Research Projects

The main focus of my lab is finding novel gene therapy approaches for intractable neurological diseases, with rapid potential for translation. We start by investigating the pathophysiological mechanisms of disease and then use novel insights to develop and improve therapeutic tools to cure them.  We use cutting-edge technologies such as CRISPR and synthetic promoters to overcome current limitations to gene therapy and develop new approaches for curing currently untreatable genetic diseases such as Dravet Syndrome and Episodic Ataxia-1, and acquired pharmaco-resistant temporal lobe epilepsies. We use techniques ranging from molecular biology to in vitro and in vivo electrophysiology, in both cell lines and animal models, and iPSC-derived neurons and organoids from patients. We collaborate with several groups worldwide to complement our techniques and to accelerate our goal of finding innovative cures for devastating pathologies.

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Gene Therapy for Epilepsy

Gene therapy holds promise as a treatment for genetic epilepsies but also as a rational replacement for surgical treatment of pharmaco-resistant focal epilepsy. However, current experimental gene therapies rely either on permanent modification of neuronal function, or on exogenous delivery of agonists to achieve on-demand modulation, and do not discriminate between neurons involved in seizures and healthy neighbour neurons. The lab aims to develop and explore  new gene therapy approaches for targeting  neurons involved in seizure generation.

Dravet Syndrome

Dravet Syndrome is a severe catastrophic neurological disorder affecting young children. Every day 3 or 4 children are diagnosed with Dravet syndrome worldwide, with symptoms including epilepsy, autism, movement disorders and sleep disturbances. To date, the majority of therapies are ineffective or poorly tolerated. Sodium channel drugs which are otherwise effective in many forms of epilepsy may even worsen Dravet syndrome. In the lab we are aiming for a therapy that will restore the normal functioning of the brain in Dravet, using CRISPR and other innovative approaches, but also to study the pathophysiology of this devastating childhood disease. 

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Promoterapy: increase promoter activity
of endogenous genes with CRISPRa

One of the major limitations of current gene therapy approaches is the limited packaging capacity of viral vectors. Promoterapy overcome these limitations by using CRISPRa to target the promoter of endogenous genes and up-regulate their expression. The lab developed this technology in collaboration with Vania Broccoli's Lab in Italy. With this tool we are able to restore physiological gene expression in genetic diseases but also to increase the translation of ion channels that are able to decrease neuronal hyperexcitability in in vivo models of epilepsy.

In vivo CRISPR editing to cure brain pathologies

Dominant-negative mutations produce faulty proteins that act antagonistically to wild type (WT) gene products, thereby decreasing their function. For this reason, classical gene therapy approaches involving exogenous gene delivery are inappropriate, and directly correcting the mutation in the genome represents the best option. CRISPR technology has developed rapidly and inserting DNA into post-mitotic cells such as neurons is now possible, although replacing endogenous sequences remains a challenge. In the lab we are using cutting-edge tools in order to achieve the complete correction of the mutated gene in vivo.

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Roles of plasticity during epileptogenesis

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Epileptogenesis is the process of development of chronic epilepsy following an initial insult. During this period brain circuitry is altered due to many modifications at the molecular, cellular and network level. Exactly how, when and where these modifications occur depends on the initial insult but it will always generate an imbalance in the excitation/inhibition ratio leading to seizures and chronic epilepsy. In the lab we are trying to better define how neuronal networks are altered during epileptogenesis in different animal models, and to develop a possible treatment for these modifications.