The research group of Prof. Dr. med. Brunhilde Wirth, Director of the Institute of Human Genetics at the University of Cologne and a principal investigator at the Center for Molecular Medicine Cologne (CMMC), who has recently received the highly endowed NRW Innovation Prize from Minister Prof. Pinkwart, is showing for the first time that a combined therapy of nusinersen (SMN-ASOs) and neurocalcin delta (NCALD) ASOs show improved protection against spinal muscular atrophy (SMA) compared to nusinersen alone.
The researchers published their findings in the renowned journal The American Journal of Human Genetics.
Spinal muscular atrophy (SMA) is a common, autosomal recessive neuromuscular disorder in humans and the most common genetic cause of infant death. In the European population about every 35th person is a carrier of SMA and about 30,000 people with SMA currently live in Europe and the USA.
Characteristic of SMA is the progressive loss of nerve cells that innervate the muscles. As a result, SMA patients suffer from muscle weakness and atrophy. The most severe form of the disease - which affects 60 percent of patients - causes a very early death.
SMA is caused by the loss of the SMN1 gene. However, all people with SMA carry one to six SMN2 copy genes that determine the severity of SMA: from type I (severe form) to type IV (adult form).
In the SMN2, but not in the SMN1 gene, an important regulatory sequence is destroyed by a single base exchange, preventing proper splicing (excision of the unimportant parts from the immature RNA and insertion of the important parts into the mature RNA). As a result, only about 10% of correct RNA and protein is produced.
Many years ago, the Wirth group found SMA-causing fundamental insight. Based on this, the first approved drug for SMA therapy has been developed and clinically tested by IONIS Pharmaceuticals and Biogen: it is an SMN antisense oligonucleotide (ASO) called Nusinersen (Spinraza).
ASOs are short RNA fragments that are stabilized by a peptide. ASOs are used therapeutically to eliminate unfavorable gene regions, to correct impaired gene processes or to reduce gene products. In this way, either more, less or an altered protein of a particular gene can be generated as needed.
The group around Prof. Wirth has also found SMA protecting genes: Plastin 3 (PLS3), Neurocalcin Delta (NCALD) and Calcineurin EF-Hand Protein 1 (CHP1). These were found in individuals who remained healthy despite their genetic predisposition to SMA.
In the current study, postdoctoral researchers Laura Torres-Benito and Svenja Schneider from the Wirth working group succeeded in developing a combined ASO therapy against SMA in a proven SMA mouse model:
The Ncald ASOs were developed by IONIS Pharmaceuticals specifically for this study.
To perform the combined therapy study, a proven SMA mouse model was used: SMA mice carry two human SMN2 genes, whereas the mouse Smn gene was knocked out. These mice die at about 2 weeks of age due to SMA. Mice were treated with either nusinersen alone or with nusinersen and NCALD-ASOs.
The combined therapy was far superior to simple therapy with only nusinersen: the mice developed symptom-free, and showed better results in all motoric, electrophysiological and histological analyses. Wirth would like to downshift the human NCALD gene with NCALD ASOs and test it on SMA patients in clinical trials with nusinersen. The knowledge has also been patented (US Patent No. 9,988,626).
Laura Torres-Benito; Svenja Schneider; Roman Rombo; Karen K. Ling; Vanessa Grysko; Aaradhita Upadhyay; Natalia L. Kononenko; Frank Rigo; C. Frank Bennett; Brunhilde Wirth.
NCALD antisense oligonucleotide therapy in addition to nusinersen further ameliorates spinal muscular atrophy in mice.
Am J Hum Genet: doi.org/10.1016/j.ajhg.2019.05008
Prof. Dr. Brunhilde Wirth
Chair - Institute of Human Genetics and Prinicpal Investigator at the Center for Molecular Medicine Cologne
Univeersity of Cologne | Uniklinik Köln
phone: #49 221 478 86464