New York-Upstate Investigating Extracellular and Intracellular Antibody Immunity to Therapeutic Adeno -Associated Viral Vectors

Overview

Gene therapies modulate disease -causing genetic mutations. Adeno -associated viral (AAV) vectors are adapted from wild-type AAVs to deliver these therapies. However, many people have been exposed to wild- type AAVs, creating immunological memory. This memory triggers extracellular antibody immune responses that prevent AAV-based gene therapies from being administered to patients. The cross-reactivity of AAV5, AAV8, and AAV9, viruses with varying genetic similarity, was tested using a murine model to determine if serotype cross -reactivity is low enough to allow for successful dosing despite pre -existing antibody immunity. Enzyme-linked immunosorbent titer assays (ELISAs) determined that AAV5 could be dosed to mice pre -immune to either AAV8 or AAV9, but AAV8 or AAV9 couldn’t be dosed when pre - immunity existed for one serotype. Immunohistochemistry staining of liver samples confirmed these results. Although, in some cases, viruses may evade extracellular antibody immunity and still endocytose into cells, bringing attached antibodies intracellularly with them. Human immune systems have developed an intracellular Fc receptor called tripartite motif-containing 21 (TRIM21) against viral species similar to AAV. If TRIM21 launches an intracellular immune response to AAV as well, bypassing AAV immunity may be more complex than initially anticipated. A THP-1 based interferon and NF-kB reporter cell line was used to measure the TRIM21-triggered immune response to AAVs. A strong reporter signal was not detected for either pathway in this assay. This study supports that dosing a low cross-reactive serotype may be a viable method to evade AAV pre -existing immunity but did not elicit a TRIM21 -triggered intracellular immune response to AAV.

Competition history

• JSHS 2024 Category not listed

Resources

• National JSHS abstract book ↗

Related projects

Closest projects by meaning, across every fair and year in the corpus.