AMEERA-1 phase 1/2 study of amcenestrant, SAR439859, in postmenopausal women with ER-positive/HER2-negative advanced breast cancer.

AMEERA-1 is a Phase 1/2 open-label single-arm study evaluating once-daily (QD) amcenestrant, an orally bioavailable selective estrogen receptor (ER) degrader, in postmenopausal women with ER+/HER2- advanced breast cancer (NCT03284957), who were mostly heavily pretreated (including targeted therapies and fulvestrant). In the dose escalation phase (Part A: n = 16), patients received amcenestrant 20-600 mg QD. Based on absence of dose-limiting toxicities, paired functional 18F-fluoroestradiol positron emission tomography, and pharmacokinetics, 400 mg QD was selected as recommended Phase 2 dose (RP2D) for the dose expansion phase (Part B: n = 49). No Grade ≥3 treatment-related adverse events or clinically significant cardiac/eye toxicities were reported. The Part B primary endpoint, confirmed objective response rate (ORR) was 3/45 at the interim analysis and 5/46 (10.9%) at the final analysis. The overall clinical benefit rate (CBR) was 13/46 (28.3%). CBRs among patients with baseline wild-type and mutated ESR1 were 9/26 (34.6%) and 4/19 (21.1%), respectively. Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations, including Y537S. In conclusion, amcenestrant at RP2D of 400 mg QD for monotherapy is well-tolerated with no dose-limiting toxicities, and demonstrates preliminary antitumor activity irrespective of baseline ESR1 mutation status.

Dupilumab pharmacokinetics in Chinese healthy subjects and patients with atopic dermatitis: Results of two randomized, double-blind, placebo-controlled studies.

BACKGROUND: Dupilumab, a fully human monoclonal antibody targeting IL-4Rα, has demonstrated rapid and sustained improvements in clinical outcomes in patients with atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps. METHODS: In a phase 1, double-blind, ascending-dose study, 30 healthy Chinese adults were randomized to single subcutaneous doses of dupilumab 200, 300, 600 mg, or placebo. In a phase 3, double-blind study, 165 Chinese adults with AD were randomized to dupilumab 300 mg or placebo every 2 weeks. RESULTS: Following single doses of dupilumab 200, 300, and 600 mg in the phase 1 study, mean serum maximum concentrations (Cmax) were 25.4 ± 4.0, 37.2 ± 14.5, and 77.3 ± 19.0 mg/L, respectively. For a 1.5-fold increase in dupilumab dose, 1.31-, 1.73-, and 1.66-fold increases in Cmax, area under the curve to real time (AUClast), and extrapolated to infinity (AUC) were observed, respectively, while a 2-fold dose increase resulted in 2.17-, 2.81-, and 2.80-fold increases, respectively. In the phase 3 study, mean dupilumab trough concentrations were 78.8 ± 32.0 and 86.4 ± 33.6 mg/L at weeks 12 and 16, respectively. CONCLUSIONS: Cmax increased approximately proportionally to dose, while AUC and AUClast increased greater than proportionally. Dupilumab pharmacokinetics were generally comparable between Chinese and non-Asian healthy subjects (single dose) and between Chinese and non-Asian AD patients (repeated doses), with differences accounted for by body weight. As differences in exposure by weight are unlikely to be clinically relevant based on late-stage study results, no dose adjustment by ethnic origin or weight is required.

Bioequivalence Study Comparing Fixed-Dose Combination of Clopidogrel and Aspirin with Coadministration of Individual Formulations in Chinese Subjects Under Fed Conditions: A Phase I, Open-Label, Randomized, Crossover Study.

