Moderator of 1 Session
Presenter of 1 Presentation
AMYLOID SEEDING EMERGES AS A POTENTIAL TARGET FOR THE TREATMENT OF AMYLOIDOSIS
Abstract
Aims
ATTR amyloidosis is caused by the systemic deposition of amyloid fibrils of transthyretin that leads to organ failure and death. Like in other amyloid disorders, current treatments show limited effects in advanced cases. We hypothesized that the presence of preformed fibrils alters the fate of amyloid deposition, and this process represents a potential therapeutic strategy for advanced ATTR amyloidosis.
Methods
We extracted fibrils from ATTR amyloidosis patients to study the mechanism of amyloid deposition in the presence of preformed fibrils. We established a multidisciplinary program to develop peptide inhibitors, ranging from protein aggregation assays to x-ray crystallography structure determination and computational inhibitor design. We evaluated these peptide inhibitors in vitro, using patient samples, and in two Drosophila models. Finally, we engineered a biosensor cell line overexpressing a transthyretin variant that carries a disease-related mutation and a fluorescent tag for drug screening.
Results
In our studies, we discovered a novel mechanism of aggregation of transthyretin, common to other amyloid precursors. That is, we found that transthyretin can polymerize into amyloid fibrils by a templating mechanism known as amyloid seeding. Our results suggest that this mechanism takes over amyloid deposition at late stages of ATTR amyloidosis in contrast to de novo protein aggregation that triggers the disease. We found that current drugs that are effective in early states do not halt amyloid seeding of transthyretin. In contrast, our anti-seeding peptides show full inhibition of amyloid seeding at substoichiometric concentrations.
Conclusions
Anti-seeding peptides may represent a novel therapeutic avenue for advanced cases of ATTR amyloidosis.