Biomimetic drug development for neurodegeneration and respiratory distress

The BRICHOS molecular chaperone prevents amyloid-β peptide (Aβ) neurotoxicity, with potential to treat Alzheimer disease (AD).

Intravenously injected BRICHOS in AD mice with established behavioral deficits and brain pathology results in unprecedented reduction of cognitive deficits, Aβ42 load, as well as inflammation around plaques. One aim is to find out optimal treatment regimes in AD mice and scale up the BRICHOS production.

Recombinant human BRICHOS from the Bri2 protein efficiently passes the blood brain barrier (BBB) in wild type mice and another aim is to investigate if this can be used to carry cargo molecules into the CNS.

Bri2 BRICHOS chaperone activity against non-fibrillar protein aggregation is turned on by physiological thiols, via formation of high molecular mass oligomers.

A third aim is to elucidate the mechanism of this novel way of chaperone activation and determine the structure of the active chaperone by cryo electron microscopy.Our work on spider silk proteins has resulted in a tool that enables efficient production of very aggregation-prone proteins.

This has made it possible to generate proteins that combine properties of lung surfactant proteins SP-B and SP-C, which function equally well as clinically used animal derived surfactants for treatment of respiratory distress syndrome (RDS) in animal models. A fourth aim is to develop these Combo peptides into a cost-efficient drug for treatment of neonatal and adult RDS.