Exploiting Epigenome Editing in Kabuki Syndrome: a New Route Towards Gene Therapy for Rare Genetic Disorders
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- success rate of fibroblasts culture
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 6 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
结局指标
主要结局
success rate of fibroblasts culture
时间窗: one year maximum after inclusion
The aim is to establish a model of KS disease from fibroblasts from patients
次要结局
- success rate of turning fibroblasts into mesenchymal stem cells(one year maximum after inclusion)
- success rate of CRISPR/Case9 gene therapy treatment on patients' cells(one year maximum after inclusion)