Group leader: Maria Grazia Biferi

The main goal of our team is to develop new therapies for motor neuron disorders (MND). Our work is focused on spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).

The use of viral vectors derived from adeno associated virus (AAV) opened novel perspectives and applications for the treatment of MNDs. 

In 2007, M. Barkats demonstrated the high potential of self-complementary AAV serotype 9 (AAV9) to efficiently transduce the central nervous system (CNS) following a systemic injection (Barkats, Patent PCT/EP2008/063297, 2007 and Martine Barkats and AAV9-SMN: from discovery to treatment). Remarkably, the first gene therapy based on this approach – Zolgensma®, – has been recently approved by the Food and Drug Administration (FDA) for the treatment of infantile forms of SMA. This represents a major breakthrough in the field of gene therapy for rare diseases.

Projects

• We are currently optimizing the AAV-mediated gene replacement approach for SMA. Our objective is to develop specific vectors targeting multiple organs affected in the disease. This will likely reduce the potential side-effects of the current therapy on the long term. We are also investigating epigenetic regulation in SMA and motor neuron degeneration. The study of epigenetic hallmarks will provide a comprehensive understanding of the disease and in particular of its different forms. Furthermore, this work will contribute to the identification of novel pathways implicated in the pathophysiology of SMA.
  The objective of these projects on the long term is to identify novel therapeutic targets, specific to each SMA patient and to design future personalized medicine approaches. 
• We are also taking advantage of the therapeutic potential of AAV vectors to find treatments for ALS. In 2017, we developed a therapeutic strategy for ALS caused by mutations in the superoxide dismutase 1 (SOD1) gene. Using an exon-skipping approach through AAV, we induced global decrease in the human mutant SOD1 in the SOD1G93A mouse model (Biferi et al., 2017). This work received the Prize4Life award “THE $1M AVI KREMER ALS TREATMENT PRIZE4LIFE”. We are currently furthering the pre-clinical development of this approach in collaboration with Généthon.
• A big part of our research effort focuses on the development of a therapeutic strategy for ALS and fronto-temporal dementia (FTD) caused by mutations in C9ORF72 gene. This is the most common form of ALS (40% of familial forms and 7% of sporadic cases). The mutation results in a gain-of-function and a loss of C9ORF72 protein expression (Reviewed by Cappella et al., IJMS 2019). Our strategy aims to simultaneously target all the pathological mechanisms, using AAV vectors. We are also generating novel experimental models to better understand the disease.

Composition and expertise of the group

Contact

Maria Grazia Biferi : mg.biferi@institut-myologie.org

Keys publications (past 5 years)

