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Transient genome editor delivery

The state-of-the-art delivery vector for genome editors is an adeno-associated virus (AAV), which can effectively transduce tissues and effect efficient genome editing. However, long-term expression of the genome editors from AAV is not ideal due to potential off-target edits, which can occur in sites of the genome similar to the therapeutic target and can compromise the therapeutic effect. In CTVR, we develop transient delivery methods to achieve efficient, precise editing without off-target effects.

The purified genome editors – enzymatically active complexes of genome editor protein and guide RNA, called ribonucleoproteins – are the most transient and chemically defined way to edit DNA. We manufacture the ribonucleoproteins and package them in nanoparticles, and such candidate drug leads to therapeutic editing in the eye, as we demonstrated in a rd12 mouse model of Leber Congenital Amaurosis. We further develop the ribonucleoprotein technology to increase efficacy and demonstrate its potential in other retinal degeneration models, such as retinitis pigmentosa model rd6.

In another approach, we generate virus-like particles, biologics, which contain our designed ribonucleoproteins enclosed in a lipid vesicle manufactured by cultured cells. We prepare the virus-like particles with a clinical-grade purity, and so far we found that they have an enormous potential to effect therapeutic genome editing.

Stay tuned, as we continue to develop nanoparticle and virus-like particle technologies to achieve therapeutic editing!

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References:
1. Holubowicz, R., Du, S.W., Felgner, J. et al. Safer and efficient base editing and prime editing via ribonucleoproteins delivered through optimized lipid-nanoparticle formulations. Nat. Biomed. Eng 9, 57–78 (2025). https://doi.org/10.1038/s41551-024-01296-2

2. An, M., Raguram, A., Du, S.W. et al. Engineered virus-like particles for transient delivery of prime editor ribonucleoprotein complexes in vivo. Nat Biotechnol 42, 1526–1537 (2024). https://doi.org/10.1038/s41587-023-02078-y

3. Banskota S., Ragguram A., Suh S. et al. Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins. Cell 185 (2), 250-265 (2022). https://doi.org/10.1016/j.cell.2021.12.021