Engineered amphiphilic peptides enable delivery of proteins and CRISPR-associated nucleases to airway epithelia

Sateesh Krishnamurthy, Christine Wohlford-Lenane, Suhas Kandimalla, Gilles Sartre, David K. Meyerholz, Vanessa Théberge, Stéphanie Hallée, Anne-Marie Duperré, Thomas Del’Guidice, Jean-Pascal Lepetit-Stoffaes, Xavier Barbeau, David Guay and Paul B. McCray ()
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Sateesh Krishnamurthy: University of Iowa
Christine Wohlford-Lenane: University of Iowa
Suhas Kandimalla: University of Iowa
Gilles Sartre: University of Iowa
David K. Meyerholz: University of Iowa
Vanessa Théberge: Feldan Therapeutics, Québec
Stéphanie Hallée: Feldan Therapeutics, Québec
Anne-Marie Duperré: Feldan Therapeutics, Québec
Thomas Del’Guidice: Feldan Therapeutics, Québec
Jean-Pascal Lepetit-Stoffaes: Feldan Therapeutics, Québec
Xavier Barbeau: Feldan Therapeutics, Québec
David Guay: Feldan Therapeutics, Québec
Paul B. McCray: University of Iowa

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract The delivery of biologic cargoes to airway epithelial cells is challenging due to the formidable barriers imposed by its specialized and differentiated cells. Among cargoes, recombinant proteins offer therapeutic promise but the lack of effective delivery methods limits their development. Here, we achieve protein and SpCas9 or AsCas12a ribonucleoprotein (RNP) delivery to cultured human well-differentiated airway epithelial cells and mouse lungs with engineered amphiphilic peptides. These shuttle peptides, non-covalently combined with GFP protein or CRISPR-associated nuclease (Cas) RNP, allow rapid entry into cultured human ciliated and non-ciliated epithelial cells and mouse airway epithelia. Instillation of shuttle peptides combined with SpCas9 or AsCas12a RNP achieves editing of loxP sites in airway epithelia of ROSAmT/mG mice. We observe no evidence of short-term toxicity with a widespread distribution restricted to the respiratory tract. This peptide-based technology advances potential therapeutic avenues for protein and Cas RNP delivery to refractory airway epithelial cells.

Date: 2019
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DOI: 10.1038/s41467-019-12922-y

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