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Rett syndrome is a rare, genetic neurodevelopmental disorder. Trofinetide is a synthetic analog of glycine–proline–glutamate, the N-terminal tripeptide of the insulin-like growth factor 1 protein, and has demonstrated clinical benefit in phase 2 studies in Rett syndrome. In this phase 3 study ( https://clinicaltrials.gov identifier NCT04181723 ), females with Rett syndrome received twice-daily oral trofinetide ( n  = 93) or placebo ( n  = 94) for 12 weeks. For the coprimary efficacy endpoints, least squares mean (LSM) change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire for trofinetide versus placebo was −4.9 versus −1.7 ( P  = 0.0175; Cohen’s d effect size, 0.37), and LSM Clinical Global Impression–Improvement at week 12 was 3.5 versus 3.8 ( P  = 0.0030; effect size, 0.47). For the key secondary efficacy endpoint, LSM change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant–Toddler Checklist Social Composite score was −0.1 versus −1.1 ( P  = 0.0064; effect size, 0.43). Common treatment-emergent adverse events included diarrhea (80.6% for trofinetide versus 19.1% for placebo), which was mostly mild to moderate in severity. Significant improvement for trofinetide compared with placebo was observed for the coprimary efficacy endpoints, suggesting that trofinetide provides benefit in treating the core symptoms of Rett syndrome. Results from the LAVENDER phase 3 study demonstrate that trofinetide, a synthetic analog of glycine–proline–glutamate, provides significant therapeutic benefits in the core symptoms of Rett syndrome

Background and Objective Trofinetide, a synthetic analog of tripeptide glycine-proline-glutamate, is an investigational agent for the treatment of Rett syndrome, a neurodevelopmental disorder with affected individuals requiring lifelong support. Food can affect the pharmacokinetic profile of a drug, and this phase 1 study assessed the potential effect of food on the pharmacokinetics of trofinetide. The study also evaluated the potential effect of evening dosing on trofinetide bioavailability and characterized the pharmacokinetic profile of trofinetide in urine. Methods A 60 mL oral solution of trofinetide (12 g) was administered in three dosing periods: morning fasted (A; reference), morning fed (B), and evening fasted (C). Healthy adult subjects (18−45 years) were randomized to sequence ABC ( n = 19) or BAC ( n = 22). Blood and urine samples were collected at scheduled timepoints for trofinetide pharmacokinetic analysis. Bioequivalence was confirmed if 90% confidence intervals for geometric mean ratio between B/A or C/A fell within 80–125% equivalence limits for area under the concentration-time curve (AUC) and maximum concentration ( C max ) in whole blood. Results Bioequivalence criteria were met for all conditions (i.e., morning fed vs. morning fasted and evening fasted vs. morning fasted) except C max in the fed versus fasted condition, which was just below the bioequivalence limit (75.49%), suggesting a negligible food effect and lack of diurnal variation on bioavailability. Trofinetide was primarily excreted unchanged in urine. Trofinetide was well tolerated, and there were no significant changes in vital signs or laboratory parameters. Conclusion This study supports dosing of trofinetide without regard to food.

Inflammasomes are multiprotein complexes nucleating around an NLR (Nucleotide-binding domain and Leucine-rich Repeat containing protein), which regulate the secretion of the pro-inflammatory interleukin (IL)-1β and IL-18 cytokines. Monocytes and macrophages, the main cells expressing the inflammasome genes, adapt to their surrounding microenvironment by a phenotypic polarization towards a pro-inflammatory M1 phenotype that promotes inflammation or an anti-inflammatory M2 phenotype important for resolution of inflammation. Despite the importance of inflammasomes in health and disease, little is known about inflammasome gene expression in relevant human cells and the impact of monocyte and macrophage polarization in inflammasome gene expression. We examined the expression of several members of the NLR, caspase and cytokine family, and we studied the activation of the well-described NLRP3 inflammasome in an experimental model of polarized human primary monocytes and monocyte-derived macrophages (M1/M2 phenotypes) before and after activation with LPS, a well-characterized microbial pattern used in inflammasome activation studies. Our results show that the differentiation of monocytes to macrophages alters NLR expression. Polarization using IFN-γ (M1 phenotype), induces among the NLRs studied, only the expression of NOD2. One of the key results of our study is that the induction of NLRP3 expression by LPS is inhibited in the presence of IL-4+IL-13 (M2 phenotype) at both mRNA and protein level in monocytes and macrophages. Unlike caspase-3, the expression of inflammasome-related CASP1 (encodes caspase-1) and CASP4 (encodes caspase-4) is up-regulated in M1 but not in M2 cells. Interestingly, the presence of LPS marginally influenced IL18 mRNA expression and secretion, unlike its impact on IL1B. Our data provide the basis for a better understanding of the role of different inflammasomes within a given environment (M1 and M2) in human cells and their impact in the pathophysiology of several important inflammatory disorders.