INTRODUCTION: Simultaneous administration of acetylsalicylic acid (ASA) and clopidogrel has demonstrated efficacy in the treatment of acute coronary syndrome. Clopidogrel + ASA in a fixed-dose combination (FDC) provides a pharmaceutical option to enhance adherence to the coadministration of dual antiplatelet therapy (DAPT). Herein, we evaluate the bioequivalence of enteric ASA and clopidogrel in an FDC compared with simultaneous administration of the individual formulations. METHODS: This study is a randomized, single-center, open-label, three-sequence, three-period, two-treatment, crossover study conducted in healthy Chinese male and female subjects under fed conditions. Subjects were randomized to receive, in each period, a single dose of (1) a combination tablet containing 75-mg clopidogrel and 100-mg enteric ASA (test formulation) or (2) coadministration of one 75-mg clopidogrel tablet and one 100-mg enteric-coated ASA tablet (reference formulations) under fed conditions. Plasma samples were analyzed for ASA, salicylic acid, clopidogrel, and the clopidogrel metabolite SR26334. For ASA, the reference-scaled average bioequivalence (RSABE) analysis was conducted for Cmax of ASA because within-subject standard deviation (SDW) was ≥ 0.294 for log-transformed Cmax. RESULTS: The point estimate (test/reference geometric mean ratio) was between 0.80 and 1.25, and the upper one-sided 95% confidence interval (CI) for the scaled average bioequivalence metric was ≤ 0 (-0.08). AUC of ASA as SDW was < 0.294 for log-transformed AUClast and AUC. Estimates of 90% CIs for log-transformed AUClast and AUC ratios were within the bioequivalence range of 0.80 to 1.25 (0.98-1.08 and 1.00-1.10, respectively). For clopidogrel, the 90% CIs for the ratios comparing log-transformed Cmax, AUClast, and AUC ratios of clopidogrel following administration of test versus reference formulation were calculated using the ABE method and were well within the acceptable range of 0.80 to 1.25 (1.02-1.12, 0.92-0.99, and 0.92-0.98, respectively). CONCLUSION: FDC of ASA and clopidogrel was bioequivalent to the simultaneous administration of the individual formulations in healthy Chinese subjects under fed conditions. TRIAL REGISTRATION: CTR20190376.

Translational strategy using multiple nuclear imaging biomarkers to evaluate target engagement and early therapeutic efficacy of SAR439859, a novel selective estrogen receptor degrader.

PURPOSE: Preclinical in vivo nuclear imaging of mice offers an enabling perspective to evaluate drug efficacy at optimal dose and schedule. In this study, we interrogated sufficient estrogen receptor occupancy and degradation for the selective estrogen receptor degrader (SERD) compound SAR439859 using molecular imaging and histological techniques. MATERIAL AND METHODS: [18F]FluoroEstradiol positron emission tomography (FES-PET), [18F]FluoroDeoxyGlucose (FDG) PET, and [18F]FluoroThymidine (FLT) PET were investigated as early pharmacodynamic, tumor metabolism, and tumor proliferation imaging biomarkers, respectively, in mice bearing subcutaneous MCF7-Y537S mutant ERα+ breast cancer model treated with the SERD agent SAR439859. ER expression and proliferation index Ki-67 were assessed by immunohistochemistry (IHC). The combination of palbociclib CDK 4/6 inhibitor with SAR439859 was tested for its potential synergistic effect on anti-tumor activity. RESULTS: After repeated SAR439859 oral administration over 4 days, FES tumoral uptake (SUVmean) decreases compared to baseline by 35, 57, and 55% for the 25 mg/kg qd, 12.5 mg/kg bid and 5 mg/kg bid treatment groups, respectively. FES tumor uptake following SAR439859 treatment at different doses correlates with immunohistochemical scoring for ERα expression. No significant difference in FDG uptake is observed after SAR439859 treatments over 3 days. FLT accumulation in tumor is significantly decreased when palbociclib is combined to SAR439859 (- 64%) but not different from the group dosed with palbociclib alone (- 46%). The impact on proliferation is corroborated by Ki-67 IHC data for both groups of treatment. CONCLUSIONS: In our preclinical studies, dose-dependent inhibition of FES tumoral uptake confirmed target engagement of SAR439859 to ERα. FES-PET thus appears as a relevant imaging biomarker for measuring non-invasively the impact of SAR439859 on tumor estrogen receptor occupancy. This study further validates the use of FLT-PET to directly visualize the anti-proliferative tumor effect of the palbociclib CDK 4/6 inhibitor alone and in combination with SAR439859.

