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 |
|---|
- Maria Chatzifrangkeskou, David Yadin, Thibaut Marais, Solenne Chardonnet, Mathilde Cohen-Tannoudji, et al.. Cofilin-1 phosphorylation catalyzed by ERK1/2 alters cardiac actin dynamics in dilated cardiomyopathy caused by lamin A/C gene mutation. Human Molecular Genetics, 2018, 27 (17), pp.3060-3078. ⟨10.1093/hmg/ddy215⟩. ⟨hal-01962065⟩
- Manuela Zinni, Marina Colella, Aline Rideau Batista Novais, Olivier Baud, Jérôme Mairesse. Modulating the Oxytocin System During the Perinatal Period: A New Strategy for Neuroprotection of the Immature Brain?. Frontiers in Neurology, 2018, 9, pp.229. ⟨10.3389/fneur.2018.00229⟩. ⟨hal-03971408⟩
- Natalia Niemir, Laura Rouvière, Aurore Besse, Marie Vanier, Jasmin Dmytrus, et al.. Intravenous administration of scAAV9-Hexb normalizes lifespan and prevents pathology in Sandhoff disease mice. Human Molecular Genetics, 2018, 27 (6), pp.954-968. ⟨10.1093/hmg/ddy012⟩. ⟨hal-03862562⟩
- Thomas Goiran, Eric Duplan, Mounia Chami, Alexandre Bourgeois, Wejdane El Manaa, et al.. β-Amyloid Precursor Protein Intracellular Domain Controls Mitochondrial Function by Modulating Phosphatase and Tensin Homolog–Induced Kinase 1 Transcription in Cells and in Alzheimer Mice Models. Biological Psychiatry, 2018, 83 (5), pp.416-427. ⟨10.1016/j.biopsych.2017.04.011⟩. ⟨hal-02360864⟩
- Jieun Lee, Piera Smeriglio, Constance Chu, Nidhi Bhutani. Human iPSC-derived chondrocytes mimic juvenile chondrocyte function for the dual advantage of increased proliferation and resistance to IL-1β. Current Stem Cell Research & Therapy, 2017, 8 (1), pp.244. ⟨10.1186/s13287-017-0696-x⟩. ⟨hal-03818865⟩
- F. Puzzo, P. Colella, M. G. Biferi, D. Bali, N. K. Paulk, et al.. Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid alpha-glucosidase. Science Translational Medicine, 2017, 9 (418), pp.aam6375. ⟨10.1126/scitranslmed.aam6375⟩. ⟨hal-02881011⟩
- Corinne Bos. Modélisation et analyses physiopathologiques de la Sclérose Latérale Amyotrophique liée à l'ubiquiline 2 à l'aide de vecteurs AAV10. Neurosciences [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2017. Français. ⟨NNT : 2017PA066223⟩. ⟨tel-02332677⟩
- Aurore Besse, Mariane Roda, Stéphanie Astord, Thibaut Marais, Maria Grazia Biferi, et al.. AAV9-mediated SMN expression restricted to the CNS does not rescue SMA mice.. 22nd World Muscle Society Congress, Oct 2017, Saint Malo, France. ⟨hal-04003302⟩
- Maria Grazia Biferi, Mathilde Cohen-Tannoudji, Ambra Cappelletto, Benoit Giroux, Marianne Roda, et al.. A New AAV10-U7-Mediated Gene Therapy Prolongs Survival and Restores Function in an ALS Mouse Model. Molecular Therapy, 2017, 25 (9), pp.2038-2052. ⟨10.1016/j.ymthe.2017.05.017⟩. ⟨hal-03829068⟩
- Piera Smeriglio, Jieun Lee, Nidhi Bhutani. Soluble Collagen VI treatment enhances mesenchymal stem cells expansion for engineering cartilage. Bioengineering & Translational Medicine, 2017, 2 (3), pp.278-284. ⟨10.1002/btm2.10078⟩. ⟨hal-03818854⟩
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