LAUREN R. MOORE, MATTHIAS SCHROFF
Exicure Inc, USA

Abstract

Antisense oligonucleotides (ASOs) have enormous potential for the treatment of genetic disorders. Targeted drug delivery to disease-relevant tissues remains the greatest obstacle for the development of ASO therapeutics for a broader spectrum of diseases. Next-generation delivery approaches like spherical nucleic acids (SNAs) and ASO conjugates aim to combat ASO delivery limitations, and thereby decrease the effective dose, dose frequency, and off-target effects of ASOs. SNAs and ASO conjugated drugs have progressed to clinical trials for diseases of the skin and liver, organs that were historically challenging to target with ASOs. In this article, we will discuss how innovative approaches like SNAs and conjugates may improve drug delivery and expand the therapeutic potential of ASOs for many more diseases.

Despite federal programs aimed at incentivizing therapeutic development for rare disorders, the vast majority of the over 300 million individuals diagnosed with a rare disease lack access to any approved effective, therapeutic intervention (1). Rapid innovations in molecular biology and genomics have undoubtedly expanded our understanding of rare diseases. Indeed, the underlying genetic cause has been identified for about 70% of rare diseases, and that percentage is rapidly growing with an estimated 250 new causative or risk gene variants identified each year (1, 2). Unfortunately, identifying the genetic basis of these diseases rarely translates to a full understanding of the complex pathological mechanisms that contribute to disease. Thus, the wealth of new genetic information available has translated to surprisingly few approved treatments for rare diseases.

Antisense oligonucleotides (ASOs) have arisen as a potentially powerful and precise approach for the treatment of currently intractable rare genetic disorders. ASOs are short sequences of synthetic, chemically-modified single-stranded RNA or DNA, typically 16-25 nucleotides in length, that can induc ...