[Antisense constructs, therapeutics of the future?]

Area of Science:

• Oligonucleotide chemistry and antisense technology.
• Molecular biology and nucleic acid therapeutics.
• Cancer research and drug development.

Context:

• Antisense oligonucleotides are susceptible to enzymatic degradation, limiting their therapeutic efficacy.
• Developing nuclease-stable and cell-permeable antisense agents is crucial for effective gene silencing.
• Targeting specific mRNA molecules offers a strategy for controlling gene expression and cellular function.

Purpose:

• To investigate molecular modifications for creating stable and effective antisense oligonucleotides.
• To evaluate hexitol nucleic acids (HNA) as potential antisense therapeutics due to their high affinity for RNA.
• To assess the antiproliferative and gene expression inhibitory effects of modified oligonucleotides and HNA.

Summary:

• Two strategies were explored: 1) Conjugating small aliphatic diols to oligonucleotides to enhance nuclease stability and cellular uptake, demonstrating selective in vivo tumor growth inhibition. 2) Utilizing hexitol nucleic acids (HNA) for mRNA translation inhibition via steric hindrance, showing activity against Plasmodium, ICAM-1, and Ha-ras mRNA expression.
• Modified oligonucleotides with 3'-end diol conjugation achieved selective tumor growth inhibition in vivo.
• Hexitol nucleic acids (HNA) effectively inhibited Plasmodium, ICAM-1, and Ha-ras mRNA expression using a lipofection protocol, indicating efficient uptake.

Impact:

• The development of nuclease-stable oligonucleotides with enhanced uptake provides a viable strategy for selective antiproliferative effects.
• Hexitol nucleic acids (HNA) show significant potential as antisense therapeutics, with cellular uptake not being a limiting factor.
• These findings pave the way for novel antisense therapies targeting various diseases, including cancer and infectious diseases.