NON-COMMUNICABLE DISEASES / Cardiovascular Disorders
Cardiovascular disorders, cardiac regeneration, adeno-associated virus (AAV), gene therapy, angiogenesis, microRNAs. Molecular biology of HIV-1 infection
Description of Research
The Group aims to identify proteins and microRNAs controlling cardiac protection and regeneration that might be exploited for the therapy of heart diseases. In this group, the Molecular Cardiology Unit (F. Loffredo) uses models of engineered heart tissue to study the biology of cardiomyocytes.
A large part of the activity exploits viral vectors based on the adeno-associated virus (AAV) to deliver to genes in the heart that induce therapeutic angiogenesis or promote tissue regeneration. In this area, the Group has developed procedures for the direct, in vivo selection of therapeutically useful genes upon transduction of cDNA and microRNA libraries cloned into AAV. Work from the Group has led to the identification of microRNAs promoting cardiac regeneration in vivo. The Group is also interested in certain basic aspects of the molecular biology of AAV, with particular reference to the identification of the cellular proteins that regulate AAV infection.
Since March 2020, part of the research of the Group has been redeployed to elucidate the mechanisms that regulate SARS-CoV-2 infection. These studies have led to the discovery of a new mechanism which regulates the coronavirus Spike protein function and is involved in COVID-19 pathogenesis.
An important study including the Group has recently shown the therapeutic efficacy of a monoclonal antibody targeting Bone Morphogenetic Protein (BMP) 1.3 after myocardial infarction. The study proved that this antibody promotes cardiomyocyte survival after an ischemic insult and, at the same time, it modulates fibrotic remodeling, resulting in more elastic scarring and improved cardiac function (Vukicevic et al. Nature Communications, 2022). An excellent recent work by the Group performed a screen to search for drugs blocking syncytia formation induced by the SARS-CoV-2 infection, and identified the antihelminthic drug niclosamide as the most effective compound exerting anti-viral activity. These findings have revealed a new mechanism for COVID-19 disease pathogenesis and supported the repurposing of niclosamide for therapy (Braga et al. Nature 2022).
Braga L, Ali H, Secco I, Chiavacci E, Neves G, Goldhill D, Penn R, Jimenez-Guardeño JM, Ortega-Prieto AM, Bussani R, Cannatà A, Rizzari G, Collesi C, Schneider E, Arosio D, Shah AM, Barclay WS, Malim MH, Burrone J, Giacca M. 2021. Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia. Nature 594, 88-93 PubMed link
Gladka MM, Kohela A, Molenaar B, Versteeg D, Kooijman L, Monshouwer-Kloots J, Kremer V, Vos HR, Huibers MMH, Haigh JJ, Huylebroeck D, Boon RA, Giacca M, van Rooij E. 2021. Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner. Nat Commun 12, 84 PubMed link
Gabisonia K, Prosdocimo G, Aquaro GD, Carlucci L, Zentilin L, Secco I, Ali H, Braga L, Gorgodze N, Bernini F, Burchielli S, Collesi C, Zandonà L, Sinagra G, Piacenti M, Zacchigna S, Bussani R, Recchia FA, Giacca M. 2019. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature 569, 418-422 PubMed link
Lesizza, P., Prosdocimo, G., Martinelli, V., Sinagra, G., Zacchigna, S., Giacca, M. 2017. Single-Dose Intracardiac Injection of Pro-Regenerative MicroRNAs Improves Cardiac Function After Myocardial Infarction. Circ Res 120, 1298-1304 PubMed link
Ruozi, G., Bortolotti, F., Falcione, A., Dal Ferro, M., Ukovich, L., Macedo, A., Zentilin, L., Filigheddu, N., Gortan Cappellari, G., Baldini, G., Zweyer, M., Brazzoni, R., Graziani, A., Zacchigna, S., Giacca, M. 2015. AAV-mediated in vivo functional selection of tissue-protective factors against ischaemia. Nature Commun 6, 7388 PubMed link
Eulalio, A., Mano, M., Dal Ferro, M., Zentilin, L., Sinagra, G., Zacchigna, S., Giacca, M. 2012. Functional screening identifies miRNAs inducing cardiac regeneration. Nature 492, 376-81 PubMed link