Overcoming Challenges in the Development of mRNA Therapeutics

This year, the 15th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology took place in Prague, Czech Republic. We show posters, which have been presented during the event.

Overcoming Challenges in the Development of mRNA Therapeutics

INTRODUCTION

The messenger RNA (mRNA) platform is evaluated for its potential to transform modern medicine. Unlike recombinant DNA technology, mRNA is easily produced and provides the capacity for rapid development of a wide range of applications in vaccines and therapeutics for major human diseases including cancer, heart disease and Alzheimer’s.

Despite significant progress, development of mRNA therapeutics is associated with major challenges which include formulation for parenteral administration, the prevalent route for large molecule actives; stability in the formulation and after administration; transport, intracellular delivery, and uptake; and safety, including immune related, off-target binding and sequence-induced toxicity. This poster summarizes ongoing research with vitamin E TPGS for emerging approaches in overcoming challenges associated with development of novel, high potential mRNA therapeutics.

VITAMIN E TPGS IN mRNA THERAPEUTICS

Vitamin E TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate), has been shown to function as solubilizer, emulsifier, and absorption enhancer of lipophilic and poorly soluble drugs. In addition, it enhances drug bioavailability and efficacy through inhibition of the P-glycoprotein mediated drug efflux and other mechanisms which reduce first-pass metabolism and facilitate its transport, cell uptake and function.

Its properties include antioxidant function primarily due to its tocopherol component, available as free tocopherol in the product and metabolism after absorption, and high thermal degradation temperature (199.3°C).

The safety of vitamin E TPGS has been evaluated in studies by the National Institutes of Health, the Cystic Fibrosis Foundation, and research organizations. Major clinical studies in animals and humans supported its use in drug formulations, medical foods, dietary supplements, foods and beverages, personal care, and animal nutrition and health products. A recent report by the European Food Safety Authority (EFSA) on the overall safety of vitamin E TPGS provided updated evaluation. The safety and efficacy of vitamin E TPGS expanded research and development in major areas of formulation, delivery, and efficacy including mRNA therapeutics.

THE mRNA STABILITY CHALLENGE

The physical and chemical properties of mRNA contribute to its inherent instability with direct impact on formulation, delivery, efficacy and safety. Its solubility in water, single stranded structure and the presence of the 2’ hydroxyl group makes it prone to chemical and enzymatic degradation. Hydrolysis is likely major part of chemical degradation. Oxidation however, which produces reactive oxidative species, has been implicated in acceleration of degradation and generation of harmful byproducts. Their direct effect on immune responses and inflammation is associated with reduced efficacy, adverse effects and toxicity.

Stability in the formulation and delivery system

Formulation of mRNA therapeutics for the prevalent parenteral administration requires exposure to mixing and other processing for incorporation to the delivery system, and heating (sterilization). Oxidation is receiving increased attention for its direct effect on mRNA but also the lipid component of the formulation, especially of the prevalent lipidbased nanoparticle (LNP) delivery systems.

Stability after administration

Degradation of mRNA, prior to cellular uptake at the target site, produces nucleotide metabolites which inhibit cell proliferation especially in central nervous system tissues. Oxidation after administration contributes to inflammatory responses, off-target protein expression, and overall safety and efficacy.

Effect of Vitamin E TPGS on mRNA stability

The antioxidant function of d-alpha-tocopherol in vitamin E TPGS reduces production and adverse effects of reactive oxygen species and supports oxidative stability of mRNA in the formulation and after delivery. The antioxidant function supports synergism in mRNA functionality by reducing the production of reactive oxygen species, rate of degradation to harmful byproducts, inflammation and toxicity.

OTHER APPLICATIONS IN mRNA THERAPEUTICS

Component of mRNA delivery systems

Ongoing research suggests that incorporation of vitamin E TPGS into nanoparticles reduces hepatic filtration and opsonization and increases the systemic concentration of the nanoparticles and therefore the efficacy of the payload. For LNP, the prevalent delivery system for mRNA therapeutics, the antioxidant and other properties support overall stability, and safety.

Formation of prodrugs and conjugates

Prodrugs and conjugates show great potential for reduced toxicity, improved stability, delivery to the active sites, increased activity and reduced multi drug resistance. Research on the use of vitamin E TPGS in the formation of prodrugs and drug conjugates was accelerated by promising results with the cancer treatment and chemotherapy agents doxorubicin cisplatin, 5-fluorouracil, and paclitaxel. Polymer-drug conjugates combine the properties of polymers and drugs for encapsulation efficiency, biodegradable and biocompatible systems, especially nanoparticle systems, and as adjuvants for dissolving, adsorbing, or chemically binding active ingredients. These properties of vitamin E TPGS are evaluated for potential novel applications of the mRNA technology including products for oral and other non-parenteral administration.

Multidrug resistance

Oxidation and degradation, facilitated by the cytochrome P450 family of enzymes (CYP), reduce the bioavailability and efficacy of active pharmaceutical and other compounds and may increase their adverse side effects. Vitamin E TPGS shows promise through its inhibition of the P-gp efflux and the activity of cytochrome P450 and multidrug resistance proteins.

CONCLUSION

Ongoing research indicates that vitamin E TPGS is a powerful tool in overcoming challenges in the development of novel, high potential mRNA therapeutics. Of major significance is the support of stabilitythrough antioxidant function on mRNA and the prevalent lipid nanoparticle delivery systems in the formulation before and after administration. The antioxidant effect on stability, associated reduction of reactive oxidative species, and additional properties support formulation and hybrid delivery systems which enhance transport, cellular uptake, and reduce the rate of degradation, generation of harmful byproducts, and toxicity.

See the full poster on Overcoming Challenges in the Development of mRNA Therapeutics here

(click the picture to download the poster)

Source: Andreas M Papas, Overcoming Challenges in the Development of mRNA Therapeutics, Antares Health Products, East Tennessee State University

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