// Sep 2026
ππ― ππͺπ·π° Gene Editing Needs Robust Iteration, Not One-Time Optimization
Potent, tolerable, and development-ready gene editing is not achieved through a single design decision. It improves through iteration: optimizing the editor, RNA chemistry, guide design, delivery vehicle, and target biology as one connected system.
This is especially true in the liver. LNP-mediated delivery has created a practical path for transient RNA delivery, but performance still depends on many interacting variables. A strong editor is not enough if the RNA composition is weak. A potent lipid nanoparticle (LNP) is not enough if the guide is underperforming. Development depends on making each component better, then carrying those learnings forward.
Drug Substance Optimization Can Unlock Potency
For in vivo editing, the drug substance is more than a single variable. It is the combined performance of the RNA payload, guide RNA, chemical modifications, and their compatibility with the LNP delivery system.
At ElevateBio, HAO1 has served as a useful in vivo liver target for optimizing LNP-RNA drug substances. In mouse studies, internal mRNA modifications and guide RNA modifications increased editing potency, with individual changes producing meaningful gains. These results show why optimization cannot stop at editor selection (see presentation and data). RNA design and chemistry can materially change in vivo editing outcomes.
Cross-Modality Learning Accelerates Development
The value of an integrated platform is that improvements in one modality can inform the next. Learnings from HAO1-targeted nuclease experiments helped guide more complex RNA payload strategies, including RT editing. In mouse studies, our internal formulation, LNP1, delivered an RT editor targeting HAO1, and the addition of an accessory protein improved editing.
The same feedforward logic supported base editing development. A proprietary LNP and adenine base editor were used to target PCSK9 in vivo, producing efficient editing with reductions in serum PCSK9 and total cholesterol. Those learnings helped inform subsequent NHP-ready editing work.
In Vivo Readiness Requires More Than Potency
Potency matters, but it is only one part of the development equation. Advanced therapy programs also need tolerability, translatability, and a path to improved follow-on editors.
ElevateBioβs LNP1-delivered A-base editor produced functional editing and target protein reduction in NHPs, with minimal transient liver enzyme changes across evaluated doses. Platform feedforward then enabled faster selection of follow-up editors, including engineered variants and alternate systems that improved in vitro potency.
In vivo gene editing advances fastest when optimization is iterative and integrated. By connecting RNA design, guide chemistry, LNP formulation, protein engineering, and preclinical validation, ElevateBio helps partners move from early editing concepts toward in vivo-ready programs with greater speed and higher potency without compromise.
Tyler McCullough, Ph.D
Tyler McCullough, Ph.D., is the Associate Director of Translational Biology at ElevateBioβs Life Edit Therapeutics. He brings 11 years of extensive experience in gene editing with a focus on Lipid Nanoparticle (LNP) and Adeno-Associated Virus (AAV) delivery systems targeting various organs, including the eye, muscle and liver. His expertise includes IND-enabling studies, from mice up to non-human primates (NHP).
Previously, Dr. McCullough held several roles at Life Edit, such as Senior Scientist, Preclinical Development. In this role, he was responsible for conducting preclinical studies, including first-in-mouse editing with proprietary systems and delivery methods. His work helped generate critical in vivo editing data that contributed to securing key partnerships.
During his academic career, Dr. McCullough collaborated with industry leaders in gene editing, independently designing and executing studies that led to one of the first therapeutic CRISPR-based editing studies in NHPs. He completed his post-doctoral fellowship at Duke University and earned his Ph.D. in Genetics from the University of Florida. Additionally, he holds a Master of Health Science from John Hopkins University and Bachelor of Science in Microbiology and Cell Science from the University of Florida.
