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NCALD inhibition protects against spinal muscular atrophy: from gene to therapy The research group of Professor Dr. Brunhilde Wirth at the Institute of Human Genetics (Univ. Hospital of Cologne) and the Center for Molecular Medicine Cologne (CMMC) has succeeded to identify Neurocalcin delta, a neuronal sensor protein as a protective modifier of spinal muscular atrophy. This work has been published in the prestigious American Journal of Human Genetics on January 26, 2017. Proximal spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disease and the most frequent genetic cause of infant death. In the European population, approximately every 35th person is a carrier of SMA and about 30,000 SMA affected people are currently living in Europe and the US. A hallmark of SMA is the progressive loss of nerve cells which innervate the muscles; as a consequence, SMA patients suffer from muscle weakness and atrophy. The most severe form of the disease (affecting 60% of patients) causes premature death. The group of Prof. Wirth analyzed several SMA affected families, in which some family members remained unaffected by SMA, although they carry homozygous SMN1 deletion and only 4 SMN2 copies, which usually cause type III SMA. In a four generation SMA family the group has identified a novel genetic modifier, Neurocalcin delta (NCALD), by applying a combined genetic and gene expression strategy. In this family, low levels of NCALD protected five individuals from developing SMA, despite carrying the predisposing SMA mutation. Markus Riessland, former postdoc in Prof. Wirth´s lab, analyzed Neurocalcin delta at the mechanistic and functional level in different neuronal cells and in the zebrafish model, where he found that downregulation of NCALD triggered neuronal differentiation and rescued impaired neuronal outgrowth phenotype caused by low SMN level. Furthermore, he established the hypothesis and methods to study the role of NCALD in endocytosis. Indeed, reduced NCALD level rescued the impaired endocytosis in SMA and reestablished the synaptic transmission from nerve to muscle. Anna Kaczmarek and Svenja Schneider, both PhD students in the Wirth lab, worked on different SMA mouse models to show the impact of NCALD reduction in a mammalian model organism. Reduction of NCALD in combination with low dose of SMN antisense oligonucleotides (ASOs) rescued nerve cell impairment and restored motoric abilities in a severely affected SMA mouse. In December 2016, the first SMN ASO-based therapy (SPINRAZA, Nusinersen), developed by IONIS Pharmaceuticals and Biogen, was FDA approved. Since the Wirth group showed that low dose of SMN-ASOs in a combinatorial therapy with NCALD reduction protects even against the most severe type of SMA in mice, NCALD turns into a highly interesting gene that could be downregulated in a combinatorial ASO therapy to further increase treatment efficacy. Wirth and Riessland have patented the NCALD downregulation for neuroprotective therapies. Publication: Riessland M*, Kaczmarek A*, Schneider S*, Swoboda KJ, Löhr H, Brander C, et al. Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis. Am J Hum Genet. 2017; DOI: http://dx.doi.org/10.1016/j.ajhg.2017.01.00 *equally contributing first authors