Development of Framework Nucleic Acid based platform technology for intradermal and transdermal delivery of oligonucleotides therapeutics
DescriptionIntradermal and transdermal delivery of oligonucleotide therapeutics is a preferred administration route for treating skin disorders and vaccination. Unfortunately, delivery of naked oligonucleotides across the stratum corneum is challenging. Unmodified oligonucleotides are rapidly degraded by nucleases and have low membrane permeability because of their high molecular weight and negative charges. Nanoparticle-based topical formulations have been positioned to tackle this issue. However, there is a lack of precision in controlling the skin penetration depth of existing nanoformulations. This proposal aims at developing a platform technology for the precise intradermal/transdermal delivery of oligonucleotides using Framework Nucleic Acids (FNAs) as carriers. Our preliminary experiments have demonstrated the efficacy of topically applied FNAs to penetrate into the skin and to deliver molecular therapeutic agents for managing pathological skin diseases. The skin penetration depth of FNAs is tightly regulated by their sizes and can be further improved with ionic liquid (IL) formulation. Here we will develop strategies for integrating therapeutic antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) into FNAs. By taking skin fibrosis as a disease model, both ASOs and siRNA will target Transforming Growth Factor beta 1 in skin fibroblasts to modulate the expression and deposition of collagen.Finally, ASO-FNAs and siRNA-FNAs will be formulated with ILs. The therapeutic effect will be examined in the hypertrophic scar rabbit ear model and be benchmarked to topical corticosteroid treatment. Short-term and long-term safety will be examined in this process as well. Upon project completion, the FNA formulation will have broad applicability since therapeutic oligonucleotides can be designed to modulate any gene alteration responsible for other diseases, including psoriasis, atopic dermatitis, and skin cancers. It can also be used to deliver DNA/RNA vaccines against infectious diseases.
|Effective start/end date||1/01/22 → …|