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder due to MEFV mutations and one of the most frequent Mediterranean genetic diseases. The observation of many heterozygous patients in whom a second mutated allele was excluded led to the proposal that heterozygosity could be causal. However, heterozygosity might be coincidental in many patients due to the very high rate of mutations in Mediterranean populations. To better delineate the pathogenicity of heterozygosity in order to improve genetic counselling and disease management. Complementary statistical approaches were used: estimation of FMF prevalence at population levels, genotype comparison in siblings from 63 familial forms, and genotype study in 557 patients from four Mediterranean populations. At the population level, we did not observe any contribution of heterozygosity to disease prevalence. In affected siblings of patients carrying two MEFV mutations, 92% carry two mutated alleles, whereas 4% are heterozygous with typical FMF diagnosis. We demonstrated statistically that patients are more likely to be heterozygous than healthy individuals, as shown by the higher ratio heterozygous carriers/non carriers in patients (p<10(-7)-p<0.003). The risk for heterozygotes to develop FMF was estimated between 2.1 × 10(-3) and 5.8 × 10(-3) and the relative risk, as compared to non carriers, between 6.3 and 8.1. This is the first statistical demonstration that heterozygosity is not responsible for classical Mendelian FMF per se, but constitutes a susceptibility factor for clinically-similar multifactorial forms of the disease. We also provide a first estimate of the risk for heterozygotes to develop FMF.

A number of issues limit the utility of the definitions and classifications of autoinflammatory disease proposed to date. In this Perspectives, the authors propose a new clinically-based definition and classification of autoinflammatory diseases. In addition, a potential future approach to classification of the entire spectrum of immunological diseases is discussed. The notion of 'autoinflammatory' disease was introduced at the end of the 1990s, and, since then, this concept has rapidly evolved. As a result, multiple definitions of autoinflammatory disease, and classifications of conditions encompassed by these definitions, have been proposed; this succession highlights advances that have been made in understanding of the innate immune system, and especially the roles of IL-1β and the inflammasome in autoinflammtory conditions. However, the definitions and classifications that have been suggested to date face a number of structure and content issues. We therefore propose another, more clinically-oriented, definition: autoinflammatory diseases are diseases with clinical signs of inflammation, associated with elevated levels of acute-phase reactants, which are attributable to dysfunction of the innate immune system, genetically-determined or triggered by an endogenous factor. From this foundation, we propose a clinically-based classification of autoinflammatory diseases, and go on to discuss how immunological diseases as a whole, including autoimmune diseases, can be appropriately located within a continuum only if the classification process is multidimensional. For this purpose, we appeal to the philosophical concepts of family resemblance and signature.

We report on a familial Mediterranean fever (FMF) patient homozygous for p.M694V in the MEFV gene who developed chronic myelomonocytic leukemia (CMML) leading to an uncontrolled and fatal inflammatory syndrome. Plasma levels of IL-6 and IL-18 were found to be very high, as compared to healthy controls and CMML-free FMF patients. Our study unveils the interplay between two different disorders involving the same target cells, suggesting that in myelodysplasia with inflammatory manifestations, mutations in genes causing autoinflammatory syndromes, like MEFV , can be present and thus could be sought. Early chemotherapy with interleukin inhibitors could be proposed in such unusual situations.

We report on a familial Mediterranean fever (FMF) patient homozygous for p.M694V in the MEFV gene who developed chronic myelomonocytic leukemia (CMML) leading to an uncontrolled and fatal inflammatory syndrome. Plasma levels of IL-6 and IL-18 were found to be very high, as compared to healthy controls and CMML-free FMF patients.Our study unveils the interplay between two different disorders involving the same target cells, suggesting that in myelodysplasia with inflammatory manifestations, mutations in genes causing autoinflammatory syndromes, like MEFV, can be present and thus could be sought. Early chemotherapy with interleukin inhibitors could be proposed in such unusual situations.