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

Cystic Fibrosis Clinical Trial

— ONB-CFTR  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05100823
• Other study ID #: RECHMPL20_0423
• Secondary ID: 2020-A03529-30
• Status: Recruiting
• Phase: N/A
• Start date: March 30, 2022
• Est. completion date: September 30, 2027

Study information

• Verified date: November 2023
• Source: University Hospital, Montpellier
• Contact: Anne Bergougnoux, PhD, PharmD
• Phone: +33 411759879
• Email: anne.bergougnoux[@]inserm.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: September 30, 2027
• Est. primary completion date: September 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Procedure:
• Nasal cells sampling
Nasal epithelium brushing in intermediate turbinate using a specific curette following a local anesthesia with Xylocaine 5% nebulizer.
• Rectal biopsy sampling
Forceps Biopsy Procedure (Servidoni et al., 2013) Only for volunteer patients included in the Montpellier center.

Locations

Country	Name	City	State
France	Montpellier University Hospital	Montpellier

Sponsors (4)

Lead Sponsor	Collaborator
University Hospital, Montpellier	Foch Hospital, Suresnes, FRANCE, Hôpital Cochin, Hôpital Necker-Enfants Malades

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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	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).	The increase will be assessed in comparison to oligonucleotide-control effect by using semi-quantitative fluorescent PCR, western blot and electrophysiological assays (Ussing chamber).	21 days after the air-liquid switch of epithelia (i.e. full differentiation)
Secondary	Assessment of the amount of CFTR mRNA with normal splicing under the conditions tested.	That parameter will be quantified in comparison to oligonucleotide-control effect by using quantitative PCR assays.	21 days after the air-liquid switch of epithelia (i.e. full differentiation)
Secondary	Assessment of the amount of mature CFTR proteins under the conditions tested.	That parameter will be quantified in comparison to oligonucleotide-control effect by using western blot assays.	21 days after the air-liquid switch of epithelia (i.e. full differentiation)
Secondary	Assessment of the CFTR channel activity under the conditions tested.	That parameter will be quantified 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	Increase of CFTR channel function using ONB-CFTR and CFTR modulators (correctors and/or potentiators) under the conditions tested.	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)