The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression program to control neurite outgrowth

The mitotic deacetylase complex (MiDAC) is a recently identified histone deacetylase (HDAC) complex. While other HDAC complexes have been implicated in neurogenesis, the physiological role of MiDAC remains unknown. Here, we show that MiDAC constitutes an important regulator of neural differentiation. We demonstrate that MiDAC functions as a modulator of a neurodevelopmental gene expression program and binds to important regulators of neurite outgrowth. MiDAC upregulates gene expression of pro-neural genes such as those encoding the secreted ligands SLIT3 and NETRIN1 (NTN1) by a mechanism suggestive of H4K20ac removal on promoters and enhancers. Conversely, MiDAC inhibits gene expression by reducing H3K27ac on promoter-proximal and -distal elements of negative regulators of neurogenesis. Furthermore, loss of MiDAC results in neurite outgrowth defects that can be rescued by supplementation with SLIT3 and/or NTN1. These findings indicate a crucial role for MiDAC in regulating the ligands of the SLIT3 and NTN1 signaling axes to ensure the proper integrity of neurite development

Inhaled levodopa in Parkinson's disease patients with OFF periods: A randomized 12-month pulmonary safety study

Introduction: CVT-301 is an orally inhaled levodopa therapy approved for the intermittent treatment of OFF episodes in Parkinson's disease patients who are taking a standard oral levodopa regimen. This open-label, randomized, controlled study over 12 months characterizes the safety, including pulmonary safety, of CVT-301 84 mg (nominal respirable levodopa fine-particle dose, 50 mg). Methods: Patients experiencing motor fluctuations were randomized 2:1 to CVT-301 or an observational cohort (OC) receiving oral standard of care. Pulmonary safety was assessed using spirometry and carbon monoxide diffusion capacity (DLCO). Exploratory efficacy endpoints, assessed only for CVT-301, included change in Unified Parkinson's Disease Rating Scale Part III (UPDRS-III), patients achieving ON within 60 min and remaining ON at 60 min, Patient Global Impression of Change (PGIC) scale, and total daily OFF time. Results: Of 408 patients randomized, 310 completed the study (204 in CVT-301 and 106 in OC). Mean 12-month changes from baseline for CVT-301 were −0.105 L (FEV1) and −0.378 mL/min/mm Hg (DLCO), and for OC were −0.117 L and −0.722 mL/min/mm Hg, respectively. Between-group comparisons were not statistically significant. For FEV1/FVC the 12-month change was −0.3 and −1.6, respectively, which was a significant between-group difference. However, between-group differences were not significant at 3 and 9 months and all changes from baseline were small (<2.0%). UPDRS-III scores improved from predose to 60 min postdose at all assessments; 80%–85% of patients switched ON within 60 min and remained ON; and >75% reported improvement in PGIC. OFF time decreased by 1.32–1.42 h/day. Conclusion: CVT-301 84 mg induced no clinically significant differences in pulmonary function compared with the OC. Improvements in motor scores, OFF time, and patient-reported outcomes support clinical efficacy for up to 12 months

Ecdysteroids affect Drosophila ovarian stem cell niche formation and early germline differentiation

Ecdysteroids affect Drosophila ovarian stem cell niche formation and early germline differentiation. The steroid hormone ecdysone regulates germline development and stem cell niche establishment in the Drosophila ovary by modulating TGF-β signalling and cell adhesion

Interaction of SET domains with histones and nucleic acid structures in active chromatin

Changes in the normal program of gene expression are the basis for a number of human diseases. Epigenetic control of gene expression is programmed by chromatin modifications—the inheritable “histone code”—the major component of which is histone methylation. This chromatin methylation code of gene activity is created upon cell differentiation and is further controlled by the “SET” (methyltransferase) domain proteins which maintain this histone methylation pattern and preserve it through rounds of cell division. The molecular principles of epigenetic gene maintenance are essential for proper treatment and prevention of disorders and their complications. However, the principles of epigenetic gene programming are not resolved. Here we discuss some evidence of how the SET proteins determine the required states of target genes and maintain the required levels of their activity. We suggest that, along with other recognition pathways, SET domains can directly recognize the nucleosome and nucleic acids intermediates that are specific for active chromatin regions

Pulmonary Safety and Tolerability of Inhaled Levodopa (CVT-301) Administered to Patients with Parkinson\u27s Disease

