Download NCALD inhibition protects against spinal muscular atrophy: from

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