Engineering of affinity proteins for modulation of the sortilin-progranulin axis
Time: Fri 2026-03-06 13.00
Location: F3 (Flodis), Lindstedtsvägen 26 & 28, Stockholm
Video link: https://kth-se.zoom.us/j/63010543236
Language: English
Subject area: Biotechnology
Doctoral student: Moira Ek , Proteinvetenskap, Proteinteknologi
Opponent: Professor Sara Snogerup Linse, Lunds Universitet, Lund, Sweden
Supervisor: Professor John Löfblom, Proteinvetenskap, Proteinteknologi; Doktor Hanna Lindberg, Proteinvetenskap, Proteinteknik; Professor Stefan Ståhl, Proteinvetenskap, Proteinteknologi
QC 2026-02-11
Abstract
Considerable advances have been made within protein-based dementia therapy in the last few years. Nevertheless, efficient, broadly accessible treatment for this devastating group of disorders remains elusive. In particular, frontotemporal dementia (FTD), is a disorder with very few treatment options. Reduced levels of the secreted protein progranulin (PGRN) is part of the pathological mechanism of a subgroup of FTD. Consequently, elevation of PGRN constitutes a potential therapeutic strategy for this condition.
The work in this thesis aims to modulate PGRN levels using small affinity proteins, and to provide novel knowledge about aspects of PGRN regulation. The PGRN-related proteins sortilin and prosaposin (PSAP) constitute two interconnected pathways for PGRN degradation, making them interesting targets for efforts to increase PGRN levels. In four research papers, this thesis details the investigation and development of small affinity proteins targeting sortilin and PSAP, using methods of directed evolution.
In the first two studies, sortilin-binding proteins were developed based on affibody molecules, with tunable affinity through the combination of several affibody-based domains or peptides derived from natural sortilin ligands. These small affibody-based fusion proteins elevated extracellular PGRN levels in an in vitro model system, with comparable potency to a clinically evaluated sortilin-binding antibody. In the third study, these sortilin-binding proteins were combined with newly developed PSAP-binding affibody molecules. Through simultaneous binding of PSAP and sortilin, these bispecific proteins elevated extracellular PGRN levels beyond the effect of monospecific sortilin-binding proteins alone, constituting a novel strategy with therapeutic potential. In the fourth study, methods of directed evolution were applied to investigate the incompletely understood interaction between sortilin and its propeptide. This provided novel sequence-level information, and identified short peptides with potential as sortilin-binding domains for biotechnological applications.
In conclusion, this thesis provides a toolbox of small affinity proteins for the modulation of the interaction network consisting of PGRN, sortilin, and PSAP. Given the disease involvement of these proteins, the here developed binders hold potential both for therapeutic applications in and beyond FTD, and as tools for furthering our understanding of the sortilin-progranulin axis.