Viral vectors in neurodegenerative diseases: immune responses and therapeutic applications

Abstract

Gene transfer-based therapies utilizing viral vectors have undergone remarkable advancements and hold significant promise in addressing neurodegenerative diseases in recent years, whose potential mechanisms include replacing or silencing pathogenic genes and delivering neurotrophic factors. Current preclinical research focuses on developing novel strategies in gene modification to combat neurodegenerative disorders. Numerous clinical trials involving viral vectors in the nervous system are either on-going or completed. Despite these advancements, progress in this field remains constrained by immune responses triggered by viral vectors, which can be triggered through innate and adaptive pathways. The present review will focus on the advances in the development and application of viral vector-based gene therapies for neurodegenerative diseases and summarize the related immune responses, aiming to provide a forward-looking perspective for this emerging arena.

Keywords: AAV; gene therapy; immune responses; neurodegenerative disease; viral vector.

Figure 1

Mechanism of immune responses against AAV-mediated gene transfer. The graph shows the different type of immune responses that are elicited upon injection of AAV vectors. Toxicities are underlined and listed next to the components of the immune responses that contribute. PAMP, Pathogen-Associated Molecular Pattern; MDA5, Melanoma Differentiation-Associated protein 5; CpG, unmethylated CpG motifs; DCs, dendritic cells; dRNA, double stranded RNA; MHC, Major Histocompatibility Complex. Created in BioRender. Wang, Y. (2025) https://BioRender.com/4dt5yfl.

Figure 2

Immunomodulatory strategies and hepatic immune tolerance. (A) Major immunosuppressive approaches used to reduce anti-transgene immune responses, categorized by their main cellular targets. (B) Liver's role in immune tolerance mediated by key resident cells such as Kupffer cells and liver sinusoidal endothelial cells (LSECs). Created in BioRender. Wang, Y. (2025) https://BioRender.com/r8hrxah.