SMERIGLIO Lab

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
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108 documents

  • Pranay Agarwal, Hong-Pyo Lee, Piera Smeriglio, Fiorella Grandi, Stuart Goodman, et al.. A dysfunctional TRPV4–GSK3β pathway prevents osteoarthritic chondrocytes from sensing changes in extracellular matrix viscoelasticity. Nature Biomedical Engineering, 2021, 5 (12), pp.1472-1484. ⟨10.1038/s41551-021-00691-3⟩. ⟨hal-03815571⟩
  • Sestina Falcone, T. Marais, M. Traoré, C. Gentil, J. Mésseant, et al.. Unraveling the role of GDF5 therapeutic potential in Amyotrophic Lateral Sclerosis. 18ème Journée de la Societé Française de Myologie, Nov 2021, Saint-Etienne (FR), France. ⟨hal-04002180⟩
  • Piera Smeriglio. Neurofilaments as biomarkers for Spinal Muscular Atrophy. Fondation Garches annual meeting, Nov 2021, PARIS, France. ⟨hal-04002720⟩
  • Manuela Zinni, Julien Pansiot, Marina Colella, Valérie Faivre, Andrée Delahaye-Duriez, et al.. Impact of Fetal Growth Restriction on the Neonatal Microglial Proteome in the Rat. Nutrients, 2021, 13 (11), pp.3719. ⟨10.3390/nu13113719⟩. ⟨hal-03971304⟩
  • Fiorella Carla Grandi, Nidhi Bhutani. Mapping 5-Hydroxymethylcytosine (5hmC) Modifications in Skeletal Tissues Using High-Throughput Sequencing. Methods in Molecular Biology, 2021, Methods in Molecular Biology, 2221, pp.101-108. ⟨10.1007/978-1-0716-0989-7_8⟩. ⟨hal-04198967⟩
  • S. Elouej, I. Nelson, E. Cohen, R. Ben Yaou, A. Isapof, et al.. Functional validation of a novel variant of the SPTAN1 gene identified in a family with distal motor myopathy with nerve involvement. 26th International Congress of the World Muscle Society (WMS), Sep 2021, Virtual conference, United Kingdom. Neuromuscular Disorders, 31, pp.S72, 2021, ⟨10.1016/j.nmd.2021.07.100⟩. ⟨hal-03983822⟩
  • Piera Smeriglio. Intercepting OA disease progression by modulating the epigenetic profile via TET1 inhibition. 29th European Orthopedic Research Society, Sep 2021, Rome, Italy. ⟨hal-04002708⟩
  • Stephanie Holden, Fiorella Grandi, Oumaima Aboubakr, Bryan Higashikubo, Frances Cho, et al.. Complement factor C1q mediates sleep spindle loss and epileptic spikes after mild brain injury. Science, 2021, 373 (6560), ⟨10.1126/science.abj2685⟩. ⟨hal-04198976⟩
  • Nicolas Vignier, Maria Chatzifrangkeskou, Luca Pinton, Hugo Wioland, Thibaut Marais, et al.. The non-muscle ADF/cofilin-1 controls sarcomeric actin filament integrity and force production in striated muscle laminopathies. Cell Reports, 2021, 36 (8), pp.109601. ⟨10.1016/j.celrep.2021.109601⟩. ⟨hal-03350074⟩
  • Muhammad Farooq Rai, Chia-Lung Wu, Terence Capellini, Farshid Guilak, Amanda Dicks, et al.. Single Cell Omics for Musculoskeletal Research. Current Osteoporosis Reports, 2021, 19 (2), pp.131-140. ⟨10.1007/s11914-021-00662-2⟩. ⟨hal-04199024⟩
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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