The researchers have published their results (January 26, 2017) in the renowned science journal The American Journal of Human Genetics.
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.
The reseach team of Brunhilde Wirth investigated several families affected by SMA, where some family members remained healthy, despite the fact that the SMN1 gene was lost and that only four SMN2 gene copies were present. This genetic change would normally cause SMA. Further analysis of the forth generation of a SMA family lead to the discovery of a novel SMA protecting gene - the so-called Neurocalcin delta (NCALD).
Using a combined strategy of linkage and transcriptome analysis, and targeted resequencing, the research team of Brunhilde Wirth 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 demonstrating 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.
Dr. Markus Riessland has analyzed the mechanistic and functional effects of NCALD in different neuronal cells and the zebrafish model. He concluded that the down-regulation of NCALD triggers a neuronal differentiation of the cells and thus the growth of the neurons affected by SMN mutations can be saved. Based on his findings that reduced NCALDs actually save impaired endocytosis in SMA and restore the synaptic transmission from the nerve to the muscle Markus Riessland hypothesized that NCALD might play a role in endocytosis.
Using three different SMA models - C. elegans, zebrafish, and mouse - Anna Kaczmarek and Svenja Schneider, both doctoral students, proved that NCALD down-regulation ameliorates or rescues SMA-derived disease pathologies at MN and NMJ level and improves motoric abilities. They found that the reduction of NCALD in combination with low-dose SMN antisense oligonucleotides (ASOs) showed a positive effect on nerve cells and restored the motor skills in a heavy SMA animal model.
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.
Press Release from SMA Europe - an umbrella organisation founded in 2006 - which includes Spinal Muscular Atrophy (SMA) patient and research organisations from across Europe.
In December 2016, the first SMN ASO-based therapy (SPINRAZA, Nusinersen), approved by IONIS Pharmaceuticals and Biogen, was approved by the American Medicines Agency (FDA). As the Wirth group showed that low doses of SMN-ASOs in a combinatorial therapy with NCALD reduction is effective even in the severely affected SMA mouse model, a combinatorial SMN and NCALD ASO therapy promises new improved therapeutic possibilities even in SMA patients. Prof. Wirth and Dr. Riessland have patented NCALD down-regulation for SMA and neuroprotective therapies.
Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis.
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.
The American Journal of Human Genetics (2017), http://dx.doi.org/10.1016/j.ajhg.2017.01.005
*authors with equal contributions
The press release from the University Hospital Cologne:
For further information, please contact:
Prof. Dr. Brunhilde Wirth
Institute for Human Genetics
Foto: Uniklinik Köln