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 |
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- Marina Colella, Isabella Panfoli, Matteo Doglio, Michela Cassanello, Maurizio Bruschi, et al.. Adenosine Blood Level: A Biomarker of White Matter Damage in Very Low Birth Weight Infants. Current Pediatric Reviews, 2022, 18 (2), pp.153-163. ⟨10.2174/1573396318666220127155943⟩. ⟨hal-03971247⟩
- Alice Frerot, Véronique Baudouin, Aline Rideau-Batista, Anne Couderc, Catherine Garel, et al.. Prenatal bone abnormalities in three cases of familial hypocalciuric hypercalcemia. Prenatal Diagnosis, 2022, 42 (5), pp.583-588. ⟨10.1002/pd.6134⟩. ⟨hal-03971189⟩
- Michela Bruschi, Neety Sahu, Mamta Singla, Fiorella Grandi, Pranay Agarwal, et al.. A Quick and Efficient Method for the Generation of Immunomodulatory Mesenchymal Stromal Cell from Human Induced Pluripotent Stem Cell. Tissue Engineering: Parts A, B, and C, 2022, 28 (9-10), pp.433-446. ⟨10.1089/ten.TEA.2021.0172⟩. ⟨hal-04198911⟩
- Piera Smeriglio. Uncovering the epigenetic control of paracrine crosstalk between motor neurons and skeletal muscles in SMA. Padua days on muscle and mobility medicine, Mar 2022, Padua, Italy. ⟨hal-04002751⟩
- Piera Smeriglio. Roundtable: ALS & Motor Neuron Diseases: what avenues for the future?. ALS and motor neuron diseases, Mar 2022, PARIS, France. ⟨hal-04002761⟩
- Michela Lisjak, Alessia de Caneva, Thibaut Marais, Elena Barbon, Maria Grazia Biferi, et al.. Promoterless Gene Targeting Approach Combined to CRISPR/Cas9 Efficiently Corrects Hemophilia B Phenotype in Neonatal Mice. Frontiers in Genome Editing, 2022, 4, ⟨10.3389/fgeed.2022.785698⟩. ⟨hal-03862537⟩
- Coralie Hakibilen, Florence Delort, Marie-Thérèse Daher, Pierre Joanne, Eva Cabet, et al.. Desmin Modulates Muscle Cell Adhesion and Migration. Frontiers in Cell and Developmental Biology, 2022, 10, ⟨10.3389/fcell.2022.783724⟩. ⟨hal-03876281⟩
- Valentin Jacquier, Manon Prévot, Thierry Gostan, Rémy Bordonné, Sofia Benkhelifa-Ziyyat, et al.. Splicing efficiency of minor introns in a mouse model of SMA predominantly depends on their branchpoint sequence and can involve the contribution of major spliceosome components. RNA, 2022, 28 (3), pp.303-319. ⟨10.1261/rna.078329.120⟩. ⟨hal-03687098⟩
- Piera Smeriglio. Formation of a European network to initiate a European data collection, along with development and sharing of treatment guidelines for adult SMA patients. 254th ENMC workshop for adult SMA, Jan 2022, Online, France. ⟨hal-04002740⟩
- Giorgia Querin, Maria Grazia Biferi, Pierre-Francois Pradat. Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials. Journal of Neuromuscular Diseases, 2022, 9 (1), pp.25-37. ⟨10.3233/JND-210754⟩. ⟨hal-03538900⟩
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