Description du projet
Cibler les défaillances multiviscérales pour traiter l’amyotrophie spinale
L’amyotrophie spinale (AMS) est une maladie neuromotrice provoquée par des niveaux réduits de la protéine de survie du motoneurone (SMN). La protéine SMN est systématiquement exprimée dans le système nerveux central (SNC) et les organes périphériques. La restauration des niveaux de protéine SMN constitue une stratégie très efficace ayant été validée dans le cadre de thérapies cliniques. L’objectif du projet SMABEYOND, financé par l’UE, est d’étudier le rôle de la protéine SMN dans les organes périphériques et de déterminer les défaillances intrinsèques mises en évidence chez les patients atteints d’AMS. Le but ultime consiste à développer des modèles de maladie AMS dérivés des patients et de tester l’effet thérapeutique du traitement AMS systémique sur les organes périphériques.
Objectif
Spinal Muscular Atrophy (SMA) is a monogenic motoneuron disease with a neuromuscular phenotype resulting in infant death in severe cases. Besides motoneurons in the central nervous system (CNS), there is growing evidence of an involvement of peripheral organs. SMA is caused by reduced Survival of Motoneuron (SMN) protein levels and SMN is ubiquitously expressed. Therefore, SMA patients show reduced SMN levels also in peripheral organs. A restoration of SMN levels in the CNS is a potent therapeutic strategy which led to the approval of two different compounds: Spinraza is an antisense oligonucleotide which increases SMN mRNA, Zolgensma is an adeno-associated virus increasing expression of SMN. However, both strategies focus on the restoration of CNS SMN levels without a sustainable effect on peripheral organs. In 2020, approval of a third drug, Risdiplam, a systemic SMN enhancer, is expected. Although patients greatly benefit from a treatment of the neuromuscular phenotype they face a precarious future: there is no comprehensive landscape of vulnerable organs and no approved treatment for the periphery. We will analyze intrinsic defects in peripheral organs (WP1), evaluate the organ specific molecular and cellular functions of the SMN protein in relevant organs (WP2), and translate these findings to SMA patient derived models, which we will treat with a systemic SMA drug currently under clinical evaluation (WP3). The SMA field involves stakeholders, which allow early stage researchers to personally interact with basic scientists, clinicians, pharmaceutical companies and patient organizations. For our training network, we will combine this vertical integration with a broad perspective on multiple organ systems in SMA. The training strategy assures career options and employability of early stage researchers beyond the SMA field. We will go beyond the motoneuron and identify organs, mechanisms and molecules that could be targets for the peripheral aspects of SMA.
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MSCA-ITN - Marie Skłodowska-Curie Innovative Training Networks (ITN)Coordinateur
76185 Karlsruhe
Allemagne