Implementation of a Reference-Scaled Average Bioequivalence Approach for Highly Variable Acetylsalicylic Acid in Fixed-Dose Combination with Clopidogrel Versus Enteric Aspirin in Chinese Subjects Under Fasting Conditions: A Phase 1, Open-Label, Randomized, Crossover Study.

INTRODUCTION: Dual antiplatelet therapy, aspirin and a P2Y12 inhibitor, is recommended to prevent thrombotic complications of acute coronary syndrome. Clopidogrel plus acetylsalicylic acid combination is the most commonly used dual antiplatelet therapy recommended by international guidelines and in Chinese clinical practice. Poor adherence to dual antiplatelet therapy or premature interruption of dual antiplatelet therapy is an important contributor to cardiovascular mortality and lethal cardiovascular events. Clopidogrel + acetylsalicylic acid fixed-dose combination enhances adherence to dual antiplatelet therapy. Herein, we aimed to evaluate bioequivalence of acetylsalicylic acid and clopidogrel in fixed-dose combination compared with simultaneous administration of their individual formulations in healthy Chinese subjects under fasting conditions. METHODS: This was a randomized, single-center, open-label, three-sequence, three-period, two-treatment, crossover study with a washout period of 10 days conducted in healthy Chinese volunteers. Subjects were randomized to receive Co-Plavix® (test formulation- fixed-dose combination of 100 mg acetylsalicylic acid and 75 mg clopidogrel) once and reference formulations (coadministration of individual formulations of 100 mg acetylsalicylic acid and 75 mg clopidogrel) twice during the study period. Pharmacokinetic parameters were analyzed for acetylsalicylic acid, its metabolite salicylic acid, clopidogrel, and its metabolite SR26334. As acetylsalicylic acid shows high intrasubject variability, the reference-scaled average bioequivalence (RSABE) approach was implemented for acetylsalicylic acid analysis, while bioequivalence of clopidogrel was assessed using the average bioequivalence method. Point ratios and confidence intervals (CIs) for AUC, AUClast, and Cmax for acetylsalicylic acid and clopidogrel were calculated. RESULTS: In total, 171 healthy subjects were enrolled in this study. Subjects were randomized and 170 subjects were treated with test or reference formulation; 164 subjects completed the study. Regarding acetylsalicylic acid exposure, as reference within-subject standard deviation (SDW) was at least 0.294 for acetylsalicylic acid Cmax, AUClast, and AUC, the RSABE analysis method was used to assess bioequivalence for all three parameters. The point estimates were within the 0.80-1.25 range (1.19, 1.09, and 1.04, respectively), and upper one-sided 95% CIs of scaled average bioequivalence metric were at most 0 (- 0.30, - 0.14, and - 0.10, respectively). Thus, bioequivalence was demonstrated with acetylsalicylic acid. Bioequivalence was also achieved with clopidogrel as the 90% CIs for geometric mean ratios of clopidogrel Cmax, AUClast, and AUC were within the bioequivalence range (0.80-1.25). CONCLUSION: Application of the reference-scaled average bioequivalence approach to evaluate bioequivalence of acetylsalicylic acid in Chinese male and female healthy volunteers under fasting conditions demonstrated bioequivalence of test and reference formulations. TRIAL REGISTRATION: CTR20181695.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Dupilumab in Healthy Adult Subjects.

