Periodic Reporting for period 1 - SMABEYOND (Spinal Muscular Atrophy (SMA) beyond motoneuron degeneration: multi-system aspects)
Reporting period: 2020-10-01 to 2022-09-30
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.
Abstract of SMABEYOND Proposal, #956185.
Abstract of SMABEYOND Proposal, #956185.
Spinal Muscular Atrophy (SMA) is a fatal disease caused by low levels of the Survival of Motoneuron (SMN) protein. The decrease of this essential protein causes neurodegeneration and neurodevelopmental defects of neurons responsible for the innervation of skeletal muscles. However, SMN is expressed in all cells and tissues leading to multisystemic symptoms in SMA, e.g. affecting liver, pancreas, heart, vasculature, and kidney. The SMABEYOND Project aims to increase the understanding of peripheral phenotypes, analyze the dysregulations in different organs and elucidate the effects of the therapies available to treat SMA. SMABEYOND researchers covering preclinical and clinical aspects of the disease. First, the Consortium produced large sets of molecular data derived from peripheral organs with regard to elucidate dysregulations in SMA. Those data are currently analyzed in a comparative way to identify pathomechanisms common to several organs as well tissue-specific dysregulations. This has been performed at different stages of the disease to unravel developmental defects in addition to degeneration. Second, the Consortium analyses in its ongoing work specific previously identified pathomechanisms in peripheral organs, tissues and cells. Those include e.g. posttranslational modifications, translational defects and dysregulation of the cytoskeleton.
The SMABEYOND Consortium will elucidate organ-specific, peripheral defects of SMA until the end of the projects. This research allows to differentiate between early developmental defects and degenerative aspects of the disease. Moreover, the work of the Consortium will elucidate pathomechanisms of SMA and the effects of available therapies both on the molecular and systemic levels. This work will directly help to improve existing therapies and meets patient needs with regard to improve their health on a systemic level. SMA is a model disease which allows to understand mechanisms of a motoneuron disease with a systemic impact on all organs. This will improve the research and development of therapies also for other neuromuscular diseases and, therefore, has a large socio-economic and societal impact.