Genetic models of animals phylogenetically distant from human diseases are now used in clinical research. Recently, the proof of concept that genetic models could be obtained by somatic gene transfer in various animal species (including non-human primates), makes it possible to better mimic brain diseases associated with specific genetic mutations. Indeed, the development of these new models allows :
- the testing of new therapeutic strategies and the establishment of a proof of concept of their efficacy;
- the development and in vivo validation of new methods of analysis of brain functioning, such as behavioural tests or biomedical imaging approaches.
Within NeurATRIS, applications of Magnetic Resonance Imaging (MRI) (including diffusion tensor imaging, fMRI) and NMR spectroscopy (MRS) provide information on anatomical damage to the central nervous system, degeneration of fibre bundles and biochemical defects. New methods under development in the pre-clinical stage provide functional information, such as local glutamate or glucose concentrations (Glu-CEST, Glucose-CEST). However, the precise investigation of neurodegenerative mechanisms associated with the different pathologies of interest to NeurATRIS, such as abnormal protein aggregation, axonal pathologies or demyelination, requires the implementation of other complementary imaging approaches.
With regard to Positron Emission Tomography (PET), newly developed radiotracers such as 11C-PIB or 18F-DPA714 are currently used to detect senile plaques and inflammation in neurons, although their relative specificity remains currently disputed. Numerous developments of other innovative, more specific radiotracers are currently ongoing and will benefit from the newly available production capacities within NeurATRIS, allowing the provision of carbon-11, Fluorine 18 and Zirconium 89 labelled radioligands to the scientific community.
Although clinical improvement is the ultimate goal of therapeutic developments, the reliability of clinical biomarkers used for lesion or therapeutic monitoring may present some limitations depending on the stage of development of the disease or because of interferences (e.g. drugs). Disease assessment scales exist, but they do not always provide a reliable relationship between the mechanism of action of a new treatment and the actual impact on the disease.
Therefore, existing methods of lesion and therapeutic monitoring need to be refined in order to assess, in animals and in patients, the relevance, predictability and reliability of different indicators of brain dysfunction and/or recovery, both functionally and structurally in vivo.
At the same time, existing animal models are insufficiently characterised in terms of their ability to mimic the disease mechanism. Their predictability once transposed to the clinic frequently needs to be verified and validated. Thus, preclinical and clinical evaluation of the effect of new therapies has so far neglected the potential side effects of putative treatments and focused on major symptoms, leaving a wide range of motor and cognitive deficits unexplored. Identifying or refining key pre-clinical and clinical behavioural characteristics therefore remains an important challenge.The "In vivo Evaluation and Therapeutic Efficacy" research programme therefore focuses on 3 methodological aspects of the preclinical and clinical stages leading to the development and validation of:
- Relevant animal models (rodents and non-human primates) in order to accelerate the translation of new imaging techniques and behavioural methods from preclinical to clinical use.
- Specific brain imaging biomarkers, allowing in particular a longitudinal follow-up and a quantitative measurement of lesion processes and therapeutic efficacy after treatment.
- Tests to assess disease-specific motor and cognitive deficits, both in patients and in animal models.