Projektbeschreibung
Multiorganschäden zur Behandlung der spinalen Muskelatrophie erforschen
Die spinale Muskelatrophie ist eine Motoneuronerkrankung, die durch einen fortschreitenden Verlust des SMN-Proteins (Survival of Motor Neuron Protein) verursacht wird. Das SMN-Protein ist im zentralen Nervensystem und den peripheren Organen ubiquitär exprimiert. Die Wiederherstellung des SMN-Proteinniveaus im zentralen Nervensystem stellt eine wirksame Methode dar, die zur Zulassung von Behandlungen für den klinischen Einsatz geführt hat. Ziel des EU-finanzierten Projekts SMABEYOND ist es, die Rolle des SMN-Proteins in peripheren Organen zu untersuchen und die intrinsischen Schäden, die bei Menschen mit spinaler Muskelatrophie auftreten, zu ermitteln. Übergeordnetes Ziel ist es, Krankheitsmodelle, die von an spinaler Muskelatrophie Erkrankten ausgehen, zu entwickeln und die therapeutische Wirkung auf periphere Organe in der systematischen Behandlung der spinalen Muskelatrophie zu erproben.
Ziel
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)Koordinator
76185 Karlsruhe
Deutschland