FANA antisense oligonucleotides, also called FANA ASOs, are synthetic single-stranded modified oligonucleotides that allow modulation of gene expression by enzymatic degradation of a target RNA. FANA refers to the 2′-deoxy-2′-fluoro-D-arabinonucleic acid analog. Through complementary Watson–Crick base pairing, FANA ASOs can recognize and bind specific RNA sequences, including mRNAs, miRNAs, and long noncoding RNAs.
Unlike siRNAs, FANA ASOs utilize RNase H-mediated RNA cleavage for gene silencing.
After FANA ASOs bind to their RNA target, the endogenous enzyme Ribonuclease H (RNase H) recognizes the FANA/mRNA duplex and cleaves the RNA. After cleavage, the fragmented mRNA is degraded further by nucleases. The cell recycles the FANA ASOs, and the degradation of multiple mRNA copies by a single FANA ASO increases the silencing efficiency and lowers the dose required.
FANA ASOs have a phosphorothioate backbone and modified flanking nucleotides. A fluorine atom replaces the 2'-OH group, which increases the resistance of the FANA ASO to degradation and enhances binding to targeted mRNA.
Studying DNA and RNA structures and functions has attracted researchers across diverse scientific fields. The last decades saw significant developments in the field of therapeutic oligonucleotides.
The difficulty of delivering oligonucleotides to target organs and tissues limited the wide application of oligonucleotide therapy. Different research groups have extensively leveraged modified nucleic acids to unravel structural and chemical biology scientific inquiries.
2′-deoxy-2′-fluoroarabinonucleic acid (FANA) has emerged as a significant DNA-like nucleic acid with unique attributes adaptable for various biological applications (Figure 1). It contains the more electronegative and less bulky fluorine at the 2’ position, mimicking the DNA: RNA hybrid structure and supporting RNase H activity.
Figure 1: Structure of DNA and FANA oligonucleotides
Application of FANA-Antisense Oligonucleotides (FANA ASOs) oligonucleotides
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FANA ASO can target Citrus Greening Disease, known as Huanglongbing (HLB), caused by Candidatus Liberibacter asiaticus (CLas). Sandoval-Mojica et al. reported the effective suppression of CLas transmission and reduction of its impact on citrus trees, paving the way for innovative strategies in managing agricultural pathogens and safeguarding citrus cultivation.
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The chemokine CCL3 is pivotal in immune cell activation and recruitment in the injured spinal cord. A study conducted by Pelisch. et al. employed specifically designed FANA ASOs to inhibit CCL3 expression in a murine contusive SCI model. Results revealed the successful penetration of self-delivering FANA ASO molecules into the spinal cord lesion site, effectively suppressing CCL3 transcript expression
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FANA ASOS were evaluated in vitro to target the highly conserved regions in the HIV-1 genome, offering a multifaceted approach to combat HIV-1 infection. The studies of Kalot et al. and Takahashi et al. suggest that FANA ASOs are promising antisense oligonucleotide for antiretroviral therapeutics. The ability of FANA ASOs to target RNA by recruiting RNase H1 and sterically blocking RNA dimerization further enhances their therapeutic potential.
The continuous exploration of FANA in diverse scientific domains highlights its potential for groundbreaking advancements in therapeutics, genetics, and nanotechnology, contributing significantly to the evolving landscape of nucleic acid science.
Reference
Kalota A, Karabon L, Swider CR, Viazovkina E, Elzagheid M, Damha MJ, Gewirtz AM. 2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid (2'F-ANA) modified oligonucleotides (ON) effect highly efficient, and persistent, gene silencing. Nucleic Acids Res. 2006 Jan 18;34(2):451-61. [PMC]
Pelisch N, Rosas Almanza J, Stehlik KE, Aperi BV, Kroner A. Use of a Self-Delivering Anti-CCL3 FANA Oligonucleotide as an Innovative Approach to Target Inflammation after Spinal Cord Injury. eNeuro. 2021 Mar 11;8(2):ENEURO.0338-20.2021. [PMC]
Sandoval-Mojica AF, Hunter WB, Aishwarya V, Bonilla S, Pelz-Stelinski KS. Antibacterial FANA oligonucleotides as a novel approach for managing the Huanglongbing pathosystem. Sci Rep. 2021 Feb 2;11(1):2760. [PMC]