Periodic Reporting for period 1 - NEXGEN-PD (Next Generation Vaccine Platform Leveraging Skin Immunity to Provide Disease-Modifying Treatment of Parkinson’s Disease)
Reporting period: 2023-04-01 to 2024-09-30
Parkinson’s Disease (PD) is a serious neurodegenerative disorder without any curative therapy or reliable means of early diagnosis. Over 8.5 million individuals suffer from PD, enduring poorer quality of life, challenging social interactions, and great financial burdens. These numbers continue to grow rapidly. More effective treatments to delay and prevent disability are urgently needed. Pharmacological dopamine substitution combined with deep brain stimulation has offered the ability to manage PD. However, these treatments do not prevent progression, can cause major side effects, and are highly invasive. Existing treatments also only alleviate PD motor symptoms, providing no relief for non-motor symptoms. It is well agreed by scientists that diagnosing and treating PD early, before irreversible brain damage occurs, will be the most effective approach going forward.
Misfolded α-Synuclein (aSyn) aggregates exert various neurotoxic effects in the brain, and play a causal role in PD. Thus, the targeting of aSyn has become a primary focus for the development of PD therapeutics. Vaccines are one of the most promising approaches to target aSyn, but it is challenging for existing vaccines to induce a strong enough immune response to eliminate aSyn aggregates. New diagnostic tools are also required, to identify PD early enough for patients to receive treatment before irreversible brain degradation occurs.
NEXGEN proposes to develop a novel extracellular vesicle (EV)-based biomarker assay to enable and guide early intervention, and to develop the next generation of aSyn vaccines to treat PD, built on the novel proprietary WISIT (Win the Skin Immune System Trick) platform.
Misfolded α-Synuclein (aSyn) aggregates exert various neurotoxic effects in the brain, and play a causal role in PD. Thus, the targeting of aSyn has become a primary focus for the development of PD therapeutics. Vaccines are one of the most promising approaches to target aSyn, but it is challenging for existing vaccines to induce a strong enough immune response to eliminate aSyn aggregates. New diagnostic tools are also required, to identify PD early enough for patients to receive treatment before irreversible brain degradation occurs.
NEXGEN proposes to develop a novel extracellular vesicle (EV)-based biomarker assay to enable and guide early intervention, and to develop the next generation of aSyn vaccines to treat PD, built on the novel proprietary WISIT (Win the Skin Immune System Trick) platform.
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).
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).
NEXGEN produces 11 results, including 2 key exploitable results (KERs):
R1: Characteristics of five potential aSyn epitopes
R2: Three PD-WISIT constructs scalable batch-manufactured to GMP standards (KER1)
R3: Evaluation of the ability of PD-WISIT to reduce/eliminate aSyn aggregates in PD models
R4: Comparison of novel WISIT formats to conventional vaccines in key parameters as a function of dose and schedule
R5: Comparison of four ID administration modalities
R6: Optimised vaccination schedules for long-term benefits based on titre and selectivity of vi-aSynAbs
R7: Novel EVaSyn biomarker assay (KER2)
R8: List of novel potential EV-based biomarkers identified in blood and urine
R9: Preclinical evidence of immunogenicity, safety and efficacy of PD-WISIT
R10: Clinical proof of concept that PD-WISIT outperforms the benchmark PD01 vaccine
R11: HTA detailing the effectiveness of results and estimates of costs on healthcare services
R1: Characteristics of five potential aSyn epitopes
R2: Three PD-WISIT constructs scalable batch-manufactured to GMP standards (KER1)
R3: Evaluation of the ability of PD-WISIT to reduce/eliminate aSyn aggregates in PD models
R4: Comparison of novel WISIT formats to conventional vaccines in key parameters as a function of dose and schedule
R5: Comparison of four ID administration modalities
R6: Optimised vaccination schedules for long-term benefits based on titre and selectivity of vi-aSynAbs
R7: Novel EVaSyn biomarker assay (KER2)
R8: List of novel potential EV-based biomarkers identified in blood and urine
R9: Preclinical evidence of immunogenicity, safety and efficacy of PD-WISIT
R10: Clinical proof of concept that PD-WISIT outperforms the benchmark PD01 vaccine
R11: HTA detailing the effectiveness of results and estimates of costs on healthcare services