine days and monthly average number of headache days of at least moderate severity were also significantly greater with both dosing regimens of fremanezumab versus placebo (all P < 0.0001). Conclusions Quarterly and monthly fremanezumab provided early and sustained reductions in monthly migraine and monthly headache days of at least moderate severity versus placebo in migraine patients with medication overuse and documented inadequate response to 2 to 4 classes of migraine preventive medications