GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain

Ghulam Hassan Dar, Cláudia C. Mendes, Wei-Li Kuan, Alfina A. Speciale, Mariana Conceição, André Görgens, Inna Uliyakina, Miguel J. Lobo, Wooi F. Lim, Samir EL Andaloussi, Imre Mäger, Thomas C. Roberts, Roger A. Barker, Deborah C. I. Goberdhan, Clive Wilson () and Matthew J. A. Wood ()
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Ghulam Hassan Dar: University of Oxford
Cláudia C. Mendes: University of Oxford
Wei-Li Kuan: University of Cambridge
Alfina A. Speciale: University of Oxford
Mariana Conceição: University of Oxford
André Görgens: Clinical Research Center, Karolinska Institutet
Inna Uliyakina: University of Oxford
Miguel J. Lobo: University of Oxford
Wooi F. Lim: University of Oxford
Samir EL Andaloussi: Clinical Research Center, Karolinska Institutet
Imre Mäger: University of Oxford
Thomas C. Roberts: University of Oxford
Roger A. Barker: University of Cambridge
Deborah C. I. Goberdhan: University of Oxford
Clive Wilson: University of Oxford
Matthew J. A. Wood: University of Oxford

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Extracellular vesicles (EVs) are biological nanoparticles with important roles in intercellular communication, and potential as drug delivery vehicles. Here we demonstrate a role for the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in EV assembly and secretion. We observe high levels of GAPDH binding to the outer surface of EVs via a phosphatidylserine binding motif (G58), which promotes extensive EV clustering. Further studies in a Drosophila EV biogenesis model reveal that GAPDH is required for the normal generation of intraluminal vesicles in endosomal compartments, and promotes vesicle clustering. Fusion of the GAPDH-derived G58 peptide to dsRNA-binding motifs enables highly efficient loading of small interfering RNA (siRNA) onto the EV surface. Such vesicles efficiently deliver siRNA to multiple anatomical regions of the brain in a Huntington’s disease mouse model after systemic injection, resulting in silencing of the huntingtin gene in different regions of the brain.

Date: 2021
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DOI: 10.1038/s41467-021-27056-3

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