Dupilumab is a fully human monoclonal antibody directed against the interleukin (IL)-4 receptor α subunit (IL-4Rα) of IL-4 heterodimeric type I and type II receptors that mediate IL-4/IL-13 signaling through this pathway. Blockade of these receptors broadly suppresses type 2 inflammation associated with atopic/allergic diseases, including atopic dermatitis and asthma. Six phase 1 studies investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of dupilumab in healthy subjects. Two randomized, double-blind, placebo-controlled, sequential studies assessed safety and tolerability of single escalating dupilumab doses administered intravenously or subcutaneously (one included various racial groups, and one included exclusively Japanese subjects); 3 randomized, parallel-group, single-dose studies compared the pharmacokinetic profiles of different dupilumab products and formulations after single subcutaneous doses; and one study assessed dupilumab administered as fast versus slow subcutaneous injections. Dupilumab concentrations in serum were measured in all studies, and total immunoglobulin E (IgE) and thymus- and activation-regulated chemokine (TARC) concentrations were measured in 2 studies as pharmacodynamic markers. Across the phase 1 studies, dupilumab exhibited target-mediated pharmacokinetics consisting of parallel linear and nonlinear elimination, with the target-mediated phase highly dominated by nonlinearity at lower drug concentrations. Systemic exposure and tolerability of dupilumab were consistent irrespective of differences in product, formulation, or racial background. Dupilumab reduced circulating concentrations of total IgE and TARC, indicating blockade of IL-4Rα-mediated signaling. Dupilumab had a favorable safety profile across the wide range of doses administered. Together, these findings support the continued development and use of dupilumab in treatment of type 2 diseases.

Cytogenetics and holoprosencephaly: A chromosomal microarray study of 222 individuals with holoprosencephaly.

Holoprosencephaly (HPE), a common developmental forebrain malformation, is characterized by failure of the cerebrum to completely divide into left and right hemispheres. The etiology of HPE is heterogeneous and a number of environmental and genetic factors have been identified. Cytogenetically visible alterations occur in 25% to 45% of HPE patients and cytogenetic techniques have long been used to study copy number variants (CNVs) in this disorder. The karyotype approach initially demonstrated several recurrent chromosomal anomalies, which led to the identification of HPE-specific loci and, eventually, several major HPE genes. More recently, higher-resolution cytogenetic techniques such as subtelomeric multiplex ligation-dependent probe amplification and chromosomal microarray have been used to analyze chromosomal anomalies. By using chromosomal microarray, we sought to identify submicroscopic chromosomal deletions and duplications in patients with HPE. In an analysis of 222 individuals with HPE, a deletion or duplication was detected in 107 individuals. Of these 107 individuals, 23 (21%) had variants that were classified as pathogenic or likely pathogenic by board-certified medical geneticists. We identified multiple patients with deletions in established HPE loci as well as three patients with deletions encompassed by 6q12-q14.3, a CNV previously reported by Bendavid et al. In addition, we identified a new locus, 16p13.2 that warrants further investigation for HPE association. Incidentally, we also found a case of Potocki-Lupski syndrome, a case of Phelan-McDermid syndrome, and multiple cases of 22q11.2 deletion syndrome within our cohort. These data confirm the genetically heterogeneous nature of HPE, and also demonstrate clinical utility of chromosomal microarray in diagnosing patients affected by HPE.

A Quantitative Systems Pharmacology Platform to Investigate the Impact of Alirocumab and Cholesterol-Lowering Therapies on Lipid Profiles and Plaque Characteristics.

Reduction in low-density lipoprotein cholesterol (LDL-C) is associated with decreased risk for cardiovascular disease. Alirocumab, an antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduces LDL-C. Here, we report development of a quantitative systems pharmacology (QSP) model integrating peripheral and liver cholesterol metabolism, as well as PCSK9 function, to examine the mechanisms of action of alirocumab and other lipid-lowering therapies, including statins. The model predicts changes in LDL-C and other lipids that are consistent with effects observed in clinical trials of single or combined treatments of alirocumab and other treatments. An exploratory model to examine the effects of lipid levels on plaque dynamics was also developed. The QSP platform, on further development and qualification, may support dose optimization and clinical trial design for PCSK9 inhibitors and lipid-modulating drugs. It may also improve our understanding of factors affecting therapeutic responses in different phenotypes of dyslipidemia and cardiovascular disease.

Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development.

Kabuki syndrome (KS) is a rare multiple congenital anomaly syndrome characterized by distinctive facial features, global developmental delay, intellectual disability and cardiovascular and musculoskeletal abnormalities. While mutations in KMT2D have been identified in a majority of KS patients, a few patients have mutations in KDM6A. We analyzed 40 individuals clinically diagnosed with KS for mutations in KMT2D and KDM6A. Mutations were detected in KMT2D in 12 and KDM6A in 4 cases, respectively. Observed mutations included single-nucleotide variations and indels leading to frame shifts, nonsense, missense or splice-site alterations. In two cases, we discovered overlapping chromosome X microdeletions containing KDM6A. To further elucidate the functional roles of KMT2D and KDM6A, we knocked down the expression of their orthologs in zebrafish. Following knockdown of kmt2d and the two zebrafish paralogs kdm6a and kdm6al, we analyzed morphants for developmental abnormalities in tissues that are affected in individuals with KS, including craniofacial structures, heart and brain. The kmt2d morphants exhibited severe abnormalities in all tissues examined. Although the kdm6a and kdm6al morphants had similar brain abnormalities, kdm6a morphants exhibited craniofacial phenotypes, whereas kdm6al morphants had prominent defects in heart development. Our results provide further support for the similar roles of KMT2D and KDM6A in the etiology of KS by using a vertebrate model organism to provide direct evidence of their roles in the development of organs and tissues affected in KS patients.

Chromosome 1p36.22p36.21 duplications/triplication causes Setleis syndrome (focal facial dermal dysplasia type III).

Focal facial dermal dysplasias (FFDD) are characterized by congenital bitemporal or preauricular atrophic skin lesions, and either autosomal dominant or autosomal recessive inheritance. Setleis syndrome (SS), FFDD type III, is a severe form of FFDD with the ectodermal lesions plus other striking facial features. Autosomal recessive nonsense and frameshift mutations in TWIST2 have been found to cause SS in some but not all individuals. Here, we report on four unrelated individuals, one with an unclassified FFDD and the other three with classic SS. Chromosomal microarray analyses revealed unique copy number variants of 1p36 in two individuals with duplications at 1p36.22p36.21 and one with a triplication at 1p36.22p36.21. The fourth patient had normal chromosomes by microarray analysis. All four patients had normal TWIST2 exonic sequences. We propose that a dosage effect of one or more of the 30 genes in the 1.3 Mb 1p36.22p36.21 region of overlap is responsible for FFDD/SS manifestations in some individuals, and this mechanism would be inherited as an autosomal dominant trait. In patients with no duplication/triplication of the 1p36.22p36.21 region and no mutations in TWIST2, there are mutation(s) in one of the 30 genes in this region or mutations in other as yet unidentified genes at different locations that may affect the expressions of genes in this region or act independently to cause this developmental disease phenotype.

Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Severe atopic dermatitis (AD) has a high unmet need for effective and safe therapeutics. In early-phase trials, dupilumab, a fully human mAb targeting IL-4 receptor α, markedly improved disease activity, but the effect of IL-4/IL-13 blockade on AD at the molecular level has not been characterized. OBJECTIVES: We sought to evaluate dupilumab modulation of the AD molecular signature. METHODS: We performed transcriptomic analyses of pretreatment and posttreatment skin biopsy specimens from patients with moderate-to-severe AD treated weekly with 150 or 300 mg of dupilumab or placebo. RESULTS: Exacerbation of the AD transcriptome was observed in placebo-treated patients. Dupilumab improved the AD signature in a dose-dependent manner. Expression of genes upregulated in AD lesions decreased in patients treated with dupilumab by 26% (95% CI, 21% to 32%) and 65% (95% CI, 60% to 71%) for treatment with 150 and 300 mg, respectively. Genes downregulated in AD lesions increased by 21% (95% CI, 16% to 27%) and 32% (95% CI, 26% to 37%) with dupilumab (150 and 300 mg, respectively). The molecular changes paralleled improvements in clinical scores. A dupilumab treatment signature of 821 probes (>2-fold change, P < .05) significantly modulated in the 300-mg dupilumab group at week 4 compared with baseline was identified in this sample set. Significant (P < .05) decreases in mRNA expression of genes related to hyperplasia (K16 and MKI67), T cells, and dendritic cells (CD1b and CD1c) and potent inhibition of TH2-associated chemokines (CCL17, CCL18, CCL22, and CCL26) were noted without significant modulation of TH1-associated genes (IFNG). CONCLUSIONS: This is the first report showing rapid improvement of the AD molecular signature with targeted anti-IL-4 receptor α therapy. These data suggest that IL-4 and IL-13 drive a complex, TH2-centered inflammatory axis in patients with AD.

Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)-mediated inflammation could help in the treatment of related diseases, including atopic dermatitis. METHODS: We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigator's global assessment score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome. RESULTS: In the 4-week monotherapy studies, dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptome. The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigator's global assessment (P<0.001); and pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group (P<0.001). In the combination study, 100% of the patients in the dupilumab group, as compared with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P=0.002), despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids used by those who received placebo plus the topical medication (P=0.16). Adverse events, such as skin infection, occurred more frequently with placebo; nasopharyngitis and headache were the most frequent adverse events with dupilumab. CONCLUSIONS: Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not dose-limiting. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and NCT01548404.).

Dupilumab in persistent asthma with elevated eosinophil levels.

BACKGROUND: Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels. METHODS: We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs). We administered dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled glucocorticoids during weeks 6 through 9. Patients received the study drug for 12 weeks or until a protocol-defined asthma exacerbation occurred. The primary end point was the occurrence of an asthma exacerbation; secondary end points included a range of measures of asthma control. Effects on various type 2 helper T-cell (Th2)-associated biomarkers and safety and tolerability were also evaluated. RESULTS: A total of 52 patients were assigned to the dupilumab group, and 52 patients were assigned to the placebo group. Baseline characteristics were similar in the two groups. Three patients had an asthma exacerbation with dupilumab (6%) versus 23 with placebo (44%), corresponding to an 87% reduction with dupilumab (odds ratio, 0.08; 95% confidence interval, 0.02 to 0.28; P<0.001). Significant improvements were observed for most measures of lung function and asthma control. Dupilumab reduced biomarkers associated with Th2-driven inflammation. Injection-site reactions, nasopharyngitis, nausea, and headache occurred more frequently with dupilumab than with placebo. CONCLUSIONS: In patients with persistent, moderate-to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABAs and inhaled glucocorticoids were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01312961.).

Molecular analysis of the Noggin (NOG) gene in holoprosencephaly patients.

Holoprosencephaly (HPE) is the most common structural anomaly of the human forebrain. Various genetic and teratogenic causes have been implicated in its pathogenesis. A recent report in mice described Noggin (NOG) as a candidate gene involved in the etiogenesis of microform HPE. Here, we present for the first time genetic analysis of a large HPE cohort for sequence variations in NOG. On the basis of our study, we conclude that mutations in the coding region of NOG are rare, and play at most an uncommon role in human HPE.

Revision of "A 223-kb de novo deletion of PAX9 in a patient with oligodontia".