BACKGROUND: CVT-301, an inhaled levodopa (LD) formulation, is under development for relief of OFF periods in Parkinson\u27s disease (PD). Previously, we reported that CVT-301 improved OFF symptoms relative to placebo. In this study, we evaluate pulmonary function in patients treated with a single dose of CVT-301 or placebo for 3 hours, or received multiple doses/day for 4 weeks. METHODS: As part of two phase 2 studies, pulmonary safety and tolerability of CVT-301 were evaluated in PD patients experiencing motor fluctuations (≥2 hours OFF/day), Hoehn and Yahr stage 1-3, and forced expiratory volume in 1 second/forced vital capacity ratio ≥75% of predicted (in ON state). In study A, patients received single doses of oral carbidopa/LD and each of the following via the inhaled route: placebo and 25 and 50 mg LD fine particle dose (FPD) CVT-301. In study B, patients received up to 3 inhaled doses/day of 35 mg (weeks 1-2) and 50 mg LD FPD CVT-301 (weeks 3-4) versus placebo. Assessments included spirometry and treatment-emergent adverse events (TEAEs). RESULTS: In study A, (n = 24) mean age ± standard deviation was 61.3 ± 7.4 years, mean time since diagnosis was 10.5 ± 4.6 years, and mean duration of LD treatment 8.4 ± 3.7 years. Assessment of pulmonary function (predose to 3 hours postdose) showed that spirometry findings were within normal ranges, regardless of treatment groups, or motor status at screening. In study B, (n = 86) mean age was 62.4 ± 8.7 years, time since PD diagnosis was 9.4 ± 3.9 years, and duration of LD treatment 7.8 ± 3.9 years. Longitudinal assessment of pulmonary function over 4 weeks showed no significant difference in spirometry between CVT-301 versus placebo groups. In both studies, the most common CVT-301 TEAE was mild-to-moderate cough (study A: 21%; study B: 7% vs. 2% in placebo). Other common TEAEs in study B were dizziness and nausea. CONCLUSION: Acute and longitudinal assessment of pulmonary function showed that CVT-301 treatment was not associated with acute airflow obstruction in this population. CVT-301 was generally safe and well tolerated

Inhaled levodopa (CVT-301 84mg) significantly improves motor function during off periods in Parkinson\u27s disease (PD) subjects: A phase 3 study (SPAN-PD™)

Objective: To evaluate efficacy and safety of CVT-301 vs placebo in PD subjects during OFF periods. Background: CVT-301, an investigational, inhaled therapy that delivers levodopa to the lungs, is intended to treat OFF periods for patients on a dopa-decarboxylase inhibitor/levodopa regimen. Methods: A 12-week, double-blind, placebo-controlled study of PD subjects experiencing motor fluctuations. Subjects were randomized to placebo, CVT-301 84mg or 60mg (1:1:1). Treatment was up to 5 times daily. Efficacy analyses were performed using a prespecified hierarchical testing. Primary efficacy endpoint: change in UPDRS part III score at 30min from pre-to postdose with CVT-301 84mg vs placebo at week 12 evaluated during an OFF period. Key secondary endpoints: ON responders within 60min; change in UPDRS part III score at 20min postdose; improvement in PGIC; change in UPDRS part III score at 10min postdose; and total daily OFF time. Safety profile, including pulmonary function, was assessed. Nominal P-values are presented for key secondary endpoints that were not statistically significant due to the hierarchy. Results: 339 randomized subjects received at least 1 dose of CVT-301 or placebo; 290 completed the study (mean age 63.3years, mean PD duration 8.3years, mean total OFF time 5.5hours). Primary endpoint was 29.8 for 84mg vs 25.9 for placebo (P50.009). At week-12, 58% on 84mg vs 36% on placebo were ON responders within 60min (P\u3c0.05), and 71% on 84mg vs 46% on placebo reported improvement in PGIC (nominal P\u3c0.05). 84mg vs placebo improved in UPDRS part III at 10min, which was sustained for 1hour. Most common AE for 84mg vs placebo was cough (14.9% vs 1.8%). Spirometry data showed no significant pulmonary safety indicators. Conclusion: Findings confirmed that compared with placebo, CVT-301 84mg showed a clinically meaningful response in the treatment of OFF periods, based on the Shulman criteria. CVT-301 was generally well tolerated