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.
Contacts :
| Name | Position | ORCID | Group |
|---|
- Pasqualina Colella, Pauline Sellier, Manuel J Gomez, Maria G Biferi, Guillaume Tanniou, et al.. Gene therapy with secreted acid alpha-glucosidase rescues Pompe disease in a novel mouse model with early-onset spinal cord and respiratory defects. EBioMedicine, 2020, 61, pp.103052. ⟨10.1016/j.ebiom.2020.103052⟩. ⟨hal-03163331⟩
- Sahar Elouej, Delamare Marine, Marisa Cappella, Mathilde Cohen-Tannoudji, Stéphanie Astord, et al.. Analysis of off-target effects of Antisense Sequence inducing Exon Skipping in SOD1-linked Amyotrophic Lateral Sclerosis. WMS, Sep 2020, Online, France. ⟨hal-04002555⟩
- Delamare Marine, Sahar Elouej, Anne Bigot, Marisa Cappella, Maria Grazia Biferi. Development and characterization of in vitro models to test the efficiency of gene therapy approaches in SOD1-linked Amyotrophic lateral sclerosis. WMS, Sep 2020, online, France. ⟨hal-04002518⟩
- Piera Smeriglio, Fiorella Carla Grandi, Sarah Elizabeth Brook Taylor, Antoine Zalc, Nidhi Bhutani. TET1 Directs Chondrogenic Differentiation by Regulating SOX9 Dependent Activation of Col2a1 and Acan In Vitro. JBMR Plus, 2020, 4 (8), ⟨10.1002/jbm4.10383⟩. ⟨hal-03815584⟩
- Fiorella Carla Grandi, Nidhi Bhutani. Epigenetic Therapies for Osteoarthritis. Trends in Pharmacological Sciences, 2020, 41 (8), pp.557-569. ⟨10.1016/j.tips.2020.05.008⟩. ⟨hal-04199045⟩
- Aurore Besse, Stephanie Astord, Thibaut Marais, Marianne Roda, Benoit Giroux, et al.. AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice. Molecular Therapy, 2020, 28 (8), pp.1887-1901. ⟨10.1016/j.ymthe.2020.05.011⟩. ⟨inserm-03130706⟩
- Blanca Morales Rodriguez, Alejandro Domínguez-Rodríguez, Jean-Pierre Benitah, Florence Lefebvre, Thibaut Marais, et al.. Activation of sarcolipin expression and altered calcium cycling in LMNA cardiomyopathy. Biochemistry and Biophysics Reports, 2020, 22, pp.100767. ⟨10.1016/j.bbrep.2020.100767⟩. ⟨hal-03269952⟩
- Fiorella Carla Grandi, Lara de Tomasi, Mirna Mustapha. Single-Cell RNA Analysis of Type I Spiral Ganglion Neurons Reveals a Lmx1a Population in the Cochlea. Frontiers in Molecular Neuroscience, 2020, 13, ⟨10.3389/fnmol.2020.00083⟩. ⟨hal-04199052⟩
- Piera Smeriglio, Fiorella Grandi, Spoorthi Davala, Venkata Masarapu, Pier Francesco Indelli, et al.. Inhibition of TET1 prevents the development of osteoarthritis and reveals the 5hmC landscape that orchestrates pathogenesis. Science Translational Medicine, 2020, 12 (539), ⟨10.1126/scitranslmed.aax2332⟩. ⟨hal-03815589⟩
- Anne-Laure Virlouvet, Julien Pansiot, Artemis Toumazi, Marina Colella, Andreas Capewell, et al.. In-line filtration in very preterm neonates: a randomized controlled trial. Scientific Reports, 2020, 10 (1), pp.5003. ⟨10.1038/s41598-020-61815-4⟩. ⟨inserm-02536737⟩
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