Broggini L, Barzago MM, Speranzini V, Schulte T, Sonzini F, Giono M, Romeo M, Milani P, Caminito S, Mazzini G, Rognoni P, Merlini G, Pappone C, Anastasia L, Nuvolone M, Palladini G, Diomede L, Ricagno S. Nanobodies counteract the toxicity of an amyloidogenic light chain by stabilizing a partially open dimeric conformation. J Mol Biol. 2023 Dec 15;435(24):168320. doi: 10.1016/j.jmb.2023.168320. Epub 2023 Oct 20. PMID: 37865287.
\nLight chain amyloidosis (AL) is a systemic disease where fibrillar deposition of misfolded immunoglobulin light chains (LCs) severely affects organ function and results in poor prognosis for patients, especially when heart involvement is severe. Particularly relevant in this context is the cardiotoxicity exerted by still uncharacterized soluble LC species. Here, with the final goal of identifying alternative therapeutic strategies to tackle AL amyloidosis, we produced five llama-derived nanobodies (Nbs) specific against H3, a well-characterized amyloidogenic and cardiotoxic LC from an AL patient with severe cardiac involvement. We found that Nbs are specific and potent agents capable of abolishing H3 soluble toxicity in C. elegans in vivo model. Structural characterization of H3-Nb complexes revealed that the protective effect of Nbs is related to their ability to bind to the H3 VL domain and stabilise an unexpected partially open LC dimer in which the two VL domains no longer interact with each other. Thus, while identifying potent inhibitors of LC soluble toxicity, we also describe the first non-native structure of an amyloidogenic LC that may represent a crucial step in toxicity and aggregation mechanisms.
\nIRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Policlinico San Donato is a university and research hospital provided with the main clinical specialties particularly focused on the study and treatment of cardiac and great vessel diseases through a multidisciplinary approach and devoted to high quality professional training.
\r\nOur institute is a didactic center of the Università degli Studi di Milano and it hosts the Faculty of Medicine, the Faculty of Nursing Sciences and some postgraduate medical residency programs. Moreover, our hospital is a medical training center chosen by many foreign students and doctors.
\r\nIn 1988 was established the Cardiovascular Department “Edmondo Malan” comprehensive of every medical and surgical cardiovascular specialties; since then, patients from every region of Italy and from all over the world have been successfully treated.
\r\nThanks to its proven expertise and high quality health care and due to the relevant scientific contribution of its medical staff, Policlinico San Donato was recognized by the Italian Ministry of Health as Institute for Research, Hospitalization and Health Care for the study and treatment of cardiac and great vessel diseases (Istituto di Ricovero e Cura a Carattere Scientifico per lo studio e la cura delle Malattie del cuore e dei grandi vasi nell’adulto e nel bambino – Ministerial Decree, 6 March 2006).
\r\nOur research activities are directly connected with healthcare providing specialized and tailored therapies and treatment to every patient, from fetuses to oldest old people.
\r\nOur research projects are predominantly clinical with a translational approach supported by our biomolecular, bioengineering and advanced-imaging research laboratories. Heart failure, valvular heart diseases, Brugada Syndrome, congenital cardiopathies, aortic diseases and cardiometabolic diseases are the major interests of the lines of research pursued by our IRCCS.