Publicaciones científicas
Ancestral library identifies conserved reprogrammable liver motif on AAV capsid
Eric Zinn 1, Carmen Unzu 1, Pauline F Schmit 1, Heikki T Turunen 1, Nerea Zabaleta 1, Julio Sanmiguel 1, Allegra Fieldsend 1, Urja Bhatt 1, Cheikh Diop 1, Erin Merkel 1, Rakesh Gurrala 1, Bryan Peacker 2, Christopher Rios 2, Kathleen Messemer 2, Jennifer Santos 1, Reynette Estelien 1, Eva Andres-Mateos 1, Amy J Wagers 3, Christopher Tipper 1, Luk H Vandenberghe 4
Abstract
Gene therapy is emerging as a modality in 21st-century medicine. Adeno-associated viral (AAV) gene transfer is a leading technology to achieve efficient and durable expression of a therapeutic transgene. However, the structural complexity of the capsid has constrained efforts to engineer the particle toward improved clinical safety and efficacy.
Here, we generate a curated library of barcoded AAVs with mutations across a variety of functionally relevant motifs. We then screen this library in vitro and in vivo in mice and nonhuman primates, enabling a broad, multiparametric assessment of every vector within the library. Among the results, we note a single residue that modulates liver transduction across all interrogated models while preserving transduction in heart and skeletal muscles.
Moreover, we find that this mutation can be grafted into AAV9 and leads to profound liver detargeting while retaining muscle transduction-a finding potentially relevant to preventing hepatoxicities seen in clinical studies.
CITA DEL ARTÍCULO Cell Rep Med. 2022 Nov 15;3(11):100803. doi: 10.1016/j.xcrm.2022.100803. Epub 2022 Nov 2.