The PAX (paired box) genes are a family of transcription factors critical for fetal growth and organogenesis. Abnormalities of PAX2, PAX3, PAX6, and PAX9 are associated with various congenital craniofacial anomalies, including tooth abnormalities. We present here a boy with oligodontia. Dental radiographs showed that he lacked primary molars and was missing most of his permanent teeth. A genome-wide single-nucleotide polymorphism-based microarray revealed a de novo 223-kb heterozygous deletion on 14q13.3 that included the PAX9 gene. The findings in this patient illustrate the role of the PAX9 gene in tooth development and provide the first example of a de novo deletion of 14q13.3 manifesting primarily with oligodontia. This report also supports the utility of genome-wide microarrays in determining the genetic cause of craniofacial abnormalities.

Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome.

Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.

A 223-kb de novo deletion of PAX9 in a patient with oligodontia.

The PAX (paired box) genes are a family of transcription factors critical for fetal growth and organogenesis. Abnormalities of PAX2, PAX3, PAX6, and PAX9 are associated with various congenital craniofacial anomalies, including tooth abnormalities. We present here a boy with oligodontia and language delay. Dental x-rays showed that he lacked primary molars and was missing most of his permanent teeth. A genome-wide, single-nucleotide polymorphism-based microarray revealed a de novo 223-kb heterozygous deletion on 14q13.3 that included the PAX9 gene. In addition, the array showed 2 copies of the X chromosome and 1 copy of the Y chromosome, diagnostic for Klinefelter syndrome. The findings in this patient illustrate the role of the PAX9 gene in tooth development and provide the first example of a de novo deletion of 14q13.3 manifesting primarily with oligodontia. This report also supports the utility of genome-wide microarrays in determining the genetic cause of craniofacial abnormalities.

Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR.

Several studies have examined the link between the cannabinoid CB1 receptor and several neuropsychiatric illnesses, including schizophrenia. As such, there is a need for in vivo imaging tracers so that the relationship between CB1 and schizophrenia (SZ) can be further studied. In this paper, we present our first human studies in both healthy control patients and patients with schizophrenia using the novel PET tracer, [(11)C]OMAR (JHU75528), we have shown its utility as a tracer for imaging human CB1 receptors and to investigate normal aging and the differences in the cannabinoid system of healthy controls versus patients with schizophrenia. A total of ten healthy controls and nine patients with schizophrenia were included and studied with high specific activity [(11)C]OMAR. The CB1 binding (expressed as the distribution volume; V(T)) was highest in the globus pallidus and the cortex in both controls and patients with schizophrenia. Controls showed a correlation with the known distribution of CB1 and decline of [(11)C]OMAR binding with age, most significantly in the globus pallidus. Overall, we observed elevated mean binding in patients with schizophrenia across all regions studied, and this increase was statistically significant in the pons (p<0.05), by the Students t-test. When we ran a regression of the control subjects V(T) values with age and then compared the patient data to 95% prediction limits of the linear regression, three patients fell completely outside for the globus pallidus, and in all other regions there were at least 1-3 patients outside of the prediction intervals. There was no statistically significant correlations between PET measures and the individual Brief Psychiatry Rating Score (BPRS) subscores (r=0.49), but there was a significant correlation between V(T) and the ratio of the BPRS psychosis to withdrawal score in the frontal lobe (r=0.60), and middle and posterior cingulate regions (r=0.71 and r=0.79 respectively). In conclusion, we found that [(11)C] OMAR can image human CB1 receptors in normal aging and schizophrenia. In addition, our initial data in subjects with schizophrenia seem to suggest an association of elevated binding specific brain regions and symptoms of the disease.

Genetic syndromic immunodeficiencies with antibody defects.

This article reviews the major syndromic immunodeficiencies with significant antibody defects, many of which may require intravenous immunogammaglobulin therapy. The authors define syndromic immunodeficiency as an illness associated with a characteristic group of phenotypic abnormalities or laboratory features that comprise a recognizable syndrome. Many are familial with a defined inheritance pattern. Immunodeficiency may not be a major part of the illness and may not be present in all patients; thus, these conditions differ from primary immunodeficiency syndromes, in which immune abnormalities are a consistent and prominent feature of their disease.