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


110 documents

  • Julia Pereira Lemos, Liliane Patrícia Gonçalves Tenório, Vincent Mouly, Gillian Butler-Browne, Daniella Arêas Mendes-Da-Cruz, et al.. T cell biology in neuromuscular disorders: a focus on Duchenne Muscular Dystrophy and Amyotrophic Lateral Sclerosis. Frontiers in Immunology, 2023, 14, pp.120283. ⟨10.3389/fimmu.2023.1202834⟩. ⟨hal-04603915⟩
  • J. de Winter, L. van de Vondel, Gisèle Bonne, T. Stojkovic, S. Elouej, et al.. P158 Heterozygous SPTAN1 frameshift mutations cause distal myopathy with neurogenic features. 28th International Annual Congress of the World Muscle Society, Oct 2023, Charleston SC, United States. pp.S139, ⟨10.1016/j.nmd.2023.07.290⟩. ⟨hal-04280233⟩
  • Piera Smeriglio, Zalc Antoine. Cranial neural crest cells contribution to craniofacial bone development and regeneration. Current Osteoporosis Reports, 2023. ⟨hal-04166947⟩
  • Jonathan De Winter, Liedewei van De Vondel, Gisèle Bonne, Tanya Stojkovic, Sahar Elouej, et al.. Heterozygous SPTAN1 frameshift mutations cause distal myopathy with neurogenic features. Solve-RD, Solving the unsolved Rare Diseases, Final Meeting 2023, Apr 2023, Prague, Czech Republic. ⟨hal-04086227⟩
  • Mohammed Khamaysa, Muriel Lefort, Mélanie Pélégrini-Issac, Alexandra Lackmy-Vallée, Arnaud Preuilh, et al.. Analyse volumétrique du tronc cérébral : prédictibilité de la fonction respiratoire et bulbaire dans la sclérose latérale amyotrophique. JNLF 2023, Apr 2023, Lyon, France. pp.S140-S141, ⟨10.1016/j.neurol.2023.01.647⟩. ⟨hal-04086695⟩
  • Marisa Cappella. A new AAV-mediated gene therapy approach for C9orf72-linked ALS. Inaugural Symposium of the Sorbonne Université "Stem Cells and Regenerative Medicine" Network, Dec 2022, PARIS, France. ⟨hal-04006616⟩
  • Clément Pontoizeau, Marcelo Simon-Sola, Clovis Gaborit, Vincent Nguyen, Irina Rotaru, et al.. Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice. Nature Communications, 2022, 13 (1), pp.3278. ⟨10.1038/s41467-022-30880-w⟩. ⟨hal-03862521⟩
  • Amédée Mollard, Cécile Peccate, Anne Forand, Julie Chassagne, Laura Julien, et al.. Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcription. Scientific Reports, 2022, 12 (1), pp.9674. ⟨10.1038/s41598-022-13405-9⟩. ⟨hal-03828271⟩
  • Sestina Falcone, Marais T., Traoré M., Bourguiba A., Gentil C., et al.. Unraveling the role of GDF5 therapeutic potential in Amyotrophic Lateral Sclerosis. 19 Journée de la societé Française de Myologie, Nov 2022, Toulouse (FR), France. ⟨hal-04002173⟩
  • Julia Pereira Lemos. The thymus in the pathogenesis/ pathophysiology of Amyotrophic Lateral Sclerosis. Symposium of the National Institute of Science, Nov 2022, Rio de Janeiro, Brazil. ⟨hal-04006594⟩
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Agence nationale de la recherche
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Association pour la recherche sur la SLA
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