NEXGEN project has 8 specific objectives (SO):
SO1: Select and manufacture three GMP-grade novel aSyn targeting WISIT constructs (PD-WISITs), based on immunogenicity, dose relationship, selectivity, and aSyn aggregation inhibition capacity in vitro, including at least one Format A construct and one Format B construct
SO2: Generate knowledge on the mode of action of WISIT technology, including the distribution of the vaccine, initiation of the immune response (kinetics/strength), and therapeutic effects of Abs and T cells induced, via comparison to conventional vaccines
SO3: Optimise gluconeoconjugate vaccine administration via comparison of intradermal administration modalities, doses, and vaccination schedules, based on the key immune response parameters described in SO1
SO4: Develop and clinically validate a novel EVaSyn biomarker assay suitable for clinical use (non/minimally-invasive in a fluidic or microfluidic format) achieving sensitivity and specificity >80%
SO5: Identify a combination of novel potential EV-based biomarkers based on proteomic and small RNA analysis that distinguishes PD from non-PD in cryopreserved blood and urine samples
SO6: Demonstrate preclinical PD-WISIT safety and efficacy at reversing PD disease phenotype in vivo, with superior performance (reduced spreading of aSyn pathology) compared to the existing state of the art PD01A
SO7: Demonstrate PD-WISIT safety, immunogenicity, and target engagement in the clinic, with superior performance (higher aSynAb titre and CSF O-aSyn reduction) compared to published PD01A datasets
SO8: Evaluate the economic impact in Europe of WISIT technology and novel EV-based biomarkers
To achieve these objectives, work is divided into 5 technical work packages (WP).
WP1 focuses on the selection of the optimal PD-WISIT constructs, and the manufacturing of these constructs.
WP2 investigates the B cell and T cell responses generated by WISIT compared to those generated by conventional vaccines and identify the optimal doses and administration modalities for WISIT.
WP3 develops a novel EV-based biomarker assay and identify novel potential biomarkers with theranostic potential, informing on the effect of WISIT on cell-to-cell transmissible forms of aSyn.
WP4 and WP5 progress the clinical translation of PD-WISIT, beginning with preclinical in vivo demonstrations of safety and efficacy (WP4), before progressing on to phase I clinical trials of safety and evidence of immune responses and central target engagement (WP5).
