Faculty Collaboration Database

Intravitreal injection of a rationally designed AAV capsid library in non-human primate identifies variants with enhanced retinal transduction and neutralizing antibody evasion. Mol Ther 2023 Dec 06;31(12):3441-3456

Date

10/10/2023

Pubmed ID

37814449

Pubmed Central ID

PMC10727955

DOI

10.1016/j.ymthe.2023.10.001

Scopus ID

2-s2.0-85174458614 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

Adeno-associated virus (AAV) continues to be the gold standard vector for therapeutic gene delivery and has proven especially useful for treating ocular disease. Intravitreal injection (IVtI) is a promising delivery route because it increases accessibility of gene therapies to larger patient populations. However, data from clinical and non-human primate (NHP) studies utilizing currently available capsids indicate that anatomical barriers to AAV and pre-existing neutralizing antibodies can restrict gene expression to levels that are "sub-therapeutic" in a substantial proportion of patients. Here, we performed a combination of directed evolution in NHPs of an AAV2-based capsid library with simultaneous mutations across six surface-exposed variable regions and rational design to identify novel capsid variants with improved retinal transduction following IVtI. Following two rounds of screening in NHP, enriched variants were characterized in intravitreally injected mice and NHPs and shown to have increased transduction relative to AAV2. Lead capsid variant, P2-V1, demonstrated an increased ability to evade neutralizing antibodies in human vitreous samples relative to AAV2 and AAV2.7m8. Taken together, this study further contributed to our understanding of the selective pressures associated with retinal transduction via the vitreous and identified promising novel AAV capsid variants for clinical consideration.

Author List

Kellish PC, Marsic D, Crosson SM, Choudhury S, Scalabrino ML, Strang CE, Hill J, McCullough KT, Peterson JJ, Fajardo D, Gupte S, Makal V, Kondratov O, Kondratova L, Iyer S, Witherspoon CD, Gamlin PD, Zolotukhin S, Boye SL, Boye SE

Author

Miranda L. Scalabrino PhD Assistant Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antibodies, Neutralizing
Capsid
Capsid Proteins
Dependovirus
Genetic Vectors
Humans
Intravitreal Injections
Mice
Primates
Transduction, Genetic