Gene therapy 

The advent of viral gene therapy technology has greatly contributed to the study of human central nervous system (CNS) diseases in animal models, and based on encouraging results on safety and efficacy in several human clinical trials, there is an increasing hope for wider clinical translation of gene therapy for CNS diseases to the clinic. In face of the challenges presented by the complexity and unique biology of the CNS, many vector types have been used, including Lentivirus (LV), Adenovirus, Herpes-Simplex virus and Adeno-Associated Virus (AAV), LV and AAV vectors being the most widely used for their safety profile and ability to drive stable long-term expression of therapeutic transgenes in the brain of rodents, primates, and humans.

AAV is a 20-25 nm non-pathogenic parvovirus. More than 12 serotypes are available as recombinant vectors providing multiple transduction patterns in vivo. It has an excellent safety profile and has been evaluated in several Phase I/II trials for neurodegenerative diseases including Parkinson, Canavan, Batten and Alzheimer diseases.

Whereas global gene delivery to the CNS can only be achieved to a certain extent by cumbersome procedures, a stereotaxic injection leads essentially to local transduction with limited expression of the therapeutic transgene from injection sites, excepting when the therapeutic transgene encodes for a secreted protein or enzyme. Multiple site injections to address neurodegenerative disorders can potentially increase the occurrence of adverse effects.

Furthermore, AAVs are generally administered directly in situ in clinical trials (Parkinson’s disease, for example). However, the use of recently developed AAV serotypes and whose characteristic is to cross the blood-brain barrier -after peripheral intravascular administration - have raised hope for a larger delivery of therapeutic genes into the CNS.

Moreover, the intrathecal delivery of AAV has opened the possibility to target therapeutic genes to the spinal cord, dorsal root ganglia, cerebellum and possibly also into brain.  Significant progress has also been made to customize an AAV capsid that allows specific brain cell targeting, such as endothelial cells.

All these new developments in AAV technology raise important new issues for translational research:

  • the optimization of vector delivery whatever the route of administration to achieve safe but also wider diffusion of the vector in the targeted brain structure or into the whole brain
  • the prediction of vector diffusion in the human brain from studies performed in large animals, particularly in non-human primates (NHPs)
  • the development of new AAV vectors targeting therapeutic transgene in specific neuronal and glial (oligodendrocyte, astrocytes, microglia) cell populations . 
  • the improvement of the manufacturing of research grade AAV and LV in order to accelerate the translation from the proof of concept to the clinic  and to meet the quality regulatory constraints required for Phase I/II trials.
  • the control  of the host immune response against the therapeutic transgene and the capsid/envelope of the viral vector to increase the safety and efficacy of CNS gene therapy , although the CNS is often considered as an immuno privileged site,

The current leads in the field are:

  • the evaluation of alternative routes for vector delivery
  • the engineering of current vectors (AAV and LV) to improve diffusion and infectivity as well as selective brain cell tropisms
  • the actual behaviour of the brain immune system towards the gene therapy product.    



Coordinators : P. Aubourg, Ph. Moullier

Collaborators : Ph. Hantraye, M. Peschanski, N. Cartier, M.A. Colle, S. Palfi