We developed a fully chemically modified, GalNAc-conjugated oligonucleotide platform that recruits endogenous ADAR for precise A-to-I RNA editing. Targeting SERPINA1  to correct the PiZZ mutation in AATD, we achieved >90% in vitro and >50% in vivo editing, restoring therapeutic M-AAT levels with subcutaneous dosing. NHP studies showed extended half-life and no toxicity, supporting a safe, durable, disease-modifying therapy and rapid expansion to other genetic diseases.

Premature termination codons (PTCs) prevent full length protein production and underpin 10% of the genetic mutations that cause rare diseases. Alltrna has developed engineered tRNAs that can readthrough PTCs and deliver the correct amino acid restoring full-length protein. This approach to treating rare disease allows Alltrna to target PTC mutations themselves instead of individual diseases. We will present multiple strategies that have enabled the development of more active engineered tRNAs and demonstrate progress toward chemically modified variants suitable for therapeutic applications.

The advent of programable therapeutics is transforming the treatment landscape for genetic and acquired diseases. The talk will discuss recent advances in oligonucleotides and genome editing therapies, as well as the design of delivery systems. Through selected case studies and pipeline insights, we will highlight technologies are converging to realize the full promise of precision medicine.

The emergence of mRNA modality as a therapeutic alternative for treatment of viruses, infectious disease, and more has highlighted the need for understanding how the design of mRNA impacts functionality of mRNA. To understanding how mRNA design impacts translation one needs to correlate the physical characterization to functional characterization of mRNA. We will discuss various strategies for assessing the impact of mRNA design on physical and functional characterization of mRNA.

mRNA therapeutics have redefined vaccine development, yet their transformative potential in cancer gene therapy remains largely unrealized. At Strand Therapeutics, we are pioneering a programmable mRNA platform designed to expand the therapeutic window of cytokine-based immunotherapies by combining the potency of self-replicating mRNA with sophisticated genetic circuit engineering. This approach aims to deliver precise and controlled immune activation with improved safety across a range of solid tumors.

Active cellular targeting using lipid nanoparticles (LNPs) represents the next generation of RNA delivery vehicles. In my presentation, I will detail four payloads: locked nucleic acids (LNA), siRNA, mRNA, CRISPR mRNA, and sgRNAs in a single LNP. I will highlight several studies, including novel therapeutics for IBD, for hematological malignancies, for expressing a toxin protein in cancer, and for therapeutic genome editing. Special emphasis will be made on CMC challenges.

xRNA™ uses high-throughput combinatorial screening to improve the expression profile of conventional mRNA ~100-fold, demonstrating NHP half-life durability of 3.6-fold improvement over WT mice. xRNA-encoded GLP-1 agonist (xGLP1) administered weekly outperformed daily-dosed FDA-approved comparators in pre-diabetic mice, inducing substantial weight loss and improved glucose homeostasis. Moreover, single-dose administration of xGLP-1 significantly reduced HbA1c >3 weeks in diabetic mice. xRNA thus potentially enables monthly/quarterly therapeutic regimens, compatible with at-home self-administration intramuscularly.

mRNA therapeutics is rapidly emerging as a groundbreaking strategy for treating cardiovascular diseases (CVD), which claimed 20 million lives globally in 2022 and affects 650 million people. Despite advances in medicine, the need for curative therapies remains urgent. In my presentation, I will share a decade of our work on mRNA therapies that promote cardiac function and repair, combat fibrosis, cell death, and hypertrophy in CVD models. Additionally, we introduce novel cell-specific mRNA expression platforms, advancing the field of CVD therapeutics.