42. AAV-mediated gene therapy causes functional improvements in a murine model of infantile neuronal ceroid lipofuscinosis (INCL, Batten Disease)

Abstract

Active Aβ peptide-based immunotherapies have shown promise in preclinical mouse Alzheimer's disease (AD) models, but application in human trials was accompanied by brain inflammation in a subset of trial participants. Immune response-shaping vaccine platforms may impart therapeutic benefit and simultaneously mitigate adverse effects. Herein, we describe the use of herpes simplex virus (HSV)-derived amplicons to elicit distinctive immune responses against Aβ. Two vaccine vectors were constructed: one expressing Aβ1–42 alone (HSVAβ), and a second expressing Aβ1–42 fused in-frame with the molecular adjuvant tetanus toxin Fragment C (HSVAβ/TtxFC). Peripheral administration of HSVAβ/TtxFC augmented humoral responses to Aβ and reduced CNS Aβ deposition in Tg2576 AD mice. Interestingly and unexpectedly, HSVAβ vaccination was uniquely toxic, and incited the expression of pro-inflammatory molecule transcripts within the hippocampi of Tg2576 mice. However, the few surviving HSVAβ-vaccinated Tg2576 mice exhibited the most dramatic reduction in Aβ deposit numbers as compared to HSVAβ/TtxFC-inoculated counterparts. Vaccination of non-transgenic littermates with either amplicon vector produced detectable humoral responses but resulted in no observable toxicity. This paradigm may serve as a relevant model to study the inflammatory component presenting in Aβ peptide-vaccinated human subjects. Ongoing and future studies involve assessment of vaccine-elicited cellular immune responses, effects on brain amyloid deposition and memory behavior, and employment of co-delivered immunomodulatory genes to shape the immune responses elaborated to the Aβ antigen. A detailed characterization of CNS immunological responses in the setting of AD is highly relevant to development of safe vaccines.