According to a new study published in Neurobiology of Disease, morpholino antisense oligonucleotide against ISS-N1 plus a small molecule compound called RG7800 significantly increased full-length survival motor neuron (SMN) protein production and resulted in better survival in a mouse model of spinal muscular atrophy (SMA). Moreover, when given to mice who were already symptomatic, the dual treatment was still able to completely rescue motor unit function.

“These positive outcomes indicate there is no toxicity or competition when two SMN splice modifying therapies are coadministered,” the researchers wrote. “Clinical trials of combined therapies should be considered in symptomatic SMA patients.”

SMA is characterized by a deficiency in functional SMN protein, which is essential for the health and survival of motor neurons. Most SMN protein is produced by the SMN1 gene, which is mutated in people with SMA. In humans, there is also a second SMN-producing gene, SMN2, but due to a base substitution in exon 7, most of the messenger RNA (mRNA) made from this gene misses exon 7, resulting in the production of unstable SMN protein.

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ISS-N1 is a negative regulator of exon 7. Therefore, inhibiting it with an antisense oligonucleotide enhances the inclusion of exon 7 in the SMN2 mRNA. RG7800 is an orally active preclinical compound that also increases SMN2 exon 7 inclusion by binding to 2 sites in the SMN2 transcripts.

Read more about early signs of SMA

Research has shown that increasing SMN levels before symptom onset provides better therapeutic benefits.

Here, a team of researchers led by Arthur Burghes, PhD, tested the dual treatment approach in mice missing exon 7 from the SMN gene before, during, and after symptom onset. Their aim was to investigate whether these 2 mechanistically distinct treatments could improve outcomes both before and after motor neuron loss.

They found that the dual therapeutic approach rescued motor function, even in symptomatic animals with no loss in function at 100 days of age; mice missing exon 7 from the SMN gene normally die around 14 days of age.

This dual approach should be tested in human clinical trials, the authors of the study wrote. 


Kray KM, McGovern VL, Chugh D, Arnold WD, Burghes AHM. Dual SMN inducing therapies can rescue survival and motor unit function in symptomatic ∆7SMA mice. Neurobiol Dis. Published online August 20, 2021. doi:10.1016/j.nbd.2021.105488