Casein kinase 2 activity is a host restriction factor for AAV transduction

Izabela Kraszewska, Katarzyna Sarad, Kalina Andrysiak, Aleksandra Kopacz, Luisa Schmidt, Marcus Krüger, Józef Dulak, Agnieszka Jaźwa-Kusior

Research output: Contribution to journalArticlepeer-review

Abstract

So far, the mechanisms that impede AAV transduction, especially in the human heart, are poorly understood, hampering the introduction of new, effective gene therapy strategies. Therefore, the aim of this study was to identify and overcome the main cellular barriers to successful transduction in the heart, using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs), iPSC-derived cardiac fibroblasts (iPSC-CFs), and primary endothelial cells to model vector-host interactions. Through phosphoproteome analysis we established that casein kinase 2 (CK2) signaling is one of the most significantly affected pathways upon AAV exposure. Transient inhibition of CK2 activity substantially enhanced the transduction rate of AAV2, AAV6, and AAV9 in all tested cell types. In particular, CK2 inhibition improved the trafficking of AAVs through the cytoplasm, impaired DNA damage response through destabilization of MRE11, and altered the RNA processing pathways, which were also highly responsive to AAV transduction. Also, it augmented transgene expression in already transduced iPSC-CFs, which retain AAV genomes in a functional, but probably silent form. In summary, the present study provides new insights into the current understanding of the host-AAV vector interaction, identifying CK2 activity as a key barrier to efficient transduction and transgene expression, which may translate to improving the outcome of AAV-based therapies in the future.

Original languageEnglish
Pages (from-to)84-102
Number of pages19
JournalMolecular Therapy
Volume32
Issue number1
DOIs
StatePublished - 3 Jan 2024
Externally publishedYes

Keywords

  • AAV
  • adeno-associated viral vectors
  • gene therapy
  • induced pluripotent stem cells
  • transduction efficiency

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