Examples include the introduction of G-clamps, pseudoisocytosine, and the substitution of bases with amine, thione, halogen, alkyl, alkenyl, or alkynyl groups.
[4] ASO-based drugs employ highly modified, single-stranded chains of synthetic nucleic acids that achieve wide tissue distribution with very long half-lives.
[5][6][7] For instance, many ASO-based drugs contain phosphorothioate substitutions and 2' sugar modifications to inhibit nuclease degradation enabling vehicle-free delivery to cells.
ASOs do not penetrate the blood brain barrier when delivered systemically but they can distribute across the neuraxis if injected in the cerebrospinal fluid typically by intrathecal administration.
[10] Under the terms of the FDA's accelerated approval program, a confirmatory study will be conducted in presymptomatic gene carriers to provide additional evidence.
In December 2019, golodirsen (Vyondys 53) received FDA approval[17] for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript.
In August 2020, viltolarsen (Viltepso) received FDA approval for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript.
Over the following years, an antisense oligonucleotide later named nusinersen was developed by Ionis Pharmaceuticals under a licensing agreement with Biogen.
[29][30] A follow-on drug to Inotersen is being developed by Ionis Pharmaceuticals and under license to Akcea Therapeutics for hereditary transthyretin-mediated amyloidosis.
In this formulation the ASO is conjugated to N-Acetylgalactosamine enabling hepatocyte-specific delivery, greatly reducing dose requirements and side effect profile while increasing the level of transthyretin reduction in patients.