At this year’s ASGCT annual meeting, the scientific symposium “Therapeutic Applications of Non-Viral RNA: Therapy Strategies” featured investigators from University of Pennsylvania and Moderna Therapeutics who provided deep insight on the advantages of RNA technology for drug development.
First, Hamideh Parhiz, PharmD, PhD, University of Pennsylvania presented a talk titled “Targeted Lipid Nanoparticle Platform for in vivo Delivery of mRNA Therapeutics.” Dr. Parhiz started by discussing key advantages of mRNA, as opposed to other macromolecules such as DNA and proteins, for therapeutic strategies. From dosing requirements, to rate of expression, and ease of delivery, mRNA molecules as a therapeutic modality often outperform the effectiveness of other macromolecules.
For example as opposed to DNA, which would need to transit through the cell membrane and cytoplasm to reach the nucleus, mRNA molecules are rapidly processed by the cytosolic translation machinery, necessitating fewer molecules and expediting protein production. Additionally, genomic integration, a potential risk with some DNA therapeutics, is absolutely by-passed, resulting additionally in transient protein production that may be more easily optimized to achieve desirable therapeutic benefits.
Dr. Parhiz shared that the mRNA’s versatility, enabling the rapid production of either secreted, intracellular, or membrane bound proteins, is a particularly strong benefit of this therapeutic vehicle. Lastly, advances in mRNA synthesis methods such as the use of chemically modified nucleosides (e.g., pseudouridine) together with optimized purification methodologies, have enabled the effective use of in vitro transcribed (IVT) mRNA macromolecules as drugs. Together these advantageous properties and synthetic advances have helped to significantly expedite the therapeutic development workflow, and thus the delivery of mRNA drugs to the clinic, often by leveraging lipid nanoparticles (LNPs) as a preferred delivery vehicle.
IVT mRNA Therapy Modalities poster. Overview of IVT mRNA structural and delivery advances enabling today’s therapies and mRNA therapy modalities advancing through clinical trials.
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Beyond the essential role of LNPs in protecting mRNAs from degradation, these multicomponent structures can also be modified to enable targeting therapeutically relevant tissues. As shared by Dr. Parhiz, whose work focuses on improving LNP tissue-targeting, a main disadvantage of this delivery vehicle is its preferred absorption by the liver. By developing a targeted LNP-mRNA platform, leveraging the specificity of antibodies, Dr. Parhiz has made possible the targeted delivery of mRNA to different cells types (e.g., endothelial and T cells).
Most recently, this platform made possible the targeting of T cells in vivo, in a preclinical model of cardiac fibrosis, to generate transient CAR-T cells with specificity against activated fibroblasts (anti-Fibroblast Activated Protein or FAPCAR) (Rurik et al. 2022). Dr. Parhiz acknowledged that the use of mRNA targeted LNPs in the generation of CAR-T cells in vivo is a powerful approach that would benefit patients for whom conventional in vitro CAR-T cell production is impossible due to their low T cell counts.
Monogenic disorders represent another relevant therapeutic area where IVT mRNA drugs can make a significant impact. Dr. Lisa Rice, a scientist for the strategy team at Moderna Therapeutics, presented on “Strategies for Developing mRNA Based Therapeutics for Rare Diseases.” A number of IVT mRNA synthesis advances have been introduce at Moderna to enable the successful production of mRNA therapies such as the now well recognized COVID-19 vaccine, mRNA-1273 or Spikevax. Beyond prophylactic vaccines, Moderna’s platform is supporting developing mRNA therapies for a broad range of applications, such as cancer vaccines, intratumoral immune-oncology, localized regenerative therapies and more. Dr. Rice shared how Moderna’s IVT mRNA pipeline has been strengthened by various advances in mRNA chemistry, sequence, targeting elements, delivery strategies, and improved manufacturing processes.
For rare diseases, Moderna is leveraging LNPs for intravenous (i.v.) delivery of mRNA therapeutics. Dr. Rice shared how for protein replacement applications, modulating and optimizing the pharmacokinetics (i.e. half-life) of both the IVT mRNA and protein product is critical for best therapeutic outcomes. To this end Moderna’s team closely fine-tunes translation initiation fidelity, ensuring the production of the correct and functional protein product, often enzymes in rare diseases. Additionally, to achieve targeted protein expression in cells and tissues, Moderna’s team leverages incorporation of microRNA target sites into the IVT mRNA’s UTR sequences. Lastly, IVT mRNA immunogenicity is controlled through chemical modifications and manufacturing processes. Currently, Moderna’s team is conducting preclinical studies to optimize IVT mRNA therapies for Phenylketonuria (PKU), a rare disease characterized by the build-up of phenylalanine due to inherited mutations in the gene encoding phenylalanine hydroxylase.