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Protein deposits, known as amyloids, can wreak havoc in the human body by disrupting the functioning of tissues and organs. Insoluble amyloid deposits, which lead to a condition known as amyloidosis, are associated with more than 40 human diseases.
The EU-funded project Fibrillation identified promising techniques that prevent or reverse amyloid deposit formation and could provide a potential path to treating diseases linked to amyloidosis. These include Alzheimer’s, diabetes, and cancer.
The work was conducted by Spanish researcher Lorena Saelices, and was overseen by the world-renowned American biochemist and biophysicist David Eisenberg at the University of California, Los Angeles. The research contributed to the development of molecular agents, called inhibitors, which prevent amyloid clumps from forming, potentially providing novel treatments for many disorders.
“Proteins aggregated into the amyloid state are associated with 40 or more clinically defined pathologies, and often a distinct single protein is associated with each pathology,” Eisenberg says. “My hypothesis is that by inhibiting protein aggregation, we can halt disease progression.”
A new approach
Saelices’ research targeted the build-up of abnormal deposits of the blood protein transthyretin (TTR) in various organs of the human body. Transthyretin amyloidosis (ATTR) is a progressive fatal condition characterised by the build-up of abnormal deposits of TTR. Most patients with ATTR develop symptoms in early adulthood, and will progressively suffer severe organ impairment, often leading to cardiac arrest and death.
Current treatments for hereditary cases of ATTR, which is estimated to affect 47 in 100 000 people in Europe, rely on liver transplants to slow progression of the condition, but a number of novel therapies are also being explored.
Saelices and Eisenberg, working with a team at the Eidgenössische Technische Hochschule Zürich, Switzerland, as part of Fibrillation, identified two segments of transthyretin responsible for amyloidosis. They believe that by targeting these two segments, it should be possible to prevent the abnormal formation of transthyretin around the cells of organs and tissues.
Using x-rays and electron diffraction, a technique to study matter by firing electrons at a sample and observing the resulting interference pattern, Saelices and the team in the Eisenberg lab have been able to determine the structures of amyloid deposits associated with TTR.
In the Fibrillation project, the team developed TTR-specific inhibitors, called TabFH. These adhere to the two identified segments of the TTR proteins. In laboratory tests these inhibitors successfully prevented the abnormal aggregation of TTR. The project ended in May 2015.
Researchers continue to evaluate these TTR inhibitors — with promising results. At the University of California, Eisenberg has used this technique to design an effective inhibitor that functions on tumour suppressor p53, a protein dubbed “the guardian of the genome” for its role in preventing genetic mutation and therefore cancer formation.
“This inhibitor, called ReACp53, reactivates p53 function, thereby killing certain cancer cells, and shrinking ovarian cancer tumours,” Eisenberg says.
The University of California has applied for patents for TabFH, ReACp53 and other inhibitors, some of which have been licensed to a company for further development — a step that could lead to a range of novel treatments for amyloidosis and many other disorders associated with abnormal protein aggregation.
Saelices’ research in Fibrillation was funded through the EU’s Marie Skłodowska-Curie fellowship programme.