Transthyretin amyloidosis and therapy: bridging the gap between laboratory and clinical research

This proposal sets out an ambitious programme of research that aims to deepen our understanding of transthyretin (TTR) amyloidosis, and to narrow the gap between biochemical/biophysical studies and clinical approaches and therapy.

The research focuses on molecular level characterisation of various clinically-derived mutants that have markedly different stabilities – some strongly pathogenic and some protective.

These mutations have profound consequences for molecular stability and the amyloid pathologies caused; in addition there is evidence that specific mutants impart specificity for the tissues afflicted.

The work will involve systematic studies using a powerful range of biophysical techniques to characterise the regions of the TTR molecule that cause instability as well as the way the degradation products assemble into fibrils and deposit.

This approach will be deployed alongside the testing of novel drug candidates that are being designed to prevent amyloid formation. In addition, parallel analyses will be carried out using TTR derived from the plasma of afflicted patients.

There will be a fundamental emphasis on linking in vitro to in vivo and ex vivo research, aimed ultimately at new effective clinical therapies.

The work will involve extensive collaboration with the Centre for Amyloidosis at the Royal Free Hospital in London, and make full use of national Swedish research infrastructures as well as international facilities to which Sweden subscribes.