Kabuki Syndrome 1Epi-KABNCT03855631
Exploiting Epigenome Editing in Kabuki Syndrome: a New Route Towards Gene Therapy for Rare Genetic Disorders
An observational study of Kabuki Syndrome 1, run by University Hospital, Montpellier at 1 site in France.
Trial 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… Read more about this study
- Who is it for?
- Ages 6 years and older
- Conditions the study is for
- Kabuki Syndrome 1
- What is being tested?
- Intervention on primary cultured cells
- How many people
- 8 participants
- Where
- 1 siteFrance
- Study dates
- 28 Sep 2020to 27 Nov 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Pediatric population with KS and healthy adult (unaffected sex match parents of patients)
Who may be able to join
- For the patient = to have a Kabuki syndrome authenticated by molecular genetics (proof of mutation in the KMT2D gene)
- For parents = having the same sex as your child
- To be affiliated to a French social security system
- Authorize the participation of the study
Who cannot join
- Not be affiliated to a social security scheme (CMU is included)
- Existence of a significant coagulation ruble (especially thrombocytopenic purpura in Kabuki patients with platelet counts < 20,000 Units).
- Genetic skin disease responsible for poor healing
- Refusal to participate in the child's and/or parent's study
Trial locations and contacts
1 site in 1 country.
About this study
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 CRISPR/Cas9 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.
Read the 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 CRISPR/Case9 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 CRISPR/Cas9 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 CRISPR/Cas9 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 CRISPR/Cas9 method.
- Conditions
- Kabuki Syndrome 1
- Being tested
- Intervention on primary cultured cells
- Keywords
- Kabuki syndrome CRIPSR/Cas9 KMT2D
- Medical subject headings
- Kabuki syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Intervention on primary cultured cellsGenetic
The intervention includes primary cultured cells, reprograming them into mesenchymal stem cells and CRISPR/Case9 gene therapy treatment on patients' cells
| Study group | Role | What they receive |
|---|---|---|
| Kabuki syndrome/ unaffected parents | Intervention on primary cultured cells from 4 patients with KS and sex match parents Receives: Genetic: Intervention on primary cultured cells |
What is being measured
The primary outcome is the main question the study is designed to answer.
success rate of fibroblasts culture
The aim is to establish a model of KS disease from fibroblasts from patients
Measured: one year maximum after inclusion
Secondary outcomes (2)
success rate of turning fibroblasts into mesenchymal stem cells
The aim is to determine the success rate of turning fibroblasts into mesenchymal stem cells
Measured: one year maximum after inclusion
success rate of CRISPR/Case9 gene therapy treatment on patients' cells
The aim is to evaluate the ability to return to normal after CRISPR/Case9 gene therapy treatment on patients' cells
Measured: one year maximum after inclusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Feb 2019
- Study start28 Sep 2020
- Primary completion27 Nov 2020
- Study completion27 Nov 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Kabuki Syndrome 1Studies of the same condition, open and under way.
- More trials run by University Hospital, MontpellierThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Montpellier
- Sponsor type
- University, hospital or other
- Collaborators
- Association Française contre les Myopathies Telethon
- Responsible party
- Sponsor
- Investigators
- Alessio Zippo, PhD, Principal investigator, Center of Integrative Biology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03855631
- Sponsor's protocol ID
- RECHMPL18_0242
- Acronym
- Epi-KAB
- Status last verified
- Nov 2020
- First submitted
- 22 Feb 2019
- Last updated
- 1 Dec 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Exploiting Epigenome Editing in Kabuki Syndrome: a New Route Towards Gene Therapy for Rare Genetic Disorders
- ClinicalTrials.gov ID
- NCT03855631
- Acronym / sponsor ID
- Epi-KAB / RECHMPL18_0242
- Conditions
- Kabuki Syndrome 1
- Keywords
- Kabuki syndrome CRIPSR/Cas9 KMT2D
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- University Hospital, MontpellierUniversity, hospital or other
- Collaborators
- Association Française contre les Myopathies Telethon
- Study start
- 28 Sep 2020 (actual)
- Primary completion
- 27 Nov 2020 (actual)
- Study completion
- 27 Nov 2020 (actual)
- First posted
- 27 Feb 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 CRISPR/Cas9 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.
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 CRISPR/Case9 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 CRISPR/Cas9 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 CRISPR/Cas9 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 CRISPR/Cas9 method.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Kabuki syndrome/ unaffected parents | – | Genetic: Intervention on primary cultured cellsIntervention on primary cultured cells from 4 patients with KS and sex match parents |
Who may qualify
- Ages
- 6 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Pediatric population with KS and healthy adult (unaffected sex match parents of patients)
Key inclusion criteria (4 listed)
- For the patient = to have a Kabuki syndrome authenticated by molecular genetics (proof of mutation in the KMT2D gene)
- For parents = having the same sex as your child
- To be affiliated to a French social security system
- Authorize the participation of the study
Key exclusion criteria (4 listed)
- Not be affiliated to a social security scheme (CMU is included)
- Existence of a significant coagulation ruble (especially thrombocytopenic purpura in Kabuki patients with platelet counts < 20,000 Units).
- Genetic skin disease responsible for poor healing
- Refusal to participate in the child's and/or parent's study
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Intervention on primary cultured cellsThe intervention includes primary cultured cells, reprograming them into mesenchymal stem cells and CRISPR/Case9 gene therapy treatment on patients' cells | Genetic | Kabuki syndrome/ unaffected parents |
Primary outcome
success rate of fibroblasts culture
Time frame: one year maximum after inclusion
The aim is to establish a model of KS disease from fibroblasts from patients
2 secondary outcomes
success rate of turning fibroblasts into mesenchymal stem cells
Time frame: one year maximum after inclusion
success rate of CRISPR/Case9 gene therapy treatment on patients' cells
Time frame: one year maximum after inclusion
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Dec 2020.
Related trials for Kabuki Syndrome 1
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Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
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RecruitingObservational study
Characterization and Contribution of Genome-wide DNA Methylation (DNA Methylation Episignatures) in Rare Diseases With Prenatal Onset
Rare Fetal Genetic Diseases, Congenital Malformation
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alessio Zippo, PhD principal investigator
Center of Integrative Biology
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Kabuki Syndrome 1, run by University Hospital, Montpellier at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
success rate of fibroblasts culture (time frame: one year maximum after inclusion). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Dec 2020.