Edor Kabashi

Translational research for neurological disorders

Edor Kabashi
  • Rima Nabbout
  • Thomas Blauwblomme
  • Claire Bar
  • Sorana Ciura
  • Anca Marian
  • Hortense de Calbiac
  • Maria-Letizia Campanari
  • Raphael Munoz-Ruiz
  • Doris-Lou Demy

Neurological disorders : The challenge of this millennium

Neurological diseases are the major challenge of our health system, affecting a large percentage our population, with 38% estimated to suffer from one of these disorders, and costing billions of euros per year. Treatment options are limited, or inexistent, for the majority of neurological conditions. To overcome this challenge, there is an urgent need to develop various areas of translational research for major neurological disorders. For this, we aim to develop animal and cellular models that are appropriate for both fundamental research and for high-throughput screens of bioactive compounds and genetic therapy.

The focus of Dr. Kabashi’s team has been to develop translational approaches for a better understanding and treatment of Amyotrophic Lateral Sclerosis (ALS). ALS is a prevalent neurodegenerative disease of the motor system. The team has contributed to ALS research with the discovery of TDP-43 mutations, functionally characterized these mutations in the first vertebrate model of the gene, and demonstrated a genetic interaction with other major ALS genes, notably FUS. The team is currently developing zebrafish transgenic lines for the major genes in ALS, using state of the art genomic editing tools to combine simultaneous gene knockout and expression of the mutant alleles. Using these innovative disease models the team aims to study the functional interactions amongst major genetic factors and their converging effect on key ALS pathogenic mechanisms: autophagy degradation, stress granule formation and RNA regulation. The team is also working with an engineering design startup to develop better methodologies for high-throughput screening in zebrafish models of ALS to accelerate therapy development.

Figure 1 : Genetics and mechanistic insight for ALS and related neurological disorders

Neuronal excitability : From ALS to epilepsy

A major feature of ALS is an altered excitability of the motor circuit, a prevalent clinical hallmark in the diagnosis of this neurological disorder. Epilepsy is also characterized by the aberrant activation and excitability of neuronal circuits. Therefore, through an approach featuring molecular and physiological state of the art methodology, our team is seeking to define shared pathogenic mechanisms that lead to altered excitability in specific subsets of neurons related to these disorders.

Dr. Rima Nabbout, who leads the Reference Center for Rare Epilepsies (CReER) at Necker Hospital, is coordinating the epilepsy research project, bridging the clinical and fundamental aspects for an integrative approach. CReER is internationally renowned for the phenotypic classification of patients, the genetic analysis of large patient cohorts leading to the identification of novel genetic factors, and, in recent years, for spearheading successful clinical trials.

 

Translational approach for neuronal excitability disorders

Our team is involved in all the aspects of translational research in an integrative approach, from a better characterization of patients and their genetic markers, to modelling and fundamental research to identify appropriate therapeutic targets, and ultimately developing clinical trials to test novel treatments. This research is highly patient driven, with extensive phenotyping using the multidisciplinary expertise in clinical testing and the state-of-the-art platforms that are available at the Imagine Institute in the Necker Hospital site (e.g. genomic sequencing, electrophysiology, metabolic screening, imaging), while fostering collaborations with a network of national and international collaborations.

In order to identify novel genetic interactors, patient cohorts of epileptic conditions and ALS are being screened for disease-causing variants. We are developing cellular and animal models for these novel genetic variants to elucidate common pathophysiological signature occurring in disease. Using novel unbiased screening protocols we aim to identify pharmacological and genetic modifiers of pathological phenotypes. To accomplish this objective we rely on the power of zebrafish as a vertebrate model amenable to high-content phenotype-based screens. Factors that are neuroprotective in multiple animal and cellular models of disease will be fast-tracked to initial clinical trials. Through this approach we aim to be at the forefront of translational research for neurological disorders to advance therapeutic treatment for a range of these common neurological diseases.

Figure 2 : Translational approach to reaching therapies for neurological disorders: Focus on epilepsy

 

Major Publications :

1. Devinsky, Nabbout, et al. N Engl J Med. 2017 376:2011-2020. 

2. Kabashi. Lancet Neurol. 2017 May;16(5):348.

3. Sellier, …, Kabashi, et al.. EMBO J. 2016 12:1406-8.

4. French, …, Nabbout, et al. Lancet. 2016;388:2153-2163.

5. Rau,…, Kabashi, et al.  Nat Commun. 2015 May 28;6:7205.

6. Lattante, …, Kabashi. Trends Genet. 2015 May;31(5):263-73.

7. Lattante, …, Kabashi. Neurology. 2014 Sep 9;83(11):990-5.

8. Nava, …, Nabbout, et al. Nat Genet. 2014 Jun;46(6):640-5

9. Zhang, …, Nabbout. Am J Hum Genet. 2014 Apr 3;94(4):547-58.

10. Ciura, …, Kabashi. Ann Neurol. 2013 74:180-7.

 

Funding Major Grants:

ERC Consolidator Grant-ALS-Networks 2017-2022

ANR C9ORF72 2017-2021

ANR ToFU 2016-2020

AFM-Telethon 2016-2019

ERA-Net E-rare RNA-ALS funded by the ANR 2014-2018

Frick Foundation for ALS Research 2017-2019