Dokument: Drug discovery for rare neurological disorders using human cellular models

Titel:	Drug discovery for rare neurological disorders using human cellular models
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=73438
URN (NBN):	urn:nbn:de:hbz:061-20260623-154050-0
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Wittich, Annika [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 56,53 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 29.05.2026 / geändert 29.05.2026
Beitragende:	Prof. Dr. Prigione, Alessandro [Gutachter] Prof. Dr. Gültekin Tamgüney, Erdem [Gutachter]
Stichwörter:	Drug discovery, Rare neurological disorders, iPSCs
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:	Rare neurological diseases, though individually infrequent, collectively represent a growing global health challenge. Drug development for therapeutic modalities addressing neurological diseases is hindered by high failure rates due to poor preclinical to clinical translation of candidates, resulting e.g., from limited blood–brain barrier (BBB) permeability. Human iPSC-derived in vitro models improve physiological relevance and predictability for early decision making during drug development, thereby potentially reducing clinical failure. This study developed and utilized scalable 2D- and 3D human (iPSC)-based platforms to identify and validate treatment options for Leigh syndrome (LS), Parkinson’s disease (PD), melanoma brain metastasis (MBMs), and Multiple sulfatase deficiency (MSD). Sildenafil, a phosphodiesterase-5 inhibitor, was identified as a promising BBB-permeable drug candidate for LS, ameliorating disease characteristics. Tyrphostin A9 was discovered to have neuroprotective effects in PD, and talarozole and sertaconazole, previously identified through computational and yeast screening methods, were validated in iPSC-derived brain organoids from an LS patient. Furthermore, an iPSC-derived 3D organoid co-cultured with melanoma cells and disseminated cancer cells confirmed that selinexor is effective against melanoma brain metastasis without causing neurotoxicity. Lastly, a large-scale high-throughput screen using fibroblasts from an MSD patient led to the identification of six new compounds that enhanced sulfatase activity to a greater extent than the previously identified clinical candidate tazarotene. These findings underscore the importance and relevance of integrated human 2D- and 3D-in-vitro-based platforms to accelerate therapeutic discovery for rare neurological diseases.
Lizenz:	Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie
Dokument erstellt am:	23.06.2026
Dateien geändert am:	23.06.2026
Promotionsantrag am:	11.12.2025
Datum der Promotion:	09.04.2026