Abstract Details

D - Oligonucleotide Therapeutics (including siRNAs, aptamers, antagomirs, miRNAs, shRNA, antisense, and splice switching oligos, plasmids)

1709: Successful In Vivo Oral Delivery of Biologically Active and Therapeutic Anti-Inflammatory mRNA-Targeted Oligonucleotides with a Lipid Nanocrystal Delivery Platform

Type: Poster Session

Poster Board Number: 1709

Presentation Details

Session Title: Friday Posters: Oligonucleotide Therapeutics






Background: There has been little progress in the oral delivery of nucleic acid therapeutics beyond the liver. Matinas BioPharmas’ lipid nanocrystal (LNC) platform successfully delivers oral amphotericin-B in patients with cryptococcal meningitis, and other ex vivo work has shown avid LNC uptake by innate immune cells. Prior studies have shown the in vitro efficacy of two mRNA-targeted oligos - one knocking down IL-17A, the other knocking down TNFa. LNC formulations of both have shown greater cytokine knock-down than “naked” oligos in vitro. The present work evaluated the in vivo efficacy of oral LNC formulations of these oligos in two inflammatory disease models. Methods: Psoriasis in BALB/c mice was induced with 31.25 mg of 5% Imiquimod (IMQ) applied daily for 6 days. There were 5 treatment groups (n=10/group): untreated controls, IMQ alone, IMQ plus one of two different LNC-oligo formulations administered daily by oral gavage, and IMQ plus anti-IL-17A antibodies. Skin Erythema and scaling was scored daily. The study was terminated at day 7; cytokine mRNA levels in the psoriatic skin lesions were determined by qRT-PCR. Colitis in C57BL/6 mice was induced with 3.5% DSS in drinking water for 5 days. There were 6 treatment groups: untreated controls, DSS alone, DSS plus one of two different LNC-oligo formulations, DSS plus LNC formulated scrambled oligos, and DSS plus a TNFa neutralizing antibody. Daily disease activity scores were measured; animals were sacrificed at day 14 and serum TNFa and tissue (colon) TNFa mRNA (qt-PCR) were measured. Results: In the imiquimod psoriasis model (Figure 1) daily oral administration of an LNC formulation of the IL-17A targeted oligo resulted in both knock-down of skin IL-17 mRNA, and significant improvement in clinical parameters of redness and scaling. Similarly, in the DSS colitis model (Figure 2), daily oral administration of an oral LNC formulation of the TNFa targeted oligo resulted in reductions of colon TNFa mRNA and significant reductions in serum TNFa levels, as well as significant improvements in disease activity scores. Thus, we have shown successful oral delivery of two RNAi oligos targeting different inflammatory cytokines in two different disease models; with documented biological/molecular activity as well as therapeutic efficacy. Conclusions: The LNC delivery platform can successfully orally deliver biologically active (and potentially therapeutic) oligonucleotides targeting key cytokines in inflammatory disease models. While these initial results are promising, there is still some individual heterogeneity of response; future work will be focused on optimizing the LNC formulations to improve delivery efficiency, increase their potency, and extend the application of oral cytokine-targeting oligo therapeutics in other inflammatory diseases. models.

Plain Language Summary

In recent years there has been little progress in orally delivered therapeutic nucleic acids outside of the liver. Matinas BioPharma's new lipid nanocrystal (LNC) delivery platform has been used in humans to orally deliver an antifungal drug (that was previously IV-only) in critically ill patients with brain fungal infections. We have extended this work to show how LNCs allowed successful oral delivery of two different small oligonucleotides in animal inflammatory disease models; each showed both biological activity and potential therapeutic effects. Small therapeutic anti-inflammatory oligonucleotides can be orally delivered outside the liver.

Hui Liu¹, Vinod Ramgolam², Jeffrey Bender², Miriam Mikhael¹, Amra Tabakovic¹, Tzong-Jen Sheu¹, Partha Samadder¹, Thomas Hoover¹, James J. Ferguson<sup>1

1</sup>Matinas BioPharma, Bedminster, NJ,²TargetSite Therapeutics, New Haven, CT"