Abstract 4245: Selection of AAV capsids by evaluating transgene delivery using human organoid models

Abstract

Abstract Recombinant adeno-associated viruses (AAVs) play a pivotal role in gene therapy, a promising approach aimed at treating various genetic disorders by introducing modified genetic material into cells or tissues. These AAV capsids are utilized as a vector in transferring genetic material into host cells. In discovery research, many AAV serotypes are developed in parallel to identify the optimal subtype for subsequent preclinical and clinical use. However, gene therapies have found limited success in clinical translation, in part, due to variable transgene delivery efficacy between traditional in vitro and in vivo models and human models. This study presents an organoid-based approach that mimics human physiology, as well as organ-specific features and cell diversity within an organ. Organoids are 3D structures derived from stem cells that resemble the cellular architecture and functionality of a specific organ. Compared to conventional 2D cell cultures, organoids provide a more comprehensive modeling of complex cell signaling, cell-cell and cell-extracellular matrix interactions, simulating the complex interplay between various cell types and functions. Within this study, several human-based organoid models were built, cerebral and cardiac, and verified by identifying the expression level of known marker genes through RNA sequencing. Five different AAV serotypes were utilized to evaluate transgene efficacy using each type of organoid model. Expression of delivered GFP transgene within each organoid was then compared to evaluate transduction and select the optimal AAV serotype in comparison to commercial wild-type AAVs. We outline the use of human organoid as an improved preclinical model for selecting AAV serotypes and evaluating transgene delivery efficacy to help provide better guidance for gene therapy development when moving into clinical research. Citation Format: Yingying Fu, Zhen Qi, Zhanguan Zuo, Spencer Chiang, An Ouyang, Glory Gao, Shuge Guan, Jin-Qiu (Jessie) Chen, Rosanna Zhang, Cheng Wang. Selection of AAV capsids by evaluating transgene delivery using human organoid models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4245.