Composition and method of lipid nanoparticles carrying oligonucleotides
T2019-066 Novel lipid nanoparticles used for carrying antisense oligonucleotides with improved targeting for cancer treatment
Lung cancer is the leading cause of cancer related deaths in the US with approximately 150,000 deaths in 2017. Currently, mildly ineffective chemotherapeutics ripe with adverse side effects are the standard treatment. Antisense oligonucleotides (ASOs) are able to selectively modulate expression of target genes by preventing mRNA translation into protein. ASOs already have been shown to have promising efficacy in preclinical studies. Akt-1 and Bcl2 are considered significant potential targets for inhibition via ASOs due to their roles in various cancer pathways. Under current production methods, ASOs face in vivo challenges like nuclease degradation, low target binding affinity, low membrane permeability, and off-target effects.
Researchers at The Ohio State University, led by Dr. Robert Lee of the College of Pharmacy, have solved a number of these problems through their innovative use of lipid nanoparticles, gapmer design strategy through the addition of 2'-O-methyl modifications, and T7 peptide for tumor targeting. The use of the lipid nanoparticle allows for improved durability of the ASOs and increased membrane permeability. The gapmer design via the 2'-OMe modification protect the ASOs from nucleases thus mitigating the risk for degradation. The T7 peptide conjugation with the nanoparticle provides improved targeting of and uptake into tumor cell thus also decreasing off target effects. These results were confirmed both in vivo and in vitro. The triumvirate of ASO modification, nanoparticle encapsulation, and peptide conjugation provides adequate solutions to a number of the problems plaguing ASO cancer treatments. In addition, nanoparticle-based co-delivery of a synergistic ratio of two oligos against separate targets, bcl-2 and akt-1, lead to increased therapeutic efficacy.
- Cancer treatment
- Drug delivery
- Decreased degradation from nucleases
- Improved longevity
- Increased membrane permeability
- Decreased off-target effects
- Improved targeting
The Ohio State University laboratory that developed this technology has expertise in a range of areas related to lipid nanoparticles. They specialize in custom-design LNP for various cargo and in developing products tailored to the specific clinical application. The lab is focused on nucleic acid drug delivery and can be used for mRNA, plasmid DNA, siRNA, miRNA, antisense ODN, CpG ODNs and sgRNA for CRISPR gene editing, and any gene therapy related applications. The laboratory is open for collaboration for additional cargos and investigational routes.