Triple treatment with elexacaftor, tezacaftor, and ivacaftor in patients with cystic fibrosis who had one Phe508del allele and a minimal-function mutation resulted in sustained improvement in FEV
1
, ...sweat chloride concentration, and the number of pulmonary exacerbations.
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a ...CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.
This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40–90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548.
Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean LSM treatment difference of 10·0 percentage points 95% CI 7·4 to 12·6, p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference −45·1 mmol/L 95% CI −50·1 to −40·1, p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points 95% CI 11·8 to 23·0, p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor.
Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.
Vertex Pharmaceuticals.
This companion article to the VX-445 report shows that VX-659, a new CFTR potentiator, when administered with tezacaftor and ivacaftor improved lung function, sweat chloride concentration, and ...symptoms in patients with cystic fibrosis who harbored one or two Phe508del alleles.
This preclinical, phase 2 report shows that VX-445, a CFTR potentiator when administered with tezacaftor and ivacaftor, improved lung function and reduced sweat chloride concentrations and symptoms ...in patients harboring one or two Phe508del alleles.
It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used ...next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with -7 and 7q- developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (
) that result in diminished quantity and/or function of the CFTR anion channel.
, the most common ...CF-causing mutation (found in ∼90% of patients), causes severe processing and trafficking defects, resulting in decreased CFTR quantity and function. CFTR modulators are medications that increase the amount of mature CFTR protein (correctors) or enhance channel function (potentiators) at the cell surface. Combinations of CFTR correctors and potentiators (
lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous for
-CFTR and a minimal function mutation,
a mutation that produces either no protein or protein that is unresponsive to currently approved CFTR modulators. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and function
and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two
-
alleles. Here, we present the rationale and design of four randomised phase 3 studies, and their open-label extensions, evaluating VX-659 (ECLIPSE) or VX-445 (AURORA) plus tezacaftor and ivacaftor in patients with one or two
-
alleles.
Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously ...undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions.
We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants.
Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.Arg26Glnx1, p.Gly36Valx1, p.Arg38Trpx2, p.Arg38Glnx1, p.Gly51Argx2, p.Ser54Argx2, p.Asn124Lysx5) and one the homeodomain (p.Asn260Tyrx1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease.
Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.
Hepatic injury and chronic wounding are characterized by increased synthesis of extracellular matrix proteins including hyaluronan (HA). Recently, it has been recognized that low‐molecular‐weight ...fragments of HA, but not native HA (e.g., high‐molecular‐weight HA), induce inflammatory gene expression, and activate the transcriptional regulator, nuclear factor κB (NF‐κB). The inducible isoform of nitric oxide synthase (iNOS) is induced by cytokines and/or lipopolysaccharide (LPS) through the NF‐κB signal transduction pathway. Because of this association, we hypothesized that HA fragments might also stimulate iNOS gene transcription. The aims of this study were therefore to determine whether HA or HA fragments induced iNOS in hepatic cells, and to characterize the signaling pathway. HA fragments (100 μg/mL) markedly stimulated iNOS messenger RNA (mRNA) in endothelial and Kupffer cells, but minimally induced this mRNA in hepatocytes and stellate cells. High‐molecular‐weight HA (200 μg/mL) had no effect on iNOS mRNA in any cell type. The addition of interferon gamma (IFN‐γ) to HA fragments resulted in stimulation of iNOS mRNA 2‐, 3‐, 4‐, and 10‐fold above that for HA fragments alone in hepatocytes, endothelial, Kupffer, and stellate cells, respectively. The combination of HA fragments and LPS did not result in an incremental increase in iNOS mRNA induction. iNOS protein and nitrite levels (used as a measure of NO production and NOS enzymatic activity) paralleled closely iNOS mRNA expression and increased proportionally to HA fragment concentration in a dose‐dependent fashion. At 1 hour following stimulation, NF‐κB DNA binding activity was detected in extracts from Kupffer cells stimulated with HA fragments, but not in those exposed to media alone or to high‐molecular‐weight HA. Finally, inhibitors of NF‐κB blocked HA fragment–dependent iNOS mRNA induction in Kupffer and sinusoidal endothelial cells. The data indicate that HA fragments, but not high‐molecular‐weight HA, induce iNOS in liver, having the greatest effects on endothelial and Kupffer cells. We speculate that HA fragments may be an important stimulus for NO production in various forms of liver disease, particularly as a cofactor with inflammatory cytokines.
Hyaluronan (HA) is a glycosaminoglycan constituent of extracellular matrix. In its native form HA exists as a high molecular weight polymer, but during inflammation lower molecular weight fragments ...accumulate. We have identified a collection of inflammatory genes induced in macrophages by HA fragments but not by high molecular weight HA. These include several members of the chemokine gene family: macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, cytokine responsive gene-2, monocyte chemoattractant protein-1, and regulated on activation, normal T cell expressed and secreted. HA fragments as small as hexamers are capable of inducing expression of these genes in a mouse alveolar macrophage cell line, and monoclonal antibody to the HA receptor CD44 completely blocks binding of fluorescein-labeled HA to these cells and significantly inhibits HA-induced gene expression. We also investigated the ability of HA fragments to induce chemokine gene expression in human alveolar macrophages from patients with idiopathic pulmonary fibrosis and found that interleukin-8 mRNA is markedly induced. These data support the hypothesis that HA fragments generated during inflammation induce the expression of macrophage genes which are important in the development and maintenance of the inflammatory response.
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