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The future of spinal muscular atrophy treatment is combined therapies
In this research blog on spinal muscular atrophy, Dr Anna Kordala and Associate Professor Carlo Rinaldi discuss the paper ''PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice'', published in EMBO Molecular Medicine.
About Spinal Muscular Atrophy and current treatments
Spinal muscular atrophy (SMA) is a rare disease, mostly affecting babies and children, and affects around 80 children in the UK every year (1:8000 live births). It is a number one genetic killer of children under 2.
This rare disease is caused by an insufficiency of SMN protein and therefore increasing the amount of SMN protein is an aim of therapies.
There are three currently approved therapies, which means that people living with SMA can have a much longer, and possibly normal lifespan, especially those who have received treatment early on.
Limitations to current therapies
The current medications have their disadvantages. They are extremely costly and therefore reimbursement in many countries is not in place. Furthermore, they have only been on the market for a couple of years and their long-term impact is still unknown.
The therapies also have other limitations. One of therapies, based on gene therapy, can only be given to babies and not to adults, limiting the number of patients who are able to receive it. Another medication, Nusinersen, has to be given every 4 months via an intrathecal injection. Having this procedure every 4 months becomes more difficult for patients as the time goes on.
The above disadvantages combined with longer than ever predicted lifespan of individuals with SMA both are reasoned to continue to look for more therapies, especially low-cost ones and which can be delivered orally.
The approach of our study
We have tested a library of potent and selective small molecules, developed by the Structural Genomics Consortium (SGC). The small molecules in the library target epigenetic proteins, which means proteins that switch genes on and off.
We performed a screen of these molecules in the cells derived from 2-year-old SMA patients and identified that one of the molecules, called MS023, increased the amount of SMN protein.
Findings from our paper
The MS023 molecule increased the amount of SMN protein in two different cell models. Severe SMA mice treated with MS023 live longer and gain weight better (which is a surrogate endpoint for their wellbeing). In tissues harvested from these mice we see a significant upregulation of SMN in the spinal cord and skeletal muscle, two tissues most severely affected by the disease.
Most importantly we discovered the mechanism via which MS023 leads to SMN upregulation: MS023 is an inhibitor of type I PRMTs - proteins that put a methyl group on nitrogen in proteins.
HNRNPA1 is a crucial regulator of splicing and ‘decides’ how much SMN protein is being produced in SMA. So fiddling with HNRNPA1 can have effects on SMN. Here we show, that MS023 changes the methylation pattern of HNRNPA1 and that tunes up SMN.
In our study, we also show that combining MS023 with nusinersen, a current approved treatment, leads to a fivefold increase in survival (500%) of severe SMA mice, compared to nusinersen alone.
To check what is happening on a molecular level to mice treated with combination of treatment vs a single treatment, we performed a transcriptomic analysis (took a snapshot of all the RNAs currently present in the cell) of spinal cords of mice. We show that combined treatment can rescue transcripts involved in neuroinflammation processes and that might be one of the reasons the mice live so much longer, as nusinersen alone does not correct these pathways.
Our study warrants further clinical investigation of PRMT inhibition both as a stand-alone and add-on therapy for SMA.