Preparing for Patient-Customized N-of-1 Antisense Oligonucleotide Therapy to Treat Rare Diseases

Abstract

The process of developing therapies to treat rare diseases is fraught with financial, regulatory, and logistical challenges that have limited our ability to build effective treatments. Recently, a novel type of therapy called antisense therapy has shown immense potential for the treatment of rare diseases, particularly through single-patient N-of-1 trials. Several N-of-1 antisense therapies have been developed recently for rare diseases, including the landmark study of milasen. In response to the success of N-of-1 antisense therapy, the Food and Drug Administration (FDA) has developed unique guidelines specifically for the development of antisense therapy to treat N-of-1 rare diseases. This policy change establishes a strong foundation for future therapy development and addresses some of the major limitations that previously hindered the development of therapies for rare diseases.

Keywords: N-of-1; antisense oligonucleotide; atipeksen; exon skipping; milasen; muscular dystrophy; personalized medicine; rare disease; splice switching; valeriasen.

Figure 1

Common mechanisms of antisense oligonucleotides. A. RNase H-mediated degradation. ASO–mRNA double-stranded complex recruits RNase H. B. Correction of aberrant splicing. ASO binds splice sites on the transcript and sterically blocks binding of splicing factors. This approach can also be used to prevent erroneous splicing, as pictured, or can be used to exclude targeted exons. C. Reduction in translation. ASO sterically blocks ribosome binding to the transcript.