Validation of Therapeutic Efficacy Targeting the Splicing Variants in Cystic Fibrosis and CFTR Pathologies

University Hospital, Montpellier16 enrolled

Overview

Cystic Fibrosis, an inherited autosomal recessive disease, arises from mutations in the CFTR gene. For intronic mutations affecting splicing events, oligonucleotides therapy has the potential to restore the production of the full length CFTR protein. Recent scientific research has demonstrated the potential of this approach to restore full length mRNA CFTR in in vitro human airway cells. The study aims to validate the therapeutic efficacy of oligonucleotide blockers (ONB) that target splicing defects associated to splicing variants in epithelia obtained from patients with Cystic Fibrosis and CFTR-related disorders.

The study will include patients with various CFTR genotypes. The assessment of ONB (named ONB-CFTR) will be performed using an air-liquid interface model of airway epithelium, developed from nasal cells of patients, without or with a combination of existing CFTR modulators, depending on the patient' genotype. This study will also aim to build a local biobank of rectal organoids from patients (only from Montpellier, France) carrying rare CFTR disease-causing variants.

Study Type

INTERVENTIONAL

Allocation

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Cystic Fibrosis CFTR Gene Mutation

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

Inclusion Criteria: * The subject must have given their free and informed consent and signed the consent * The subject must be affiliated or beneficiary of a health insurance plan Women and men are included * The patient is at least 12 years old. * The patient has cystic fibrosis or a CFTR pathology and therefore carries two mutations (with at least one mutation affecting splicing) in the CFTR gene. * Patients who volunteer for rectal biopsy collection (only from Montpellier University Hospital) must be at least 18 years old. Exclusion Criteria: * The subject is in a period of exclusion determined by a previous study. * The subject is under judicial protection, under guardianship or under curatorship * The subject does not accept to sign consent * It turns out to be impossible to give informed information to the subject * The subject does not read the French language fluently * The subject is a pregnant or breastfeeding woman * The subject has porphyria, or has hepatic insufficiency, or suffers from epilepsy, or suffers from conduction disorders, or suffers from severe heart failure, has a cons-indication to the use of a local anesthetic spray. Specific non-inclusion criteria for rectal sampling: * the subject has thrombocytopenia * the subject has a bleeding disorder * The patient has severe inflammation of the rectum.

Outcomes

Primary Outcomes

Restoration of the correctly spliced CFTR mRNA (full length) using specific ONB-CFTR (designed for one splicing variant).

The increase will be assessed in comparison to oligonucleotide-control effect by using semi-quantitative fluorescent PCR.