Combinations of ASOs for the Modulation of SMN Expression in SMA Patients

Unmet Need
Spinal muscular atrophy (SMA) is a devastating neuromuscular disease that predominantly affects children and is the most common cause of hereditary infant mortality. The disease is caused by low levels of survival motor neuron (SMN) protein, due to recessive mutations in the SMN1 gene. Importantly, the copy number variation of SMN2, a homologous gene, influences the severity of disease in SMA patients. Therapies to treat SMA primarily aim to increase SMN expression. While gene therapies have been approved for the treatment of SMA, these therapies are not efficacious in all patients and the durability of these approaches remain unclear. Consequently, additional therapies that enhance SMN transcription are needed to improve outcomes in patients with SMA.
 
Technology Overview
JHU researchers have developed a combination therapy of two types of antisense oligonucleotides (ASOs) to achieve optimal SMN induction in SMA patients. The inventors identified a long non-coding RNA, called SMN-AS1, that is enriched in neurons and transcriptionally represses SMN expression. The inventors then developed ASOs capable of degrading SMN-AS1 and demonstrated that these ASOs increases SMN expression in patient-derived cells, cultured neurons, and the mouse central nervous system. When paired with an ASO that enhances SMN2 expression, an SMN2 splicing ASO, the combination of ASOs additively increases SMN expression and improves survival in SMA mice.
 
Stage of Development
This inventors have validated the use of two types of ASOs, to ameliorate SMA in mouse models.
 
Publications
D’Ydewalle C et al. The antisense transcript SMN-AS1 regulates SMN expression and is a novel therapeutic target for spinal muscular atrophy. Neuron 2017; 93:66-79.  
 

Category(s):