Oligonucleotide-based Therapeutics Targeting COVID-19
Oligonucleotides (ONs) are a promising class of agents in the fight against a wide variety of diseases including cancers, neuropathies, and metabolic disorders. Despite decades of research results indicating widespread clinical success, the therapeutic use of ONs have yet to be realized, which is somewhat due to the bio-pharmaceutical difficulties intrinsic to nucleic acids.
Chemically modified ONs, such as phosphorothioates and morpholinos, have been developed to circumvent some of these challenges, which resulted in six ON drugs reaching the market in the US to date. However, a high dosage requirement (and therefore, cost), difficulty in delivery to non-liver sites, and potential liver/cardiovascular toxicity remain challenges. At the same time, a range of synthetic transport vectors have been developed to facilitate ON delivery. While varying levels of laboratory success have been achieved, other than liposomes, none of these vector systems have received regulatory approval due to a range of issues such as carrier-induced toxicity/immunogenicity, inconsistency in the formulation, and limited benefit.
A range of nucleic acid-PEG conjugates, termed pacDNA, are used for gene regulation. However, all forms of pacDNA made thus far are inherently polydisperse concerning their overall molecular weight and the number of DNA strands per molecule. Such structural ambiguity may produce batch-to-batch differences and create problems for potential regulatory approval. The PI solves this problem by creating molecular pacDNA based upon fullerene C60 with well-defined numbers of DNA and polymer chains per molecule.
The PI has developed a platform technology termed pacDNA, which works by selectively blocking protein access while allowing hybridization to RNA. Based on materials proven safe, the technology can significantly improve the bioavailability and the biopharmaceutical properties of ASOs in vivo (e.g. pharmacokinetics [PK] and biodistribution). pacDNA structures for oncology targets in the lung have generated positive data in cell and mouse models of non-small cell lung cancer. When delivered via intravenous injection, the pacDNA is able to persist in the lung for several weeks.
Transforming pacDNA to target COVID-19 would only require a change in the DNA sequence, which should allow the PI to increase technology readiness rapidly. During the time that antisense DNA survives in the lung, it would reduce viral replication and protect the subject. It is envisioned that a patient will only need one or two injections to induce recovery.
- More reproducible and better quality control batch-to-batch
- Can be used to create nanoflares that are more resistant to background signals
- Oligonucleotide therapeutics (ASO, siRNA)
- Sensor development
- COVID-19 treatment
- Ke Zhang
- Well-defined Poly(ethylene glycol)-Oligonucleotide Miktoarm Star Polymers for Enzyme-resistant Nanoflares and Antisense Gene Regulation