Self-assembling Nanofiber Vaccines for Neurodegeneration

Washington University, Saint Louis MO

Investigators

Abstract

PROJECT SUMMARY Nanomaterials fabricated from de novo designed peptides, which self-organize into cross-b-rich nanofibers, are a class of molecules with numerous promising applications. Such applications could include the development of therapeutic or prophylactic vaccines against disorders associated with protein aggregation. Synthetic peptide nanofibers (PNFs) exhibit intrinsic self-adjuvanting properties and can efficiently raise antibodies against antigens conjugated at their N- or C-termini. Investigations into the mechanism and safety profiles of PNFs indicate that despite their molecular, structural, and morphological similarity to cross-b-rich pathological amyloids, PNFs are non-toxic and non-amyloidogenic. Further, PNFs induce innate immune signaling mechanisms that drive strong non-inflammatory ‘Th2-type’ antibody responses. This is significant for the development of vaccines against neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), which disproportionally impact aged individuals who are known to have an impaired immune response due to inflammaging. A key difference between developing infectious disease vaccines and vaccines for AD/FTD is that amyloid-beta (Aβ) and Tau proteins implicated in AD/FTD pathologies are self-antigens. To subvert this tolerance, vaccines targeting Aβ/tau are mixed with adjuvants that induce strong inflammation to induce robust antibody titers. Data from clinical studies indicate that proinflammatory immune responses can aggravate pre-existing neuroinflammation in AD and lead to serious side effects like encephalomyelitis. Studies show that in contrast to younger adults, adjuvant-related inflammation obstructs immune responses in older adults and that this effect can be mitigated by delivering anti-inflammatory therapies. Here we propose the development and preclinical testing of self-adjuvanting PNF vaccines targeting Aβ and Tau. Due to the modular nature of self-assembly, the same self-assembling domain linked to different conformers of Aβ and Tau can be mixed to improve the breadth of protection against AD/FTD. We hypothesize that i) PNFs bearing Aβ/Tau epitopes do not seed the formation of toxic oligomeric species, that ii) nanofibers bearing Aβ or Tau epitopes will elicit robust titers of functional antibodies in mice, and that iii) vaccination with nanofiber-based vaccines will rescue neuropathology and delay onset of dementia in transgenic mouse models of AD/FTD. Thus, we will meet the following aims: 1) Assess toxicity and seeding capacity of PNFs bearing Aβ and Tau epitopes, 2) Perform quantitative and qualitative characterization of antibody responses to Aβ and Tau PNF vaccines, and 3) Develop multiepitope Aβ and Tau PNF vaccines and determine their efficacy in transgenic mouse models. Upon successful completion of this project, we will establish peptide nanofibers as a safe and effective vaccine platform for inducing non-inflammatory and protective antibody responses against AD/FTD.