miRNA Therapeutics: Delivery and Biological Activity of Peptide Nucleic Acids Targeting miRNAs

Abstract

Peptide nucleic acids (PNAs) are DNA/RNA mimics extensively used for pharmacological regulation of gene expression in a variety of cellular and molecular systems, and they have been described as excellent candidates for antisense and antigene therapies. At present, very few data are available on the use of PNAs as molecules targeting miRNAs. miRNAs are a family of small nc RNAs that regulate gene expression by sequence-selective targeting of mRNAs, leading to a translational repression or mRNA degradation to the control of highly regulated biological functions, such as differentiation, cell cycle and apoptosis. The aim of this article is to present the state-of-the-art concerning the possible use of PNAs to target miRNAs and modify their biological metabolism within the cells. The results present in the literature allow to propose PNA-based molecules as very promising reagents to modulate the biological activity of miRNAs. In consideration of the involvement of miRNAs in human pathologies, PNA-mediated targeting of miRNAs has been proposed as a potential novel therapeutic approach.

Combined Delivery of Temozolomide and Anti-miR221 PNA Using Mesoporous Silica Nanoparticles Induces Apoptosis in Resistant Glioma Cells

“…PNAs, due to their high affi nity for nucleic acids, their sequence selectivity, and their high stability toward both chemical and biological degradation, have been used as antisense agents and have been shown to be able to effi ciently target miRNAs. [48][49][50][51][52] We thus chose PNA as the anti-miR component to be used in combination with the mesoporous silica nanoparticles. Furthermore, the overall charge of the PNAs can easily be tuned either by conjugation with suitable peptides (directly introduced during the PNA solid-phase synthesis), or by modifi cation of the backbone with charged substituents.…”

HypoxamiRs and Cancer: From Biology to Targeted Therapy

“…This question can certainly be formulated for hypoxamiRs, and miR-210 in particular. Recent development of anti-miRNA agents such as locked nucleic acids or peptide nucleic acids represents significant steps for therapeutic targeting of miRNAs in vivo (45,52,81,105,152). It is conceivable that inactivation of miRNAs involved in hypoxic adaptation, in combination with other anticancer agents, may be a viable strategy to target a tumor compartment that poses significant therapeutic challenges.…”

MicroRNAs as potential target in human bone and soft tissue sarcoma therapeutics

“…We have known about miRNAs and their role in mRNA regulation for over a decade; however, we still do not entirely understand the molecular mechanisms of how miRNAs regulate gene expression nor have we identified and established all the miRNA targets in the human genome (Fabbri et al, 2011). Thus, it becomes essential to understand the function and targets of miRNA by inhibiting the miRNA in a biological process.…”

“…The reason is that the liver is amongst the most successful organs in the uptake of therapeutic RNAs. Not only is the bioavailability a challenge, but also there are other hurdles in therapeutic delivery of such RNAs that include size of the RNA and mode of delivery (Fabbri et al, 2011). Any RNAs less than 50 kDa are filtered through the kidney and excreted so local delivery of the modified RNAs is preferred.…”

“…An alternative to ASOs is generating miRNA-binding RNA transcripts to sequester and inhibit specific miRNAs that can be expressed via viral vectors in cell lines, plants, or model animals (Ebert et al, 2007; Loya et al, 2009; Ebert and Sharp, 2010; Todesco et al, 2010; Fabbri et al, 2011). The first known miRNA decoy consisted of an adenoviral vector with miRNA-133 sites inserted in 3′UTR of GFP reporter gene under a RNA polymerase II promoter (Care et al, 2007).…”