New protein therapy could reverse memory loss in genetic dementia
Researchers engineered a small protein that blocks the cellular cleanup mechanism responsible for destroying brain-protective molecules in frontotemporal dementia patients. The technology, which showed 45-fold improvement over previous attempts, could offer the first disease-modifying treatment for this inherited form of dementia—opening a multi-billion dollar market opportunity in neurodegenerative disease.
Originaltitel: Biparatopic affibody engineering enables high-affinity sortilin blockade and progranulin elevation.
KTH-forskargrupp utvecklar en ny bioteknisk lösning för frontallobdemens genom att blockera sortilinproteinet, vilket öppnar vägen till att höja progranulin-nivåer hos patienter med genetiska mutationer. Framför allt ligger affibody-molekyler till grund för ett konstruktörsarbete kring biparatopa dimeravarianter — vilket innebär att två bindningsdomäner kopplas för att uppnå högre specificitet och kraft. Forskarna testade tio distinkt utformade dimetkonstruktioner och identifierade en 18,6 kDa ledarkonstruktion som erbjöd subnanomolar bindningsaffinitet — cirka 45 gånger starkare än motsvarande monomera form. I funktionella tester eleverades extracellulär progranulin effektivt. För regulatorer och investerare är detta relevant eftersom det visar ett konkret väg till kandidat för preklinisk utveckling mot en ovanlig neurologisk sjukdom med låg behandlingstillgänglighet. Affibody-plattformen öppnar även för licensering eller partnerskap inom regenerativ medicin.
Loss-of-function mutations in the gene encoding progranulin (PGRN) are a common cause of frontotemporal dementia, leading to markedly decreased PGRN levels. A potential therapeutic strategy is therefore to increase extracellular PGRN by blocking sortilin-mediated PGRN clearance. Here, we describe the systematic design and optimization of small biparatopic sortilin-binding proteins based on the non-immunoglobulin affibody scaffold. Two anti-sortilin affibody molecules were genetically fused into a panel of heterodimeric constructs exploring multiple domain orientations, linker lengths, and helix truncations. In total, ten distinct dimer variants were generated and evaluated for binding and functional activity. Optimization of domain arrangement and truncations yielded constructs exhibiting subnanomolar sortilin affinities, corresponding to up to an approximately 45-fold improvement over the strongest monomeric affibody and pronounced avidity effects. In a PGRN clearance assay, the lead 18.6-kDa dimer efficiently increased extracellular PGRN levels with an EC