Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials

Abstract

The DNA vaccine, AV-1959D, targeting N-terminal epitope of Aβ peptide, has been proven immunogenic in mice, rabbits, and non-human primates, while its therapeutic efficacy has been shown in mouse models of Alzheimer's disease (AD). Here we report for the first time on IND-enabling biodistribution and safety/toxicology studies of cGMP-grade AV-1959D vaccine in the Tg2576 mouse model of AD. We also tested acute neuropathology safety profiles of AV-1959D in another AD disease model, Tg-SwDI mice with established vascular and parenchymal Aβ pathology in a pre-clinical translational study. Biodistribution studies two days after the injection demonstrated high copy numbers of AV-1959D plasmid after single immunization of Tg2576 mice at the injection sites but not in the tissues of distant organs. Plasmids persisted at the injection sites of some mice 60 days after vaccination. In Tg2576 mice with established amyloid pathology, we did not observe short- or long-term toxicities after multiple immunizations with three doses of AV-1959D. Assessment of the repeated dose acute safety of AV-1959D in cerebral amyloid angiopathy (CAA) prone Tg-SwDI mice did not reveal any immunotherapy-induced vasogenic edema detected by magnetic resonance imaging (MRI) or increased microhemorrhages. Multiple immunizations of Tg-SwDI mice with AV-1959D did not induce T and B cell infiltration, glial activation, vascular deposition of Aβ, or neuronal degeneration (necrosis and apoptosis) greater than that in the control group determined by immunohistochemistry of brain tissues. Taken together, the safety data from two different mouse models of AD substantiate a favorable safety profile of the cGMP grade AV-1959D vaccine supporting its progression to first-in-human clinical trials.

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

“…In comparison, there was less cellular uptake of 4N+{FAM} ON and it was only present in the cytoplasm. These results indicate that ONs with phosphate modifications such as N+ or Ts might be suitable tools for the application of DNA and RNA vaccines [60], for the treatment of cancer [61], infectious diseases [62], and neurological disorders [63].…”

Spectroscopic and deep learning-based approaches to identify and quantify cerebral microhemorrhages

“…Second, the CMHs in our study were induced with LPS. Further testing of these approaches in other CMH models, such as chronic kidney disease 9 , hypertension 7 , and cerebral amyloid angiopathy 38 – 40 , in addition to human brain samples, are needed. Third, the algorithms have not been tested on different microscopes to assess if a calibration factor is needed to account for differences in camera spectral sensitivity and excitation spectrum.…”

Spectroscopic and Deep Learning-Based Approaches to Identify and Quantify Cerebral Microhemorrhages

“…Second, the CMHs in our study were induced with LPS. Further testing of these approaches in other CMH models, such as chronic kidney disease 9 , hypertension 7 , and cerebral amyloid angiopathy [38][39][40] , in addition to human brain samples, are needed. Third, the algorithms have not been tested on different microscopes to assess if a calibration factor is needed to account for differences in camera spectral sensitivity and excitation spectrum.…”