Gene therapy with therapeutic oligonucleotides

Abstract

Two major types of oligonucleotide drugs for gene silencing, short interfering RNA (siRNA) and RNase H active antisense oligonucleotides (ASOs), microRNA (miRNA) and Aptamer are being developed as therapeutic platforms orthogonal to small molecule and protein therapeutic. We outlined these oligonucleotide drugs. Despite progress in the design of new oligonucleotide chemical modifications, methods which improve potency of oligonucleotide drugs in animals are highly desirable. The insufficient delivery, poor cellular uptake and their inefficient access to target RNA during intracellular trafficking are major impediments to in vivo silencing by conventional oligonucleotide drugs. Here we developed a short DNA/RNA heteroduplex oligonucleotide (HDO) with a structure different from siRNA of double–stranded RNA and ASO of single–stranded DNA. When the DNA strand was used as 13–mer locked nucleotide acid (LNA) gapmer ASO and RNA strand was conjugated with vitamin E (α–tocopherol) (Toc–HDO), it achieved the most efficacious gene silencing in yet reported ASOs.