Combinatorial ASO therapy using SMN-dependent and SMN-independent protection against SMA
Principal investigator(s) :Dr. Laura Torres-Benito
Institution :University of Cologne
Call number :9
Start year :2017
Duration :1 year
Dr. Laura Torres-Benito, from the Wirth Lab at the University of Cologne, was granted an SMA Europe award to see if combining a compound which increases SMN production (such as Spinraza™), with a molecule involved in endocytosis called neurocalcin delta (NCALD), will counteract the disturbed function of motor neurons, even in the most severely affected type of SMA.
SMA is caused by mutation/deletion of the SMN1 gene. This gene produces a protein called SMN, which is crucial for the survival of the nerve cells involved in muscle function. The severity of SMA is determined by the copy number of a second gene, SMN2, which also produces the SMN protein, although only about 10% of the protein produced is viable.Recent studies suggest that there are additional cellular mechanisms which determine the severity of disease, in addition to copy numbers of SMN2. Despite advanced understanding of the genetics involved in SMA, the cellular mechanisms which cause SMA are not yet completely understood. The investigator’s team previously observed that a mechanism called endocytosis, the process which allows cells to recycle and transport molecules, is impaired in SMA, as a consequence of low SMN levels. This process is very important in nerve cells, because they need to be able to rapidly release neurotransmitters to communicate with each other and with muscles. Without this specialised recycling, synaptic vesicles are not recycled fast enough to keep up with nerve and muscle cell activity.
What are the researchers aiming to do and why?
Based on preliminary evidence which suggests that neither molecules (such as Spinraza™) nor drugs which restore SMN levels will be sufficient to cure SMA and building on the findings from her laboratory, Dr. Torres-Benito will be looking to see if combining a compound which increases SMN production (such as Spinraza™), with a molecule involved in endocytosis called neurocalcin delta (NCALD), will counteract the disturbed function of motor neurons, even in the most severely affected type of SMA.
How will this work benefit patients?
The current clinical trials in SMA which target SMN protein levels are showing great promise. Indeed, one such treatment has just been approved to treat all SMA patients in Europe and the US. Whilst this represents an important milestone in SMA research, it is also clear that these strategies fall significantly short of representing a cure for SMA. Therapies that target other/additional cellular and molecular pathways will likely be required to treat the full range of phenotypes and pathology observed in SMA patients across their life-span.It is hoped that this potential therapy will not only ameliorate disease symptoms in pre-symptomatically treated SMA patients, but also to substantially ameliorate SMA patients’ condition where disease symptoms are already present. At the same time, this work will facilitate the initiation of new clinical trials based on new molecular targets. The laboratory’s discovery of NCALD as a treatment for SMA and other neurodegenerative disorders has been protected by a US-patent filed on 29th July 2013 (EFS ID 16445285).