One letter. One edit. A world of difference.

Our approach

Mammals and other lower species like cephalopods have an endogenous process of modifying single bases on RNA, referred to as RNA editing. RNA editing is a natural physiological process that occurs in cells, including a mechanism mediated by an enzyme called adenosine deaminase acting on RNA, or ADAR. Our RNA editing approach involves co-opting this endogenous editing system via a proprietary engineered oligonucleotide (chemically modified RNA) to introduce precise edits.

 

Our platform

Oligonucleotide Promoted Editing of RNA (OPERA®)

We are leveraging a novel oligonucleotide delivery-based RNA editing technology (OPERA®) to develop a new class of genetic medicines for rare and highly prevalent diseases. OPERA provides precise, tissue-directed delivery of RNA editing oligonucleotides that modify the targeted native mRNA transcript to form a de novo protein with enhanced functionality. The platform combines a suite of capabilities consisting of sophisticated knowledge of transcription biology through ADAR proteins, machine learning optimization of oligonucleotides, linker chemistry expertise, along with use of a highly targeted tissue-specific delivery methodology. As such, the OPERA platform has enabled us to generate and advance a portfolio of differentiated programs that are designed to harness the body’s natural RNA editing process, providing precise yet transient single base edits to produce therapeutic proteins with augmented activity versus its endogenous counterpart. By editing RNA instead of DNA, Korro is expanding the reach of genetic medicines by delivering additional precision and tunability, which has the potential for increased specificity and improved long-term tolerability.

Supported by extensive preclinical research using in vitro assays and proprietary mouse models as well as the fundamental work of our scientific advisors and founders to elucidate key insights and know-how of ADAR biology. This enables an understanding of ADAR activity translation among different species and disease states, allowing us to develop novel lead candidates.

Enabled by the ability to identify and incorporate chemical modifications to generate a fully modified synthetic oligonucleotide. This increases our ability to generate potent oligonucleotides with drug-like properties, thereby increasing the editing and translational efficiency of our lead candidates.

Driven by data science and computational capabilities for rapid and efficient design and iteration resulting in optimal lead candidates for each disease or disease target being pursued.

Made possible by tissue-specific and validated delivery technologies that may potentially derisk our lead candidates and enhance biodistribution, specificity, durability and editing efficiency of lead candidates.

Generation 1 designs – CHORD™

Our first generated designs are called CHORD (Customized High-fidelity Oligonucleotides for RNA Deamination).

Key Advantages of CHORD™:

Synthetic CHORD oligonucleotides enable highly precise RNA edits with a low risk of off-target edits, avoiding a key safety concern associated with DNA editing and the associated risk of aberrant genome editing.
CHORD oligonucleotides are delivered using clinically validated approaches, including LNPs and tissue-specific ligands (e.g., GalNAc for the liver), that enable infrequent dosing and an acceptable tolerability profile.
CHORD oligonucleotides are transient and reversible and carry a low risk of immunogenicity. These qualities can offer an improved tolerability profile and enable the ability to re-dose patients, which are significant advantages compared with current DNA editing technologies.
Reliance on endogenous ADAR enzymes and the simple drug constructs of CHORD technology has significant advantages, compared with the complexities of multi-component exogenous complexes used for DNA editing.
CHORD oligonucleotides contain precedented chemical modifications and structural features present in several marketed oligonucleotide drugs. While guidance from the FDA and other regulatory bodies is well established for this class of therapeutics, regulators have yet to establish specific guidelines for RNA editing therapies, and clinical data has yet to be generated.

Our Focus Areas

Our OPERA® platform enables multiple therapeutic strategies. We are pursuing approaches that repair proteins by correcting pathogenic mutations, restoring a disease-causing variant back to its normal form. We are also pursuing approaches that activate or augment protein activity, engineering de novo protein variants to unlock new, therapeutically beneficial properties with a broad universe of applications.

Synthetic rescue

Synthetic rescue as an RNA editing approach is designed to augment a biological process, enabling a therapeutic intervention to compensate for, rather than directly reverse, the underlying molecular defect. By engineering targeted changes to existing proteins, synthetic rescue has the potential to address diseases where simply correcting a mutation is insufficient or where no mutation exists to correct. Our lead program, KRRO-121, exemplifies this approach. KRRO-121 is designed to generate a stabilized, de novo variant of glutamine synthetase (GS), a critical enzyme involved in ammonia clearance.

Learn more about hyperammonemia and KRRO-121

Our pipeline

Our pipeline programs demonstrate the versatility of our approach in bringing precision and tunability to genetic medicines to address a broad range of rare and highly prevalent diseases. We can repair proteins caused by genetic mutations or alter proteins to activate a biological pathway.

View our pipeline