Has The Age Of Antisense Oligonucleotides Finally Arrived?

By Sankha Pattanayak, Ph.D., Principal Investigator, Chemical Development - Oligonucleotides PRD, Syngene International Ltd.

When the United States Food and Drug Administration (FDA) approved the antisense oligonucleotide (ASO) Spinraza (nusinersen) in 2016 to treat spinal muscular atrophy, it generated a lot of enthusiasm among patients and pharma companies alike. It was the first drug to treat this fatal and previously 'undruggable' genetic neurological disorder. In the same year, the FDA granted accelerated approval to another ASO drug, ExonDys 51 (eteplirsen) to treat one more intractable genetic disease, Duchenne muscular dystrophy (DMD). The approvals rejuvenated new interest in oligonucleotide-based drugs, as evidenced by a large number (>180) of ASO candidates in active clinical trials worldwide¹. These candidates are meant to target a myriad of diseases including cancer, viral infections and several genetic disorders.

The concept of antisense oligonucleotides was, however, first demonstrated as early as 1978² when scientists showed that short single-stranded synthetic oligonucleotides could modulate RNA functions. The idea was well-received because of the overwhelming simplicity that any disease-related RNA can be targeted solely based on genomic information to alter protein expression, even when traditional small molecules may not be amenable. The next four decades have witnessed a vast development of the field, in terms of new chemistries, targeting mechanisms, pharmacology, and delivery strategies³. Notably, the technology of silencing RNAs which can be classified as a double-stranded ASO resulted in a Noble prize being awarded in 2006. The initial hope and hype have, however, mostly waxed and waned because of various reasons like unsatisfactory cellular uptake and stability, off-target effects, and high costs. Before 2016, three more drugs (fomivirsen, pegaptanib, mipomersen) were approved by the FDA but none of them attained commercial success. Despite these setbacks, the case of ASOs is stronger than ever before because of recent advances in understanding the genetic basis of human diseases and predictable potential to correct faulty protein expression by non-conventional means (e.g., splicing modifications)⁴.