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Biotherapies and modeling of neurodegenerative diseases by gene transfer

Biothérapies et modélisation par transfert de gène des maladies neurodégénératives

Group leader: Alexis Bemelmans​

Published on 25 March 2020


  Alexis Bemelmans

New developments in gene therapy

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.

Mouse neurons in primary culture co-expressing human Tau protein (red) and GFP (green). The antibody used (AT8) detects hyperphosphorylated Tau, the first stage of tauopathy.


Members of the laboratory associated with these projects


  • Vision Institute (Paris), Myology Institute (Paris), University of Lausanne, University of Lund

Recent publications

βAPP Processing Drives Gradual Tau Pathology in an Age-Dependent Amyloid Rat Model of Alzheimer's Disease.
Audrain M, Souchet B, Alves S, Fol R, Viode A, Haddjeri A, Tada S3, Orefice NS, Joséphine C, Bemelmans AP, Delzescaux T, Déglon N, Hantraye P, Akwa Y, Becher F, Billard JM, Potier B, Dutar P, Cartier N, Braudeau J.
Cereb Cortex. 2017 Oct 18:1-18.

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. 

mRNA trans-splicing in gene therapy for genetic diseases.
Berger A, Maire S, Gaillard MC, Sahel JA, Hantraye P, Bemelmans AP
Wiley Interdiscip Rev RNA. 2016 Jul;7(4):487-98.

Repair of rhodopsin mRNA by spliceosome-mediated RNA trans-splicing: a new approach for autosomal dominant retinitis pigmentosa.
Berger A, Lorain S, Joséphine C, Desrosiers M, Peccate C, Voit T, Garcia L, Sahel JA, Bemelmans AP.
 2015 May;23(5):918-930

Gene therapy of the central nervous system: general considerations on viral vectors for gene transfer into the brain
Serguera C, Bemelmans AP
 2014 Dec;170(12):727-38

Spectral-domain optical coherence tomography of the rodent eye: highlighting layers of the outer retina using signal averaging and comparison with histology.
Berger A, Cavallero S, Dominguez E, Barbe P, Simonutti M, Sahel JA, Sennlaub F, Raoul W, Paques M, Bemelmans AP.
PLoS One. 2014 May 2;9(5):e96494