PromoTeRapy · Haploinsufficiency and Intractable Epilepsy Rescue Increasing Endogenous Gene Promoter Efficiency
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-02-01 → 2018-01-31
- EU contribution
- €195,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Haploinsufficiency and Intractable Epilepsy Rescue Increasing Endogenous Gene PromoterEfficiency
The possibility to regulate gene expression for gene therapy without adding new extra genes potentially can revolutionise this field. But at the moment there are not scientific evidences to prove that this is feasible. PromoTerapy demonstrated that is possible to treat acquired or genetic epilepsies modifying gene expression. It has been the first time that was possible to increase the activity of genes without inserting new extra genes in the DNA. We used this system to restore normal level of a gene which loss of function cause a severe childhood epilepsy with autistic features (Dravet syndrome) but also to increase a protective gene against acquired intractable epilepsy induced by hippocampal damage. This project is important for the society because is the first proof of principle that severe diseases can be cured with new gene editing techniques. Diseases that till now had no treatments available.
Data: CORDIS, © European Union
Project objective
This proposal will develop a new tool to rescue haploinsufficiency, which underlies many genetic disorders of neuronal excitability, and provide a new approach to treatment of intractable epilepsy. This new tool is based on the CRISPR-On technology which can regulate the expression of endogenous genes by directly targeting their promoters, which allows expression of the full panoply of splice variants and untranslated regulatory sequences. Importantly, the method does not require integrating exogenous genes into the genome, which has potential risks of insertional mutagenesis. Haploinsufficency of SCN1A, which encodes the sodium channel Nav1.1, leads to Dravet Syndrome, a severe epilepsy. My first aim is to increase SCN1A gene expression in interneurons derived by reprogramming fibroblasts obtained from Dravet Syndrome patients. I will then determine whether this strategy can be effective in non-genetic epilepsies by applying CRISPR-On technology to increase KNCA1(Kv1.1) expression in excitatory neurons in a mouse model of focal epilepsy. This project will combine my previous experience with functional analysis of neurons in different epileptic models; an unparalleled resource of genetically-characterized patients, a well characterized model of intractable epilepsy, and gene therapy techniques at the UCL Institute of Neurology; and expertise on the CRISPR-On method and fibroblast reprogramming of international collaborators. Epilepsy is one of the most important health burdens within the clinical neurosciences, and finding tools that open new mechanistic and therapeutic insights is a high priority. My proposal exploits an opportunity to establish a new tool to treat epileptic disorders and to create an international multidisciplinary network including neurophysiology, clinical neurology, molecular biology, biophysics and genetics.
Original text from CORDIS.
Participants
- UNIVERSITY COLLEGE LONDON · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union