Perspectives in MicroRNA Therapeutics - The authors provide insight into microRNA biology, and the simplicity of anti-miR oligonucleotide drug delivery, which can restore balance and function to dysre

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Perspectives in MicroRNA Therapeutics
The authors provide insight into microRNA biology, and the simplicity of anti-miR oligonucleotide drug delivery, which can restore balance and function to dysregulated microRNA pathways of gene expression.


BioPharm International
Volume 24, Issue 10, pp. 49-53

ANTI-MIR DELIVERY AND FUNCTION


Figure 6: Functional drug delivery of anti-miRs in mouse peritoneal macrophages. Flow-cytometry studies (a) and gene-regulation studies (b) demonstrate the internalization of anti-miR and target engagement in macrophages (Sylamer analysis). Potential targets containing heptamer 1-7 (GCATTAA) or heptamer 2-8 (AGCATTA) are enriched. X-axis is ranked genes by fold change. Y axis is -log (P-value enrichment). PBS is Phosphate-buffered saline.
mRNA expression-profiling methods coupled with statistical techniques that can measure small changes in the expression of many genes have become powerful tools to further our understanding of the biological role and function of microRNAs. Relying on the scientific findings that some microRNAs are capable of regulating hundreds of messenger RNAs, studies were performed in mice to determine anti-miR delivery to different cell types. Mice were treated with a specific anti-miR (intraperitoneal injection) and multiple cell types were harvested to for mRNA expression studies using Sylamer enrichment analysis (15). Anti-miR oligonucleotides are distributed to peritoneal macrophages as evidenced by flow cytometry analysis and target gene up-regulation (see Figure 6). An analysis identifying an overrepresented set of genes associated with a specific anti-miR biological effect was conducted and a data plot from the isolated macrophages was generated that demonstrated the most up-regulated sets of genes after anti-miR treatment. P values generated for this dataset suggest statistically significant preferential up-regulation of genes matched to their target sequence after anti-miR treatment.

CONCLUSION

Targeting pathways of human disease with microRNA-based drugs represents a novel and potentially powerful therapeutic approach. Recent data demonstrate not only that dysregulated microRNAs are associated with and can cause human disease, but that selective modulation through anti-miR intervention can provide therapeutic benefits. Anti-miR oligonucleotides can be easily administered through local or parenteral injection routes with sufficient uptake of the agent to achieve sustained target inhibition in tissues and organs without the need of formulation. Improvements in anti-miR chemical design and pharmacokinetic properties will allow further exploration of microRNA biology and broaden the utility of microRNA therapeutics.

Kevin Steffy, PhD,* is the global alliance manager, Charles Allerson, PhD, is the associate director of chemistry, and Balkrishen Bhat, PhD, is the senior director of chemistry, all at Regulus Therapeutics, 3545 John Hopkins Ct., San Diego, CA 92121, tel. 858.202.6321,
.



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