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

NCT05100823 | Terminated

• 2 other identifiers: RECHMPL20_04232020-A03529-30
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cystic Fibrosis; CFTR Gene Mutation

Keywords

genetics; cystic fibrosis; personalized therapy; Antisense OligoNucleotide strategy; splicing events; intronic variant

Outcome Measures

Primary Outcomes (3)

• 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.

  21 days after the air-liquid switch of epithelia (i.e. full differentiation)

• Restoration of the mature CFTR protein using specific ONB-CFTR (designed for one splicing variant).

  The increase will be assessed in comparison to oligonucleotide-control effect by using western blot

  21 days after the air-liquid switch of epithelia (i.e. full differentiation)

• Restoration of CFTR channel function using specific ONB-CFTR (designed for one splicing variant).

  The increase will be assessed in comparison to oligonucleotide-control effect by using electrophysiological assays (Ussing chamber).

  21 days after the air-liquid switch of epithelia (i.e. full differentiation)

Secondary Outcomes (5)

• Restoration of the correctly spliced CFTR mRNA (full length) and mature CFTR protein and CFTR channel function using a pool of ONB-CFTR (a mix of specific ONB-CFTR).

  21 days after the air-liquid switch of epithelia (i.e. full differentiation)

• Assessment of the amount of CFTR mRNA with normal splicing under the conditions tested.

  21 days after the air-liquid switch of epithelia (i.e. full differentiation)

• Assessment of the amount of mature CFTR proteins under the conditions tested.

  21 days after the air-liquid switch of epithelia (i.e. full differentiation)

• Assessment of the CFTR channel activity under the conditions tested.

  21 days after the air-liquid switch of epithelia (i.e. full differentiation)

• Increase of CFTR channel function using ONB-CFTR and CFTR modulators (correctors and/or potentiators) under the conditions tested.

  21 days after the air-liquid switch of epithelia (i.e. full differentiation)

Study Arms (1)

Nasal cells sampling and/or rectal biospy

EXPERIMENTAL

Depending of the patient' genotype, specific ONB-CFTR (50 nM) will be incubated at the apical face of in vitro epithelium, alone and in combination with CFTR modulators. Efficacy of ONB will be compared to a condition with oligonucleotide control incubation. Rectal biopsies from volunteer patients were stored as a bio-bank of organoids.

Procedure: Nasal cells sampling; Procedure: Rectal biopsy sampling

Interventions

Nasal cells sampling PROCEDURE

Nasal epithelium brushing in intermediate turbinate using a specific curette following a local anesthesia with Xylocaine 5% nebulizer.

Nasal cells sampling and/or rectal biospy

Rectal biopsy sampling PROCEDURE

Forceps Biopsy Procedure (Servidoni et al., 2013) Only for volunteer patients included in the Montpellier center.

Nasal cells sampling and/or rectal biospy

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• the subject has thrombocytopenia
• the subject has a bleeding disorder
• The patient has severe inflammation of the rectum.

Sponsors & Collaborators

• University Hospital, Montpellier: lead
• Foch Hospital, Suresnes, FRANCE: collaborator
• Hôpital Necker-Enfants Malades: collaborator
• Hôpital Cochin: collaborator

Study Sites (1)

Montpellier University Hospital

Montpellier, 34090, France

Location

MeSH Terms

Conditions

Cystic Fibrosis

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2021
• First Posted: October 29, 2021
• Study Start: March 30, 2022
• Primary Completion: February 17, 2025
• Study Completion: February 17, 2025
• Last Updated: September 18, 2025

Record last verified: 2025-09

Locations

FR (1)