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Investigation of the Therapeutic Effect of an Fc-Domain Polythiophene Conjugate in Prion Diseases


Zhang, Hui. Investigation of the Therapeutic Effect of an Fc-Domain Polythiophene Conjugate in Prion Diseases. 2024, University of Zurich, Faculty of Science.

Abstract

There is a highly unmet medical need for treatments in neurodegenerative diseases including prion diseases (PrDs), Alzheimer's (AD) and Parkinson's disease (PD). Pathologically, misfolded protein aggregates are hallmarks of these protein misfolding diseases, e.g., prions in PrDs, amyloid-β (Aβ) and tau aggregates in AD, α-synuclein (α-syn) and tau aggregates in PD. In recent years, two monoclonal antibodies that target Aβ aggregates have been approved to treat AD by opsonizing Aβ aggregates and enhancing microglial phagocytosis but shown limited efficacy. Considering that in most protein misfolding diseases, multiple different protein aggregates co-occur, it is reasonable to develop a pan-amyloid therapeutic reagent. In this dissertation, I have produced a pan-amyloid bifunctional molecule. The characteristics of this molecule was confirmed by various biochemical and biological assays including surface plasmon resonance (SPR), ELISA and fibril formation assay. I found that the molecule bound to multiple protein aggregates, and enhanced the phagocytosis of these aggregates. I then tested the therapeutic effect of the molecule in an ex vivo prion model which is prion-infected cultured organotypic cerebellar slices (COCS). The molecule significantly reduced the prion load in prion infected COCS by enhancing phagocytosis of prions and protected neurons from prion toxicity. The protective efficacy of the molecule was validated at early and late stage of prion infection, indicating that the molecule could be both preventative and therapeutic. I also investigated the neural protection mechanism of the molecule. Collectively, in this dissertation, I have demonstrated a prototype of a pan-amyloid molecule, which has therapeutic potential in PrDs. In future experiments, the mechanism of the molecule will be further investigated using single-cell RNA sequencing and spatial transcriptomics analysis. Additionally, I will test the efficacy of the molecule in in vivo models of PrDs. To validate its therapeutic potential in other protein misfolding diseases, the effect of the molecule could also be tested in various other in vivo models. The biodistribution, pharmacokinetic and pharmacodynamic properties of the molecule will also be analyzed. Additionally, the design and production of the molecule will be refined.

Abstract

There is a highly unmet medical need for treatments in neurodegenerative diseases including prion diseases (PrDs), Alzheimer's (AD) and Parkinson's disease (PD). Pathologically, misfolded protein aggregates are hallmarks of these protein misfolding diseases, e.g., prions in PrDs, amyloid-β (Aβ) and tau aggregates in AD, α-synuclein (α-syn) and tau aggregates in PD. In recent years, two monoclonal antibodies that target Aβ aggregates have been approved to treat AD by opsonizing Aβ aggregates and enhancing microglial phagocytosis but shown limited efficacy. Considering that in most protein misfolding diseases, multiple different protein aggregates co-occur, it is reasonable to develop a pan-amyloid therapeutic reagent. In this dissertation, I have produced a pan-amyloid bifunctional molecule. The characteristics of this molecule was confirmed by various biochemical and biological assays including surface plasmon resonance (SPR), ELISA and fibril formation assay. I found that the molecule bound to multiple protein aggregates, and enhanced the phagocytosis of these aggregates. I then tested the therapeutic effect of the molecule in an ex vivo prion model which is prion-infected cultured organotypic cerebellar slices (COCS). The molecule significantly reduced the prion load in prion infected COCS by enhancing phagocytosis of prions and protected neurons from prion toxicity. The protective efficacy of the molecule was validated at early and late stage of prion infection, indicating that the molecule could be both preventative and therapeutic. I also investigated the neural protection mechanism of the molecule. Collectively, in this dissertation, I have demonstrated a prototype of a pan-amyloid molecule, which has therapeutic potential in PrDs. In future experiments, the mechanism of the molecule will be further investigated using single-cell RNA sequencing and spatial transcriptomics analysis. Additionally, I will test the efficacy of the molecule in in vivo models of PrDs. To validate its therapeutic potential in other protein misfolding diseases, the effect of the molecule could also be tested in various other in vivo models. The biodistribution, pharmacokinetic and pharmacodynamic properties of the molecule will also be analyzed. Additionally, the design and production of the molecule will be refined.

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Additional indexing

Item Type:Dissertation (monographical)
Referees:Aguzzi Adriano, Hornemann Simone Alexandra, Greter Melanie, Neri Dario
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
UZH Dissertations
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Place of Publication:Zürich
Date:25 April 2024
Deposited On:08 May 2024 10:52
Last Modified:18 Jun 2024 09:16
Number of Pages:99
OA Status:Closed