Current Advances

Isis and Collaborators Publish New Data on Isis’ ISIS-SMN_Rx in Nature

New data suggest a potential therapeutic benefit to restoring SMN protein not only in the CNS but also in peripheral tissue.

Isis is currently conducting IND-enabling studies on ISIS-SMN_Rx and plans to begin clinical testing in patients with SMA.

Spinal muscular atrophy (SMA) is a motor-neuron disease that is a leading genetic cause of infant mortality. Most infants born with SMA Type I, the most severe form of SMA, die within their first two years of life.¹ One child out of approximately every 6,000 to 10,000 births is born with SMA. There are approximately 30,000 - 35,000 patients with SMA in the United States, Europe and Japan.

SMA is caused by a loss of, or defect in, the survival motor neuron 1 (SMN1) gene. SMN1 produces most of the SMN protein necessary for normal motor function. Humans also have one or more copies of a related gene, SMN2, which produces a small fraction of SMN protein due to inefficient RNA splicing. The severity of SMA is determined by the amount of SMN protein in the cell.

Isis' drug, ISIS-SMN_Rx, is designed to modulate the splicing of the SMN2 gene, significantly increasing the production of functional SMN protein. In previously published results, researchers showed that ISIS-SMN_Rx increased production of functional SMN protein in mouse models of severe SMA. The increase in SMN production correlated with an increase in the number of motor neurons and improvements in behavior and survival.² Researchers also confirmed that significant drug levels of ISIS-SMN_Rx were achieved in the spinal cord of non-human primates following a single intrathecal injection.

In the published paper, Isis and collaborators evaluated the effects of restoring SMN protein in peripheral tissues, including liver and cardiac tissues, in mouse models of SMA.³ In these studies, researchers administered ISIS-SMN_Rx systemically into SMA mice and observed a prolongation of median lifespan of more than 25-fold in the animals. These data indicate that restoring SMN in peripheral tissues, in combination with partial restoration in the CNS, can dramatically improve many clinical features of SMA in this severe mouse model of SMA. This research suggests that in this mouse model of severe SMA there may be a therapeutic benefit from an increase in functional SMN protein in tissues outside of the central nervous system. Additional studies are needed to determine if these finding have any relevance in patients with severe SMA.

More information on SMA can be found at:
SMA Foundation: www.smafoundation.org
Families of SMA: www.curesma.org

More information on Isis' SMN and splicing:
SMA Splicing Factsheet.pdf

For information on clinical trials currently being conducted in the US for SMA go to clinicaltrials.gov and search for spinal muscular atrophy.

¹ National Institute of Neurological Disorders and Stroke.

²Science Translational Medicine, 'Antisense Oligonucleotides Delivered in to Mouse CNS Ameliorate Symptoms of Severe Spinal Muscular Atrophy', March 2011.

³Nature, ‘Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model’, October 2011.