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Validation of Therapeutic Efficacy Targeting the Splicing Variants in Cystic Fibrosis and CFTR Pathologies (ONB-CFTR)

Primary Purpose

Cystic Fibrosis, CFTR Gene Mutation

Status
Recruiting
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Nasal cells sampling
Rectal biopsy sampling
Sponsored by
University Hospital, Montpellier
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Cystic Fibrosis focused on measuring genetics, cystic fibrosis, personalized therapy, Antisense OligoNucleotide strategy, splicing events, intronic variant

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Montpellier University HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Nasal cells sampling and/or rectal biospy

Arm Description

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.

Outcomes

Primary Outcome Measures

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.
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
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).

Secondary Outcome Measures

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).
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.
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.
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).
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).

Full Information

First Posted
September 6, 2021
Last Updated
March 28, 2023
Sponsor
University Hospital, Montpellier
Collaborators
Foch Hospital, Suresnes, FRANCE, Hôpital Necker-Enfants Malades, Hôpital Cochin
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1. Study Identification

Unique Protocol Identification Number
NCT05100823
Brief Title
Validation of Therapeutic Efficacy Targeting the Splicing Variants in Cystic Fibrosis and CFTR Pathologies
Acronym
ONB-CFTR
Official Title
Validation of Therapeutic Efficacy Targeting the Splicing Variants in Cystic Fibrosis and CFTR Pathologies
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 30, 2022 (Actual)
Primary Completion Date
March 30, 2025 (Anticipated)
Study Completion Date
March 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Montpellier
Collaborators
Foch Hospital, Suresnes, FRANCE, Hôpital Necker-Enfants Malades, Hôpital Cochin

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystic Fibrosis, CFTR Gene Mutation
Keywords
genetics, cystic fibrosis, personalized therapy, Antisense OligoNucleotide strategy, splicing events, intronic variant

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Nasal cells sampling and/or rectal biospy
Arm Type
Experimental
Arm Description
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.
Intervention Type
Procedure
Intervention Name(s)
Nasal cells sampling
Intervention Description
Nasal epithelium brushing in intermediate turbinate using a specific curette following a local anesthesia with Xylocaine 5% nebulizer.
Intervention Type
Procedure
Intervention Name(s)
Rectal biopsy sampling
Intervention Description
Forceps Biopsy Procedure (Servidoni et al., 2013) Only for volunteer patients included in the Montpellier center.
Primary Outcome Measure Information:
Title
Restoration of the correctly spliced CFTR mRNA (full length) using specific ONB-CFTR (designed for one splicing variant).
Description
The increase will be assessed in comparison to oligonucleotide-control effect by using semi-quantitative fluorescent PCR.
Time Frame
21 days after the air-liquid switch of epithelia (i.e. full differentiation)
Title
Restoration of the mature CFTR protein using specific ONB-CFTR (designed for one splicing variant).
Description
The increase will be assessed in comparison to oligonucleotide-control effect by using western blot
Time Frame
21 days after the air-liquid switch of epithelia (i.e. full differentiation)
Title
Restoration of CFTR channel function using specific ONB-CFTR (designed for one splicing variant).
Description
The increase will be assessed in comparison to oligonucleotide-control effect by using electrophysiological assays (Ussing chamber).
Time Frame
21 days after the air-liquid switch of epithelia (i.e. full differentiation)
Secondary Outcome Measure Information:
Title
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).
Description
The increase will be assessed in comparison to oligonucleotide-control effect by using semi-quantitative fluorescent PCR, western blot and electrophysiological assays (Ussing chamber).
Time Frame
21 days after the air-liquid switch of epithelia (i.e. full differentiation)
Title
Assessment of the amount of CFTR mRNA with normal splicing under the conditions tested.
Description
That parameter will be quantified in comparison to oligonucleotide-control effect by using quantitative PCR assays.
Time Frame
21 days after the air-liquid switch of epithelia (i.e. full differentiation)
Title
Assessment of the amount of mature CFTR proteins under the conditions tested.
Description
That parameter will be quantified in comparison to oligonucleotide-control effect by using western blot assays.
Time Frame
21 days after the air-liquid switch of epithelia (i.e. full differentiation)
Title
Assessment of the CFTR channel activity under the conditions tested.
Description
That parameter will be quantified in comparison to oligonucleotide-control effect by using electrophysiological assays (Ussing chamber).
Time Frame
21 days after the air-liquid switch of epithelia (i.e. full differentiation)
Title
Increase of CFTR channel function using ONB-CFTR and CFTR modulators (correctors and/or potentiators) under the conditions tested.
Description
The increase will be assessed in comparison to oligonucleotide-control effect by using electrophysiological assays (Ussing chamber).
Time Frame
21 days after the air-liquid switch of epithelia (i.e. full differentiation)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Anne Bergougnoux, PhD, PharmD
Phone
+33 411759879
Email
anne.bergougnoux@inserm.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Magali Taulan-Cadars, PhD
Phone
+33 411759846
Email
magali.taulan@inserm.fr
Facility Information:
Facility Name
Montpellier University Hospital
City
Montpellier
ZIP/Postal Code
34090
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anne Bergougnoux, phD, PharmD

12. IPD Sharing Statement

Learn more about this trial

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

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