Mosaic Display of Multivalent Tau and A-Beta peptides on Immunogenic SNAP Liposomes

PROJECT SUMMARY Alzheimer’s disease (AD) currently affects ~6.2 million Americans, and this number is projected to increase to 14 million by 2060 unless novel treatments or interventions to prevent or delay the onset of AD are identified. Harnessing the immune system to prevent or remove Aβ and/or tau pathologies represents a promising disease- modifying therapeutic approach for the treatment of AD. Currently, all the previous and ongoing immunotherapy studies target only one epitope of either Aβ or tau protein. Because most AD cases are multifactorial, and sporadic AD is caused by multiple mechanisms, it is unlikely that a single target will be sufficient to stop or reduce the progression of AD. Based on the role of Aβ and tau in the pathogenesis of AD, our working hypothesis is that immunotherapy simultaneously targeting the multiple epitopes of both Aβ and tau is a promising approach for developing effective AD therapeutics. Under the support of STTR Phase I project (1R41AG082620, 09/2023- 07/2025), we have successfully developed a multivalent "mosaic" vaccine, termed SNAP-AD, targeting multiple epitopes of Aβ and tau simultaneously with the spontaneous nanoliposome antigen particle (SNAP) platform and achieved all the milestones. To further confirm its efficacies and toward an Investigational New Drug (IND) application, we propose three specific aims: (1) Scale SNAP-AD production and develop analytical characterization. POP BIO will develop scalable manufacture protocols for SNAP-AD and assess methods to quantify the multiple peptides present on the liposome surface. (2) Confirm the efficacy of SNAP-AD in APP/PS1 mice and P301S (PS19) mice. We will evaluate the therapeutic efficacy of SNAP-AD in a cerebral amyloidosis model (APP/PS1 mice) and a tauopathy model (P301S/PS19 mice). The brain pathologies and cognitive functions of the mice will be studied after five doses of SNAP-AD. Together with the testing in 3xTg-AD mice done already, these studies will overcome a common challenge (i.e., lacking an ideal AD mouse model replicating all aspects of this multifactorial disease) for AD drug development and thus significantly increase the confidence on SNAP-AD’s therapeutic efficacy of treating AD. (3) Study the dose selection, immune response, and safety of SNAP-AD in non-human primates (NHP). We will vaccinate rhesus macaques at four dose levels of SNAP-AD and study (i) serum antibody isotypes and titers, (ii) cellular immune responses, (iii) blood routine (CBC/chemistry), cytokines and immunogens, and (iv) bodyweight, body temperature, and general conditions including behavior. NHP antisera will also be studied for its activity to bind amyloid plaques and tangles in AD brain tissue sections. These studies will provide critical information about PK/PD and safety of SNAP-AD in NHPs. The proposed studies will further confirm the promising therapeutic effects of SNAP-AD on AD pathologies and cognitive impairment in two more transgenic mouse models of AD and reveal its immunogenicity and safety in NHP. A positive outcome of this project would further the clinical translation of a novel vaccine for the treatment of AD, which will improve the quality of life of individuals with AD.