AVI Chemistries: PMO, PPMO and PMOplus™
AVI BioPharma’s core chemistry is based on phosphorodiamidate morpholino oligomers or PMOs. PMOs are synthetic molecules based on a fundamental redesign of the natural nucleic acid structure. PMOs bind to complementary sequences of mRNA by standard nucleic acid base–pairing. Structurally, the difference between PMOs and DNA is that while PMOs have standard nucleic acid bases, those bases are bound to morpholine rings instead of deoxyribose rings and they are linked through phosphorodiamidate groups instead of phosphates. Replacement of anionic phosphates with the uncharged phosphorodiamidate groups eliminates ionization in the usual physiological pH range, so PMOs in organisms or cells are uncharged molecules. The entire backbone of a PMO is made from these modified subunits
This difference in the PMOs backbone’s chemistry differentiates AVI BioPharma’s PMO based drug candidates from both earlier–generation and many current antisense technologies. These key differences provide the pharmaceutical properties that are required for antisense technology to achieve broad drug character and potential clinical utility.
AVI has advanced its original PMO chemistry through the addition of two new PMO analogues. The first is a peptide conjugated phosphorodiamidate morpholino oligomer or PPMO, where cellular uptake of PMOs, as well as the specificity of tissue targeting, can be significantly enhanced by the PMO’s conjugation to arginine–rich cell–penetrating peptides (CPPs).
The second advance includes the addition of positive charge to certain monomers on the PMO backbone. This new PMO analogue, the PMOplus™, is very effective in overcoming the viral mutations which make certain viruses drug–resistant. AVI continues to advance additional discoveries to further optimize its core proprietary chemistry as well as to develop novel analogues that expand the range of its utility performance characteristics.
Favorable Properties of PMO, PPMO and PMOplus™
In preclinical and clinical studies, the three analogue compounds have demonstrated advantageous pharmaceutical properties including stability, specificity, efficacy, delivery and safety.
AVI’s principal competitive advantage with its PMO technology is the chemical structure of the compound backbone, which has been developed specifically to address the following pharmaceutical parameters:
Stability: Biological stability is principally determined by the resistance of the compound to degrading enzymes in the body. Because the PMO backbone has a unique and synthetic chemical structure, there are no human enzymes that degrade it. As a result, PMO drug candidates have shown excellent stability in human clinical trials.
Efficacy and specificity: Efficacy refers to the efficiency with which PMO analogues block selected RNA targets. Specificity is how accurate the compounds are in blocking only the selected targets (and not other, unrelated targets). In direct comparison with other technologies, PMO based compounds exhibit significantly better efficacy in inhibiting targeted genetic sequences and substantially greater specificity.
Delivery: To reach their genetic targets, antisense compounds must cross many barriers, including cellular and nuclear membranes. Research conducted in animal models and human clinical trials has shown that PMO and PMO analogue compounds are transported to targeted sites where they produce their effect.
Safety: Human clinical trial results indicate that PMO antisense agents have a promising safety profile. In the treatment of more than 400 patients, no serious drug–related adverse events have been observed.
Comparison of Gene-Targeted Technologies
