Search results for " CYSTIC FIBROSIS"

PTC124 derivatives as a novel approach to improve the readthrough of premature stop codons in the CFTR gene.

2011

Background Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Approximately 10% (worldwide) of patients have in-frame nonsense mutations (UAA, UAG or UGA class I mutations) in the CF trans-membrane regulator (CFTR) gene that result in premature stop codons (PTCs) in the messenger RNA (mRNA) generating truncated CFTR protein responsible for a severe CF phenotype. Pharmacological approaches have been proposed to directly overcome PTCs. Ataluren (PTC124) a small molecule that mimics the activity of aminoglycosides has been suggested to allow PTCs readthrough and to partially restore the protein function. However, des…

COMBINING TRANSLATION READTHROUGH INDUCING DRUGS AND NONSENSE MEDIATED DECAY PATWHAY INHIBITION TO THE CFTR RESCUE IN CYSTIC FIBROSIS CELL MODEL SYST…

2021

Nonsense mutations affect 10% of patients with cystic fibrosis and produce a premature termination codon in CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) mRNA causing early termination of translation and leading to lack of CFTR function. A potential therapy for nonsense mutations provides the use of small molecules able to overcome the premature stop codon (PTC) by a readthrough mechanism that lead to synthesis a complete CFTR protein. Despite the good results obtained from this approach, TRIDs efficiency is considerably reduced by the poor amount of target transcript, that is the mRNA containing the PTC. The readthrough, indeed, does not occur on the totality of target transcr…

PTC124 DERIVATIVES AS A NOVEL APPROACH TO IMPROVE THE READTHROUGH OF PREMATURE AMBER AND OCHRE STOP CODONS

2013

Nucleotide changes within an exon may alter the trinucleotide normally encoding a particular amino acid, such that a new “stop” signal is transcribed into the mRNA open reading frame. This causes the ribosome to prematurely terminate its reading of the mRNA, leading to the lack of production of a normal full-length protein. Such premature termination codon (PTC) mutations occur in an estimated 10% to 15% of many genetically based disorders (1). Pathological nonsense mutations resulting in TAG (40.4%), TGA (38.5%), and TAA (21.1%) occur in different proportions to naturally occurring stop codons (2). Several genetic disorders are characterized by opal (TGA; Cystic fibrosis, Duchenne/Becker m…

EVALUATION OF POLYAMINOACIDIC POLYMERS AS GENE TRANFER AGENTS TO RESPIRATORY EPITHELIAL CELLS AND OF THEIR BIOPHYSICAL PROPERTIES IN THE PRESENCE OF …

2010

BIOCOMPATIBLE POLYAMINOACID-BASED POLYCATIONS AS NON-VIRAL VECTORS FOR GENE THERAPY OF CYSTIC FIBROSIS.

2009

ADIPONECTIN, LEPTIN, RESISTIN LEVELS IN CYSTIC FIBROSIS ADOLESCENTS

2012

INTRODUCTION: Patients with Cystic Fibrosis, especially in adolescence, could develop endocrine and metabolic complications, related to nutritional state and chronic inflammation. They develop a progressive decrease in lean body mass correlated with the progression of lung disease. Adipose tissue is involved as well and adipocytokines are a possible link between malnutrition and long term complications. PATIENTS AND METHODS: In 24 Cystic Fibrosis adolescents we studied auxological, nutritional, glycometabolic, endocrine patterns, together with leptin, adiponectin and resistin levels. We selected patients not affected by diabetes, insulin resistance, malnutrition, acute inflammatory states s…

Nano into Micro Formulations of Tobramycin for the Treatment of Pseudomonas aeruginosa Infections in Cystic Fibrosis.

2017

Here, nano into micro formulations (NiMs) of tobramycin for the treatment of Pseudomonas aeruginosa airway infections in cystic fibrosis (CF) are described. NiMs were produced by spray drying a solution containing polymers or sugars and a nanometric polyanion–tobramcyin complex (PTC), able to achieve a prolonged antibiotic release. NiMs properties were compared to TOBIPodhaler(Novartis), the only one commercially available dry powder inhalatory formulation based on porous microparticles. Produced NiMs showed adequate characteristics for pulmonary administration, as spherical shape, micrometric size, and high cytocompatibility toward human bronchial epithelial cells. Contrarily to TOBIPodhal…

Integrated computational and experimental approaches for the identification of new molecules with readthrough activity on premature termination codon…

2015

Rescuing CFTR Protein Function: 1,3,4-oxadiazoles versus 1,2,4-oxadiazoles as readthrough inducing drugs

In Cystic fibrosis (CF) disease nonsense mutations in the CFTR gene cause the absence of the CFTR protein expression and a more severe form of the disease. About 10% of patient affected by CF show a nonsense mutation. A potential treatment of this alteration is to promote translational readthrough of premature termination codons (PTCs) by translational readthrough inducing drugs such as Ataluren (1). We reported a rationale for Ataluren promoted readthrough of PTCs by computational approach and GFP-reporter cell-based assay (2) and the observed enhancement of readthrough activity by some Ataluren derivatives (3, 4). In this context we aimed to compare the 1,2,4-oxadiazole core of Ataluren w…

OXADIAZOLE DERIVATIVES FOR THE TREATMENT OF GENETIC DISEASES DUE TO NONSENSE MUTATIONS

2018

Are disclosed oxadiazole derivatives, their use as medicaments and in particular for the treatment of diseases associated with the presence of a nonsense mutation in the gene or a premature stop codon in the mRNA, pharmaceutical formulation comprising said oxadiazole derivatives and prodrug or mixture thereof and the methods for the preparation of said Oxadiazole derivatives.