Pathogenesis, diagnostics and treatment of transthyretin amyloidosis
Transthyretin amyloidosis is a lethal systemic disorder spread all over the world. The hereditary form is rare, but a clustering area of the disease is found in for example Northern Sweden. The acquired form is probably more frequent than we previously have understood, and may be considered a part of normal ageing.
Our group has conducted research in the field since the 1980’s and we have witnessed a revolutionary change in the care and treatment of patients with this devastating disease. Our current research focuses on the study of different genetic factors (apart from TTR mutations) with possible impact on disease phenotype, potential biomarkers of disease, the impact of amyloid fibril type on disease outcome, and the accuracy of our current diagnostic methods.
Transthyretin amyloidosis (ATTR amyloidosis) is a lethal systemic disorder caused by deposition of protein fibrils (amyloid) in various organs. The amyloid is formed by misfolded transthyretin (TTR), which is mainly produced by the liver. ATTR amyloidosis is either acquired (wild-type) or inherited (hereditary ATTR amyloidosis). Hereditary ATTR amyloidosis is a rare disease that is spread worldwide with higher prevalence in certain clustering areas, of which one is located in Northern Sweden. Common clinical features are peripheral and autonomic neuropathies, GI symptoms, cardiomyopathy, and eye complications. Wild-type ATTR amyloidosis is being increasingly recognized and is characterized by cardiomyopathy mainly in elderly males.
Our group (Amyloidosis Center) is responsible for the treatment of ATTR amyloidosis in Sweden and conducts preclinical and clinical research on the pathogenesis, diagnostics and treatment of the disease since the 1980's. Throughout the years, we have explored the prevalence, penetrance and clinical picture of ATTR amyloidosis in Sweden and studied the pathogenesis of the disease, especially with respect to its gastrointestinal complications. We have also taken part in the development of new diagnostic modalities and treatments, for example liver transplantation and disease-modifying drugs (tafamidis, diflunisal, patisiran). The approval of the small interfering RNA patisiran for the treatment of hereditary ATTR amyloidosis was listed by Science as one of the top ten scientific breakthroughs in 2018.
Our current research focuses on the study of different genetic factors (apart from TTR mutations) with possible impact on disease phenotype, potential biomarkers of disease, the impact of amyloid fibril type on disease outcome, and the accuracy of our current diagnostic methods. We also participate in a number of clinical trials evaluating the effect of TTR stabilizers (diflunisal), gene therapy (patisiran) and antibodies against misfolded TTR (PRX004) for hereditary ATTR amyloidosis.