Identification of the mechanism underlying TTR amyloidosis

Transthyretin (TTR) amyloidosis is a systemic disorder that can be both inherited and sporadic and untreated it is lethal within 3-10-years.

The disease is caused by amyloid formation of the plasma protein TTR and is today treated by either stabilizing drugs, which reduce amyloid formation or by RNAi which reduces TTR expression and thus also hampers the formation of amyloid. Both therapies are very expensive and many don’t respond well implicating the need for alternatives.

Amyloid formation of TTR in vivo proceeds via the formation of non-native TTR oligomers in plasma.

In a ground-breaking discovery, we can here show that this process is controlled by the redox environment and that a non-native disulfide bridge stabilizes the pathological assemblies.

Simply adding a reducing agent effectively eliminates TTR-oligomers from plasma by converting them back to their native state. The finding exposes an Achilles heel and a completely novel therapeutic target to prevent TTR-amyloidosis.

We can further expose the presence of a protecting factor that appears to correlate with young age and intriguingly, mixing plasma from TTR-amyloidosis patientents with plasma from young healthy donors eliminates the pathological oligomers.

The purpose of this application is to elucidate redox as a putative therapeutic approach for TTR-amyloidosis and to identify the protective factor in human plasma, which hence may reveal the actual cause initiating disease onset.