Elsevier

Virus Research

Volume 274, December 2019, 197771
Virus Research

Biodistribution of adeno-associated virus type 2 with mutations in the capsid that contribute to heparan sulfate proteoglycan binding

https://doi.org/10.1016/j.virusres.2019.197771Get rights and content
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Highlights

  • Biodistribution of three AAV2 heparan binding mutants showed a unique phenotype.

  • R585A was completely defective for peripheral organs following intravenous injection.

  • All three heparan mutants showed robust brain transduction.

  • R585, 588A showed efficient retrograde transport.

  • Evidence suggests that R484 directly interacts with retrograde transport machinery.

  • A model for the effect of R585, 588A and R484A on retrograde transport is presented.

  • R585, 588A shows increased photoreceptor transduction following subretinal injection.

Abstract

We compared the phenotypes of three mutant AAV2 viruses containing mutations in arginine amino acids (R585, R588 and R484) previously shown to be involved in AAV2 heparan sulfate binding. The transduction efficiencies of wild type and mutant viruses were determined in the eye, the brain and peripheral organs following subretinal, striatal and intravenous injection, respectively, in mice and rats. We found that each of the three mutants (the single mutant R585A; the double mutant R585, 588A; and the triple mutant R585, 588, 484A) had a unique phenotype compared to wt and each other. R585A was completely defective for transducing peripheral organs via intravenous injection, suggesting that R585A may be useful for targeting peripheral organs by substitution of peptide ligands in the capsid surface. In the brain, all three mutants displayed widespread transduction, with the double mutant R585, 588A displaying the greatest spread and the greatest number of transduced neurons. The double mutant was also extremely efficient for retrograde transport, while the triple mutant was almost completely defective for retrograde transport. This suggested that R484 may be directly involved in interaction with the transport machinery. Finally, the double mutant also displayed improved transduction of the eye compared to wild type and the other mutants.

Keywords

Heparin mutant
Biodistribution
Virus gender bias
Virus retrograde transport
Liver transduction
Brain transduction
Eye transduction

Cited by (0)

1

Current address: Lacerta Therapeutics, 12085 Research Dr, Suite 46, Alachua, FL 32615.

2

Current address: Department of Optometry and Vision Sciences, Center for Neurodegeneration and Experimental Therapy, University of Alabama at Birmingham, 1670 University Blvd, VH343, Birmingham, AL 35294-0019.