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Group leader: Alexis Bemelmans
Gene therapy represents a great hope for neurodegenerative diseases, which for the most part are in a therapeutic deadlock. Although the feasibility of different gene therapy strategies has been established for a significant number of these diseases, the lack of relevant models is a stumbling block on the road to the application of these biotherapies in humans. Moreover, it is important to imagine and validate new gene transfer strategies for diseases for which there are currently no satisfactory tracks towards the development of a treatment, such as monogenic diseases with dominant mutation. The work carried out within the team thus focuses on these two aspects by using Huntington and Alzheimer as model pathologies, which respectively represent a purely genetic disease and a multifactorial disease.
We have shown in a retinitis pigmentosa model that it is possible to repair rhodopsin mutations by modifying the mRNAs of this gene, thus opening the way for transcriptional editing for dominant mutations. We are currently developing a similar strategy for Huntington, whose mutation, an amplification of CAG triplet-repeats, is dominant.
Regarding the modelization part, we have shown that it is possible to reproduce by in vivo gene transfer certain lesions present in Huntington or in Alzheimer. Compared with classical transgenesis, this method makes it possible to obtain models that can be used in other species than the mouse, more suitable for in vivo imaging. This method also has the advantage of being easily applicable in vitro to cell cultures. We have developed lentiviral vectors that express a mutated version of huntingtin (the gene responsible for Huntington's disease) and lead to the formation of nuclear neuronal inclusions in striatal neurons that are characteristic of the disease, and then the degeneration of these cells. This model is currently used to test new therapeutic leads. More recently, our team has developed AAV vectors expressing the human Tau protein which allow to reproduce degeneration by tauopathy (FIG. 1), a type of lesion found in several neurodegenerative diseases, including Alzheimer's disease. Using these vectors, our latest work demonstrates that soluble oligomeric forms of Tau are more toxic to neurons than highly aggregated forms.
Implementation of these neurodegenerative diseases models obtained by targeted gene transfer into neurons of the central nervous system will be of great value for, among other things, (i) making the transition between proofs of concept accumulated on rodent models and the human clinic; (ii) studying the etiology of these pathologies; (iii) discover relevant biomarkers; (iv) exploring new ways of treatment.
A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina.Chaffiol A, Caplette R, Jaillard C, Brazhnikova E, Desrosiers M, Dubus E, Duhamel L, Macé E, Marre O, Benoit P, Hantraye P, Bemelmans AP, Bamberg E, Duebel J, Sahel JA, Picaud S, Dalkara D.Mol Ther. 2017 Nov 1;25(11):2546-2560.
Gene therapy of the central nervous system: general considerations on viral vectors for gene transfer into the brainSerguera C, Bemelmans APRev Neurol (Paris). 2014 Dec;170(12):727-38
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