Project description
Targeting multi-organ defects for the treatment of spinal muscular atrophy
Spinal muscular atrophy (SMA) is a motor neuron disease caused by reduced levels of the survival of motor neuron (SMN) protein. The SMN protein is ubiquitously expressed in the central nervous system (CNS) and peripheral organs. Restoring SMN protein levels in the CNS constitutes a potent strategy that has led to the approval of therapies for clinical use. The aim of the EU-funded SMABEYOND project is to investigate the role of the SMN protein in peripheral organs and determine the intrinsic defects encountered in SMA patients. The ultimate goal is to develop SMA patient-derived disease models and test the therapeutic effect on peripheral organs of systemic SMA therapy.
Objective
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.
Fields of science
Programme(s)
Coordinator
76185 Karlsruhe
Germany