Descrizione del progetto
Individuare difetti multiorgano per il trattamento dell’atrofia muscolare spinale
L’atrofia muscolare spinale (SMA, Spinal Muscular Atrophy) è una malattia dei motoneuroni provocata dai ridotti livelli di proteina per la sopravvivenza dei motoneuroni (SMN, Survival Motor Neuron). La proteina SMN è ubiquitariamente espressa nel sistema nervoso centrale e negli organi periferici. Ripristinare i livelli di proteina SMN nel sistema nervoso centrale costituisce una potente strategia che ha portato all’approvazione di terapie per uso clinico. Lo scopo del progetto SMABEYOND, finanziato dall’UE, è studiare il ruolo della proteina SMN negli organi periferici e determinare i difetti intrinseci riscontrati nei pazienti affetti da SMA. L’obiettivo finale è sviluppare modelli di malattia derivati dalla SMA e testare l’effetto terapeutico sugli organi periferici della terapia SMA sistemica.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-ITN - Marie Skłodowska-Curie Innovative Training Networks (ITN)Coordinatore
76185 Karlsruhe
Germania