A potential new therapy for SMA, which could be used in conjunction with antisense oligonucleotides, such as nusinersen (marketed as Spinraza™), has been found by the Chair of our Scientific Advisory Board (SAB), Professor Brunhilde Wirth and her group in Germany.
Part-funded by SMA Europe, Professor Wirth and her group identified a novel protective genetic factor, Neurocalcin delta (NCALD), for SMA, leading to a potential new therapy.
NCALD is a regulator of neuronal function. It is involved in the transmission of molecular signals from the neuron’s exterior to its interior. Signals received by these neurons must be transmitted effectively into the cell to ensure an appropriate response. Professor Wirth and her team have previously shown that in SMA, this molecular trafficking (endocytosis) is faulty, as a consequence of low SMN, (the protein which is crucial for the survival of motor neurons and which is lacking in people with SMA). However, when the team blocked the activities of NCALD, they found that endocytosis was restored. Furthermore, NCALD coupled with a compound which increases SMN production, such as nusinersen, cell-survival was restored as were motor activities in mice affected by severe SMA.
Neurocalcin delta, a novel protective modifier for spinal muscular atrophy: A full story from gene identification to therapy
BRUNHILDE WIRTH, Institute of Human Genetics, University of Cologne
Autosomal recessive spinal muscular atrophy (SMA) affects around 1:6000 people, every 1:35 is carrier and it is the most frequent genetic cause of infant death. Recently, the first SMA therapy based on antisense oligonucleotides (ASOs), namely SPINRAZA, has been FDA-approved. SPINRAZA restores the suboptimal full-length SMN2 transcript expression and elevates SMN protein level. SMN is crucial for all cells but particularly for motor neurons (MN) and neuromuscular junctions (NMJ). In the most severe type I – accounting for 60% of SMA-affected individuals, who carry only two SMN2 copies – the elevated SMN level may be still insufficient to restore MN function life-long.
Using a combined strategy of linkage and transcriptome analysis, and targeted resequencing, the WIRTH group identified neurocalcin delta (NCALD), as a novel SMA protective modifier. Low NCALD expression was found in five asymptomatic SMN1-deleted individuals in comparison to type III SMA individuals, all carrying four SMN2 copies. They demonstrate that low SMN level reduces Ca2+ influx and impairs endocytosis. NCALD binds clathrin Ca2+-dependently and acts as a Ca2+-dependent negative regulator of endocytosis. Indeed, NCALD inhibition restores impaired endocytosis in SMA.
Using three different SMA models, C.elegans, zebrafish, and mouse, they prove that NCALD dowregulation ameliorates or rescues SMA-derived disease pathologies at MN and NMJ level and improves motoric abilities. Most importantly, a combinatorial therapy using low dose of SMN-ASOs and 50% NCALD reduction restored survival, MN and NMJ function and motoric abilities in a severe SMA mouse model. A similar strategy may cure and not only ameliorate SMA in future.
M. Riessland, A. Kaczmarek, S. Schneider, K. J. Swoboda, H. Löhr, C. Bradler, V. Grysko, M. Dimitriadi, S. Hosseinibarkooie, L. Torres-Benito, M. Peters, A. Upadhyay, N. Biglari, S. Kröber, I. Hölker, L. Garbes, C. Gilissen, A. Hoischen, G. Nürnberg, P. Nürnberg, M. Walter, F. Rigo, C. F. Bennett, M. J. Kye, A. C. Hart, M. Hammerschmidt, P. Kloppenburg and B. Wirth. “Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis“. The American Journal of Human Genetics (2017), http://dx.doi.org/10.1016/j.ajhg.2017.01.005