Role of ACTG2 Variants in Smooth Muscle Determination and Function in Pediatric Intestinal Pseudo-obstruction.

NCT06687564 | Not Yet Recruiting

• 2 other identifiers: 38RC23.03682024-A01516-41
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 3

Brief Summary

The primary objective of this study is to describe the transcriptional impact of R178, R257, R40 or A136 variants of the ACTG2 gene on iPS differentiation mechanisms up to organoids derived from PIPO patient samples versus those derived from control / WT patients (generation of IPS from cultured cell lines), at different stages of their experimental ex vivo development.

Conditions

PIPO

Keywords

PIPO; CIPO; ACTG2; pseudo-obstruction; organoid; iPS; Pediatric Intestinal Pseudo-Obstruction; Chronic Intestinal Pseudo-obstruction

Outcome Measures

Primary Outcomes (1)

• Description of the transcriptional impact of R178, R257, R40 or A136 variants of the ACTG2 gene

  Difference in transcript expression (%) in RNASeq transcriptomic analysis between samples carrying the R178, R257, R40 or A136 variants of the ACTG2 gene on the differentiation mechanisms of iPS up to organoids derived from PIPO patient samples versus those derived from control patients

  At different stages of their experimental ex vivo development (mesenchymal progenitors, determined smooth muscle cells, differentiated smooth muscle cells and 3D organization of smooth muscle) through study completion, an average of 5 years

Secondary Outcomes (5)

• Evaluate the impact of R178, R257, R40 or A136 variants of the ACTG2 gene on gastrointestinal contractile function between mutant versus WT organoids.

  At different stages of their experimental ex vivo development (mesenchymal progenitors, determined smooth muscle cells, differentiated smooth muscle cells and 3D organization of smooth muscle) an average of 5 years

• Evaluate the immunofluorescence labeling differential between mutant and WT cells from IPS and organoids

  At different stages of their experimental ex vivo development (mesenchymal progenitors, determined smooth muscle cells, differentiated smooth muscle cells and 3D organization of smooth muscle) an average of 5 years

• Evaluate the impact of R178, R257, R40 or A136 mutations of the ACTG2 gene on the actin network of fibroblasts derived from skin samples of diseased patients versus those of WTpatients.

  At different stages of their experimental ex vivo development (mesenchymal progenitors, determined smooth muscle cells, differentiated smooth muscle cells and 3D organization of smooth muscle) an average of 5 years

• Evaluate the effect of reversion of the R178, R257, R40 or A136 mutation versus WT on functionality and contractility during differentiation of cells into organoids.

  At different stages of their experimental ex vivo development (mesenchymal progenitors, determined smooth muscle cells, differentiated smooth muscle cells and 3D organization of smooth muscle) an average of 5 years

• Assessing the potential of a chemical library to correct the phenotype

  At different stages of their experimental ex vivo development (mesenchymal progenitors, determined smooth muscle cells, differentiated smooth muscle cells and 3D organization of smooth muscle) an average of 5 years

Study Arms (2)

PIPO patients

EXPERIMENTAL

PIPO patients with variants of interest

Procedure: Biopsy

WT

OTHER

Control arm, same experiments as for patients. Samples from specific cell lines

Procedure: Biopsy

Interventions

Biopsy PROCEDURE

A skin biopsy and a blood sample will be taken to culture the iPS cells and intestinal organoids.

Also known as: Blood sample

PIPO patients; WT

Eligibility Criteria

• Age: 4 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• PIPO Population:
• Minor or adult patient ≥ 4 years of age
• Patient with PIPO before age 18
• Male or female
• Patient with PIPO meeting at least 2 of the ESPGHAN criteria (Thapar et al 2018) and carrying the R178, R257, R40 or A136 mutation of the ACTG2 gene.
• Patient whose assent has been obtained and whose legal guardians have given their written informed consent
• Patient affiliated to the French Social Security system or benefiting from an equivalent plan
• WT population:
• \- iPS cell lines MS573 or WT8288 or 202CT or SD378M, from the Nantes University Hospital biological collection and generated from samples from control patients without POIC who have consented to donate their samples.

You may not qualify if:

• PIPO population :
• Patients with a history of radiotherapy treatment
• Patient with lymphocyte lineage damage

Sponsors & Collaborators

• University Hospital, Grenoble: lead

Study Sites (3)

Phymedexp Inserm U1046 - Cnrs Umr 9214

Montpellier, 34295, France

Location

Tens - Inserm Un Umr 1235

Nantes, 44035, France

Location

AP-HP Hôpital Robert Debré

Paris, 75019, France

Location

Related Publications (5)

• Zenzeri L, Tambucci R, Quitadamo P, Giorgio V, De Giorgio R, Di Nardo G. Update on chronic intestinal pseudo-obstruction. Curr Opin Gastroenterol. 2020 May;36(3):230-237. doi: 10.1097/MOG.0000000000000630.

  PMID: 32073506 BACKGROUND

• Fournier N, Fabre A. Smooth muscle motility disorder phenotypes: A systematic review of cases associated with seven pathogenic genes (ACTG2, MYH11, FLNA, MYLK, RAD21, MYL9 and LMOD1). Intractable Rare Dis Res. 2022 Aug;11(3):113-119. doi: 10.5582/irdr.2022.01060.

  PMID: 36200034 BACKGROUND

• Assia Batzir N, Kishor Bhagwat P, Larson A, Coban Akdemir Z, Baglaj M, Bofferding L, Bosanko KB, Bouassida S, Callewaert B, Cannon A, Enchautegui Colon Y, Garnica AD, Harr MH, Heck S, Hurst ACE, Jhangiani SN, Isidor B, Littlejohn RO, Liu P, Magoulas P, Mar Fan H, Marom R, McLean S, Nezarati MM, Nugent KM, Petersen MB, Rocha ML, Roeder E, Smigiel R, Tully I, Weisfeld-Adams J, Wells KO; Baylor-Hopkins Center for Mendelian Genomics; Posey JE, Lupski JR, Beaudet AL, Wangler MF. Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy. Hum Mutat. 2020 Mar;41(3):641-654. doi: 10.1002/humu.23960. Epub 2019 Dec 19.

  PMID: 31769566 BACKGROUND

• de Santa Barbara P, van den Brink GR, Roberts DJ. Development and differentiation of the intestinal epithelium. Cell Mol Life Sci. 2003 Jul;60(7):1322-32. doi: 10.1007/s00018-003-2289-3.

  PMID: 12943221 BACKGROUND

• Mahe MM, Brown NE, Poling HM, Helmrath MA. In Vivo Model of Small Intestine. Methods Mol Biol. 2017;1597:229-245. doi: 10.1007/978-1-4939-6949-4_17.

  PMID: 28361322 BACKGROUND

MeSH Terms

Conditions

Intestinal Pseudo-Obstruction

Interventions

Biopsy; Blood Specimen Collection

Condition Hierarchy (Ancestors)

Ileus; Intestinal Obstruction; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Punctures

Central Study Contacts

John Rendu, Dr

CONTACT

0476765573; jrendu@chu-grenoble.fr

Mandy Leger

CONTACT

0476768410; mleger@chu-grenoble.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Experimental, descriptive, prospective, non-randomized, controlled, comparative, monocentric in recruitment but multicentric study in procedures and analyses.

Study Record Dates

• First Submitted: October 11, 2024
• First Posted: November 13, 2024
• Study Start: February 1, 2025
• Primary Completion (Estimated): November 1, 2030
• Study Completion (Estimated): November 1, 2030
• Last Updated: January 22, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (3)