• Lauritzen I, Bécot A, Bourgeois A, Pardossi-Piquard R, Biferi MG, Barkats M, Checler F. (2019). Targeting γ-secretase triggers the selective enrichment of oligomeric APP-CTFs in brain extracellular vesicles from Alzheimer cell and mouse models. Transl Neurodegener. 2019 Dec 5;8:35. doi: 10.1186/s40035-019-0176-6. eCollection 2019. PMID: 31827783
• Le Quellec S, Dane AP, Barbon E, Bordet JC, Mingozzi F, Dargaud Y, Marais T, Biferi MG, Négrier C, Nathawani AC, Enjolras N. (2019). Recombinant Adeno-Associated Viral Vectors Expressing Human Coagulation FIX-E456H Variant in Hemophilia B Mice. Thromb Haemost. 2019 Dec;119(12):1956-1967. doi: 10.1055/s-0039-1697658. Epub 2019 Oct 28. PMID: 31659733
• Chatzifrangkeskou M, Yadin D, Marais T, Chardonnet S, Cohen-Tannoudji M, Mougenot N, Schmitt A, Crasto S, Di Pasquale E, Macquart C, Tanguy Y, Jebeniani I, Pucéat M, Morales Rodriguez B, Goldmann WH, Dal Ferro M, Biferi MG, Knaus P, Bonne G, Worman HJ, Muchir A. (2018). Cofilin-1 phosphorylation catalyzed by ERK1/2 alters cardiac actin dynamics in dilated cardiomyopathy caused by lamin A/C gene mutation. Hum Mol Genet. 2018 Sep 1;27(17):3060-3078. doi: 10.1093/hmg/ddy215. PMID: 29878125
• Niemir N, Rouvière L, Besse A, Vanier MT, Dmytrus J, Marais T, Astord S, Puech JP, Panasyuk G, Cooper JD, Barkats M, Caillaud C. (2018). Intravenous administration of scAAV9-Hexb normalizes lifespan and prevents pathology in Sandhoff disease mice.  Hum Mol Genet. 2018 Mar 15;27(6):954-968. doi: 10.1093/hmg/ddy012. PMID: 29325092
• Puzzo F, Colella P, Biferi MG, Bali D, Paulk NK, Vidal P, Collaud F, Simon-Sola M, Charles S, Hardet R, Leborgne C, Meliani A, Cohen-Tannoudji M, Astord S, Gjata B, Sellier P, van Wittenberghe L, Vignaud A, Boisgerault F, Barkats M, Laforet P, Kay MA, Koeberl DD, Ronzitti G, Mingozzi F. (2017). Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase. Sci Transl Med. 2017 Nov 29;9(418). pii: eaam6375. doi: 10.1126/scitranslmed.aam6375. PMID: 29187643
• Biferi M.G., Cohen-Tannoudji M., Cappelletto A., Giroux B., Roda M., Astord S., Marais T., Ferry A., Barkats M. (2017). A new AAV10-U7-mediated gene therapy prolongs survival and restores function in an ALS mouse model. Mol Ther. pii: S1525-0016(17)30251-4. DOI:10.1016/j.ymthe.2017.05.017. PMID: 28663100.
• Goiran T., Duplan E., Chami M., Bourgeois A.; Lauritzen I., El Manaa W., Dunys J., You H., Stambolic V., Biferi M.G., Barkats M., Pimplikar S.W., Sergeant N., Colin M., Morais V.A., Pardossi-Piquard R., Checler F., Alves da Costa C. (2017). BetaAPP intracellular domain controls mitochondrial function by modulating Pink-1 transcription in cells and in Alzheimer mice models. Biol Psychiatry. pii: S0006-3223(17)31515-9. DOI:10.1016/j.biopsych.2017.04.011. PMID: 28587718.
• Gribling-Burrer A.S., Leichter M., Wurth L., Huttin A., Schlotter F., Troffer-Charlier N., Cura V., Barkats M., Cavarelli J., Massenet S., Allmang C. (2017). SECIS-binding protein 2 interacts with the SMN complex and the methylosome for selenoprotein mRNP assembly and translation. Nucleic Acids Res. 45(9):5399-5413. doi: 10.1093/nar/gkx031. PMID: 28115638.
• Matagne V., Ehinger Y., Saidi L., Borges-Correia A., Barkats M., Bartoli M., Villard L., Roux JC. (2017). A codon-optimized Mecp2 transgene corrects breathing deficits and improves survival in a mouse model of Rett syndrome. Neurobiol Dis. 99:1-11. doi: 10.1016/j.nbd.2016.12.009. PMID: 27974239.
• Armbruster N., Lattanzi A., Jeavons M., Van Wittenberghe L., Gjata B., Marais T., Martin S., Vignaud A., Voit T., Mavilio F., Barkats M., Buj-Bello A. (2016). Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy. Mol Ther Methods Clin Dev. 3:16060. doi: 10.1038/mtm.2016.60. PMID: 27652289.
• Alves S., Marais T., Biferi M.G., Furling D., Marinello M., El Hachimi K., Cartier N., Ruberg M., Stevanin G., Brice A., Barkats M., Sittler A. (2016) Lentiviral vector-mediated overexpression of mutant ataxin-7 recapitulates SCA7 pathology and promotes accumulation of the FUS/TLS and MBNL1 RNA-binding proteins. Mol Neurodegener. 11(1):58. PMID: 27465358.
• Lauritzen I., Pardossi-Piquard R., Bourgeois A., Pagnotta S., Biferi M.G., Barkats M., Lacor P., Klein W., Bauer C., Checler F. (2016). Intraneuronal aggregation of the beta-CTF fragment of APP (C99) induces Abeta-independent lysosomal-autophagic pathology. Acta Neuropathol. 132(2):257-76. doi: 10.1007/s00401-016-1577-6. PMID: 27138984.
• Dragin N., Bismuth J., Cizeron-Clairac G., Biferi M.G., Berthault C., Serraf A., Nottin R., Klatzmann D., Cumano A., Barkats M., Le Panse R., Berrih-Aknin S. (2016). Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J Clin Invest. 126(4):1525-37. doi: 10.1172/JCI81894. PMID: 26999605.
• Tanguy Y., Biferi M.G., Besse A., Astord S., Cohen-Tannoudji M., Marais T., Barkats M. (2015). Systemic AAVrh10 provides higher transgene expression than AAV9 in the brain and the spinal cord of neonatal mice. Front Mol Neurosci. 8:36. doi: 10.3389/fnmol.2015.00036. PMID: 26283910.

Review

Gene Therapy for ALS-A Perspective.(2019) Cappella M, Ciotti C, Cohen-Tannoudji M, Biferi MG. Int J Mol Sci. 2019 Sep 6;20(18). pii: E4388. doi: 10.3390/ijms20184388. Review. PMID: 31500113

Patents

• Biferi M.G., Cappella M., Barkats M. Antisense sequences for treating amyotrophic lateral sclerosis (AIM). April 2020. EP20169064.1
• Barkats M., Biferi M.G., Voit T. Treatment of Amyotrophic Lateral Sclerosis. (AIM, CNRS, INSERM, UPMC). July 2014. WO2016016449 A1