Organoids and microphysiological systems: Promising models for accelerating AAV gene therapy studies

Abstract

The FDA has predicted that at least 10-20 gene therapy products will be approved by 2025. The surge in the development of such therapies can be attributed to the advent of safe and effective gene delivery vectors such as adeno-associated virus (AAV). The enormous potential of AAV has been demonstrated by its use in over 100 clinical trials and the FDA’s approval of two AAV-based gene therapy products. Despite its demonstrated success in some clinical settings, AAV-based gene therapy is still plagued by issues related to host immunity, and recent studies have suggested that AAV vectors may actually integrate into the host cell genome, raising concerns over the potential for genotoxicity. To better understand these issues and develop means to overcome them, preclinical model systems that accurately recapitulate human physiology are needed. The objective of this review is to provide a brief overview of AAV gene therapy and its current hurdles, to discuss how 3D organoids, microphysiological systems, and body-on-a-chip platforms could serve as powerful models that could be adopted in the preclinical stage, and to provide some examples of the successful application of these models to answer critical questions regarding AAV biology and toxicity that could not have been answered using current animal models. Finally, technical considerations while adopting these models to study AAV gene therapy are also discussed.

Progress in developing microphysiological systems for biological product assessment

“…These ongoing studies utilize human liver organoids comprising all major cell types present in the human liver, with frequencies that are physiologically relevant, enabling the evaluation of innate immune responses. 76 The recent developments in creating 3D immune organoids show promise for studying the pathways of AAV-mediated immune activation in greater detail. Functional studies on repeated dosing and therapy-induced immunity to AAV can be conducted by integrating liver and lymphoid microtissues, such as lymph nodes and spleen, into these models.…”

Organ-on-a-chip meets artificial intelligence in drug evaluation

“…Today, a variety of in vitro models have already been developed to accurately mimic the complex liver architecture and physiology, and to generalize the human liver's response to drugs [114]. Notably, these liver organoids successfully reproduce express cytochrome P450 and secrete serum albumin of hepatocytes, recapitulating the function of the native liver [115]. The liver is constituted of approximately 1 million lobules which are its constitutional unit, and contain the hepatocytes responsible for drug metabolism [116].…”

The Current Status and Use of Microphysiological Systems by the Pharmaceutical Industry: The International Consortium for Innovation and Quality Microphysiological Systems Affiliate Survey and Commentary

“…Animal models are generally good for understanding MoA but there are reports for different diseases and modalities demonstrating the poor predictive nature of animal models linked to clinical outcomes for efficacy and contributing to failure in phase 2 and 3 clinical trials (Drummond and Wisniewski, 2017;Ingber, 2022;Ramamurthy et al, 2022;Marshall et al, 2023). Animal models and MPS models replicating human disease both face the challenge of replicating the complexity, disease onset and severity, establishing relevant clinical endpoints and better understanding translational/predictive value.…”