This presentation will explore new conjugate space for siRNAs, LNA-morpholinos for stability of siRNAs, LNA and LNA isomers for RNAi, gemini Bis-siRNAs and loopmers.

Lipophilic conjugation of fully chemically stabilized small-interfering RNA supports significant and effective delivery throughout the body. Therefore, chemically engineering lipid conjugates may be a strategy to improve siRNA delivery to extrahepatic tissues. In this talk, I will describe recent progress in understanding the relationship between conjugate chemical structure and siRNA pharmacokinetic/pharmacodynamic behavior. We will exemplify that modulating conjugate chemistry supports functional delivery to a range of tissues, including heart.

GalAhead muRNA, a proprietary RNAi-based platform allows for simultaneous downregulating of multiple genes in liver hepatocytes, providing treatment of liver associated diseases. The muRNA concept allows modulation of converging biological pathways while still allowing a window to perform physiological function. muRNA can also simultaneously address two or more non-associated indications where patient populations have a considerable overlap. GalAhead muRNA offers an inspiring venue in the RNAi space providing safe and long-lasting effect in treating patients with unmet medical needs.

Wave’s PRISM platform enables the generation of chimeric backbone-containing stereopure oligonucleotides with position-controlled chemistry and stereochemical configuration. Here, we will describe how incorporating phosphoryl guanidine (PN) backbone linkages can improve the pharmacological properties of oligonucleotides designed for distinct high priority genetic targets, modalities, and tissues. Early data from our ongoing clinical trials suggests that the improved pharmacological properties of investigational PN-containing oligonucleotides are translating into the clinic.

Refractory malignant solid tumors create an immunosuppressive tumor microenvironment, which renders them resistant to standard-of-care immune checkpoint inhibitors. We developed RNAi agents to silence PD-L1 targets in tumor-associated immune cells, which mediates immune suppression in the TME. Silencing PD-L1 in antigen presenting cells remodeled the TME and increased cytotoxic T cell infiltration into the tumor. Human active PDL1 RNAi conjugate is currently in Phase 1 clinical trials for immunotherapy-refractory cancers.

The FORCE platform demonstrates targeted, neuromuscular delivery of oligonucleotides and achieved clinical translation in ACHIEVE trial for DM1 and DELIVER trial for DMD to open an opportunity for the treatment of FSHD. In preclinical models of FSHD, DYNE-302, a Fab-siRNA conjugate, achieved robust muscle delivery and target engagement, leading to appreciable benefit on muscle function and myofiber pathology.

Chemical modification has been a key enabler of clinical success for all previous classes of oligonucleotide therapeutics.  As genome editing increases its clinical reach, we describe progress in modification of guides for Cas9 nuclease, base editing and prime editing approaches, including split prime editing systems. We measure changes in both specificity and in vivo efficacy (LNP delivery co-formulated with mRNA).  

AIMers are oligonucleotides that engage endogenous ADAR enzymes to induce highly efficient and specific A-to-I RNA base editing. Our recently optimized AIMer design increases the potency, target space, and tissue targeting capabilities of RNA editing. Optimized AIMers support efficient RNA editing in both hepatic and extrahepatic tissues, including the central nervous system, kidney, and lung. We will show that AIMers support RNA editing of disease-relevant targets in multiple tissues.

This talk will focus on creating transformative genetic medicines for diseases of the liver, CNS, and beyond. At Korro, we use the “OPERA” (Oligonucleotide Promoted Editing of RNA) platform as a differentiated approach to identifying highly potent RNA editing therapeutics. This talk will also discuss Korro’s lead program, KRRO-110, which is potentially a best-in-class therapeutic for the treatment of Alpha-1 Antitrypsin Deficiency (AATD).

The goal for the next generation of CRISPR-based medicines is the development of potent and safe therapeutics that can be delivered in vivo specifically to the target cells of interest. The mRNA/LNP format is currently showing the most promise to achieve this challenging goal, and various factors can be optimized to enhance performance, including vehicle (lipid composition and targeting elements), cargo (mRNA and gRNA), and analytical method development.

ZATA's amidites enable incorporation of ON backbone modifying (cationization) groups by direct automated synthesis. Such groups can be incorporated at any number and location enabled by size of ONs. Incorporated groups do not compromise any key properties, such as hybridization, solubility, stability, and others.