Biotherapies for motor neuron disorders (ALS & SMA)

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 publication Institut de Myologie). 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.

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 (Besse et al., 2020). 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 ( Smeriglio et al., 2020).

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., 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.

Equipe Biferi au complet

Contacts :

Piera Smeriglio

Maria-Grazia Biferi
Découvrez nos expertises


Nos principales publications

  1. Smeriglio, P, Langard, P, Querin, G, Biferi, MG. The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment. J Pers Med. 2020;10 (3):. doi: 10.3390/jpm10030075. PubMed PMID:32751151 PubMed Central PMC7564782.
  2. Besse, A, Astord, S, Marais, T, Roda, M, Giroux, B, Lejeune, FX et al.. AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice. Mol Ther. 2020;28 (8):1887-1901. doi: 10.1016/j.ymthe.2020.05.011. PubMed PMID:32470325 PubMed Central PMC7403319.
  3. Cappella, M, Ciotti, C, Cohen-Tannoudji, M, Biferi, MG. Gene Therapy for ALS-A Perspective. Int J Mol Sci. 2019;20 (18):. doi: 10.3390/ijms20184388. PubMed PMID:31500113 PubMed Central PMC6771059.
  4. Puzzo, F, Colella, P, Biferi, MG, Bali, D, Paulk, NK, Vidal, P et al.. Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase. Sci Transl Med. 2017;9 (418):. doi: 10.1126/scitranslmed.aam6375. PubMed PMID:29187643 PubMed Central PMC5826611.
  5. Biferi, MG, Cohen-Tannoudji, M, Cappelletto, A, Giroux, B, Roda, M, Astord, S et al.. A New AAV10-U7-Mediated Gene Therapy Prolongs Survival and Restores Function in an ALS Mouse Model. Mol Ther. 2017;25 (9):2038-2052. doi: 10.1016/j.ymthe.2017.05.017. PubMed PMID:28663100 PubMed Central PMC5589057.
  6. Tanguy, Y, Biferi, MG, Besse, A, Astord, S, Cohen-Tannoudji, M, Marais, T et al.. Systemic AAVrh10 provides higher transgene expression than AAV9 in the brain and the spinal cord of neonatal mice. Front Mol Neurosci. 2015;8 :36. doi: 10.3389/fnmol.2015.00036. PubMed PMID:26283910 PubMed Central PMC4516891.
AFM Telethon : innover pour guérir
Agence nationale de la recherche
Fondation Thierry Latran
Association pour la recherche sur la SLA
European Commission

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