The advent of viral gene therapy technology has greatly contributed to the study of human central nervous system (CNS) diseases in animal models. Thanks to encouraging results in human clinical trials, there are growing expectations that many pre-clinical trials will move to the clinical stage. In face of the challenges presented by the complexity and unique biology of the CNS, many vector types have been tested : Lentivirus (LV), Adenovirus, Herpes-Simplex virus, Adeno-Associated Virus (AAV). 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.
AAVs are 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 have been evaluated in several Phase I/II trials for neurodegenerative or metabolic diseases (Parkinson, Canavan, Batten and Alzheimer diseases). Although the injection of genes into the CNS involves 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.
Moreover, multiple site injections to address neurodegenerative disorders can potentially increase the occurrence of adverse effects.
Until now, AAVs have been generally administered directly in situ in clinical trials (Parkinson’s disease, for example). However, the use of new AAV serotypes 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 AAVs has opened the possibility to target the spinal cord, dorsal root ganglia, and to some extent of certain areas of the brain. Significant progress has also been made to customize an AAV capsid that allows specific brain cell targeting, such as endothelial cells, astrocytes, oligodendrocytes, etc.
All these new developments in AAV technology raise important new issues for translational research, which NeurATRIS is able to address :
- the optimization of vector delivery whatever the route of administration to achieve safe but also wider diffusion of the vector in the targeted brain structures or into the whole brain
- the prediction of vector diffusion in the human brain from studies in large animal models, including non-human primates.
- the development of new AAV vectors carrying therapeutic transgene in specific neuronal and glial (oligodendrocyte, astrocytes, microglia) cell populations.
- the improvement of the manufacturing of research grade AAV 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 in order to increase the efficacy and safety level of CNS gene therapy, although the CNS is often considered an immunologically privileged site.
The current leads in the field are:
- the evaluation of alternative routes for vector delivery
- the engineering of current vectors (AAV) to improve diffusion and infectivity as well as selective brain cell tropisms
- the real behaviour of the brain immune system towards the gene therapy product.