Ignite Creation Date:
2024-05-06 @ 12:48 PM
Last Modification Date:
2024-10-26 @ 1:04 PM
Study NCT ID:
NCT03855631
Status:
COMPLETED
Last Update Posted:
2020-12-01
First Post:
2019-02-22
Brief Title:
Exploiting Epigenome Editing in Kabuki Syndrome a New Route Towards Gene Therapy for Rare Genetic Disorders
Sponsor:
University Hospital Montpellier
Organization:
University Hospital Montpellier
Study Overview
Official Title:
Exploiting Epigenome Editing in Kabuki Syndrome a New Route Towards Gene Therapy for Rare Genetic Disorders
Status:
COMPLETED
Status Verified Date:
2020-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Epi-KAB
Brief Summary:
Starting from isolating primary cells from affected patients an in vitro disease model system for KS will be developed Using alternative strategies to obtain patient-derived mesenchymal stem cells an integrative approach will be adopted for defining both the transcriptional and epigenetic regulatory networks perturbed upon the loss of function of KMT2D Combining the self-renewal potential of mesenchymal stem cells MSCs with CRISPRCas9 technology an epigenome editing approach as therapeutic strategy to rescue the activity of MLL4 will be developed
A step forward is expected towards the understanding of those the molecular mechanisms governing the aetiology of Kabuki Syndrome KS and that the proposed in vitro disease model will provide to the scientific community an experimental system to study the KS Importantly the aim is to define the molecular bases of KS and to develop a therapeutic strategy that could ameliorate some of the abnormalities associated with KS
A step forward is expected towards the understanding of those the molecular mechanisms governing the aetiology of Kabuki Syndrome KS and that the proposed in vitro disease model will provide to the scientific community an experimental system to study the KS Importantly the aim is to define the molecular bases of KS and to develop a therapeutic strategy that could ameliorate some of the abnormalities associated with KS
Detailed Description:
Main and secondary objectives
The main objective is to study the pathological role of ML mutations in KS to facilitate the identification and characterization of therapeutic strategies to improve the symptoms of patients with KS Due to the lack of treatment in the KS the aim is to develop a model of this disease from fibroblasts from patients and reprogram them into mesenchymal stem cells This approach will generate a KS-specific stem cell bio-bank allowing the identification of common disturbances caused by the loss of function LoF of KMT2D The impact of the KMT2D LoF on transcription but also the epigenetic mechanisms activated during MSC differentiation will be described Finally the therapeutic potential of an epigenome editing approach to increase the expression of the wild KMT2D allele to restore the functional activity of MLL4 in treated MSCs will be evaluated
The secondary objective is to evaluate the ability to return to normal after CRISPRCase9 gene therapy treatment on patients cells
Methodology design study population description of groups if applicable inclusion criteria non-inclusion main and secondary judgment criteria number of subjects to be included statistical analysis
Starting from primary cells isolated from affected patients an in vitro model of the disease will be developed An integrative but alternative strategy approach to obtain mesenchymal stem cells derived from patients to define normal and abnormal transcription and epigenetic circuits during KMT2D LoF will be adopted By combining the autonomous renewal potential of MSCs with CRISPRCas9 technology an approach to editing the epigenome for therapeutic purposes to restore MLL4 activity will be developed
This project will represent a step forward in understanding the molecular mechanisms responsible for KS The in vitro model will provide the scientific community with an experimental system to study KS Finally the aim is to define the molecular basis of KS and develop a therapeutic strategy to improve certain symptoms in patients with KS
Process number of visits duration of inclusions duration of follow-up
8 people will be included 4 patients with Kabuki syndrome authenticated by the molecular genetics study of the KMT2D gene
4 parents of the same sex as the patient
Feasibility
In the clinical genetics department of the Montpellier University Hospital more than 40 patients with Kabuki syndrome are followed
Impacts prospects
The identification of the consequences of mutations in the KMT2D gene on epigenetic mark changes and cellular structural changes as well as the attempt at gene correction by CRISPRCas9 will provide a better understanding of the disease and the genes that are deregulated by post-KMT2D epigenetic changes and will also open a promising path for gene therapy by CRISPRCas9 method
The main objective is to study the pathological role of ML mutations in KS to facilitate the identification and characterization of therapeutic strategies to improve the symptoms of patients with KS Due to the lack of treatment in the KS the aim is to develop a model of this disease from fibroblasts from patients and reprogram them into mesenchymal stem cells This approach will generate a KS-specific stem cell bio-bank allowing the identification of common disturbances caused by the loss of function LoF of KMT2D The impact of the KMT2D LoF on transcription but also the epigenetic mechanisms activated during MSC differentiation will be described Finally the therapeutic potential of an epigenome editing approach to increase the expression of the wild KMT2D allele to restore the functional activity of MLL4 in treated MSCs will be evaluated
The secondary objective is to evaluate the ability to return to normal after CRISPRCase9 gene therapy treatment on patients cells
Methodology design study population description of groups if applicable inclusion criteria non-inclusion main and secondary judgment criteria number of subjects to be included statistical analysis
Starting from primary cells isolated from affected patients an in vitro model of the disease will be developed An integrative but alternative strategy approach to obtain mesenchymal stem cells derived from patients to define normal and abnormal transcription and epigenetic circuits during KMT2D LoF will be adopted By combining the autonomous renewal potential of MSCs with CRISPRCas9 technology an approach to editing the epigenome for therapeutic purposes to restore MLL4 activity will be developed
This project will represent a step forward in understanding the molecular mechanisms responsible for KS The in vitro model will provide the scientific community with an experimental system to study KS Finally the aim is to define the molecular basis of KS and develop a therapeutic strategy to improve certain symptoms in patients with KS
Process number of visits duration of inclusions duration of follow-up
8 people will be included 4 patients with Kabuki syndrome authenticated by the molecular genetics study of the KMT2D gene
4 parents of the same sex as the patient
Feasibility
In the clinical genetics department of the Montpellier University Hospital more than 40 patients with Kabuki syndrome are followed
Impacts prospects
The identification of the consequences of mutations in the KMT2D gene on epigenetic mark changes and cellular structural changes as well as the attempt at gene correction by CRISPRCas9 will provide a better understanding of the disease and the genes that are deregulated by post-KMT2D epigenetic changes and will also open a promising path for gene therapy by CRISPRCas9 method
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None