NON-COMMUNICABLE DISEASES / Molecular Genetics
Research Interests
Mouse models of human diseases, gene therapy, gene editing, adeno-associated virus (AAV), liver metabolic disorders.
Description of Research
The research interests of the Group focus on the disease mechanisms of metabolic genetic diseases and the development of therapeutic approaches for their cure, ranging from pharmacological therapies to gene therapy and gene editing, using transgenic and engineered mouse models of the human syndromes.
Our project aims at developing efficacious therapies for severe pediatric liver diseases, for which there are no therapeutic alternatives except for liver transplantation, a hazardous procedure with several limitations. We are concentrating our efforts on a paradigmatic metabolic liver disease: the Crigler-Najjar Syndrome type I (CNSI). The disease is characterised by severe jaundice (elevated blood levels of bilirubin) since birth and a lifelong risk of bilirubin encephalopathy, with severe and permanent brain damage and death if untreated. The clinical management of the disease is difficult as patients have to receive life-long phototherapy treatment (about 10-12 hours/day), and its effectiveness reduces with age. Liver transplantation is currently the only definitive treatment available. We are currently participating in a network composed of several laboratories and clinical centers in Europe performing a phaseI/II clinical trial for Crigler-Najjar syndrome patients using AAV-vector mediated liver gene transfer (D’Antiga et al, 2023, NEJM).
We are testing genome editing and genome targeting approaches (with and without the use of engineered nucleases) for other liver diseases, such as ornithine transcarbamylase deficiency and citrullinemia, two very severe disorders of the urea cycle. We are also applying mRNA therapy delivered with lipid nanoparticles for acute neonatal conditions.
We are interested in setting up a therapeutic protocol for Fabry disease in order to develop a more efficient and less expensive therapeutic alternative. The strategy is based on converting the liver into a “bio-factory” that will produce high levels of circulating GLA that will be captured by the target organs, as it now occurs with the ERT approach.
Recent Publications
Figueiredo A, Rastogi ST, Ramos S, Nogueira F, De Villiers K, de Sousa AGG, Votborg-Novel L, von Wedel C, Tober-Lau P, Jentho E, Pagnotta S, Mesquita M, Cardoso S, Bortolussi G, Muro AF, Tranfield EM, Thibaud J, Duarte D, Sousa AL, Pinto SN, Kitoko J, Mombo-Ngoma G, Mischlinger J, Junttila S, Alenquer M, Amorim MJ, Vasavda C, Bosma PJ, Violante S, Drotleff B, Paixao T, Portugal S, Kurth F, Elo LL, Paul BD, Martins R, and Soares MP. A Metabolite-Based Resistance Mechanism Against Malaria. Science. 2025; https://doi.org/10.1126/science.adq6741
Simoni C, Barbon E, Muro AF, and Cantore A. In vivo liver targeted genome editing as therapeutic approach: progresses and challenges. Front Genome Ed. 2024;6:1458037
Bortolussi G, Iaconcig A, Canarutto G, Porro F, Ferrucci F, Galletta C, Diaz-Munoz C, Rawat V, De Caneva A, Olajide OJ, Zentilin L, Piazza S, Bockor L, and Muro AF. CRISPR-Cas9-mediated somatic correction of a one-base deletion in the Ugt1a gene ameliorates hyperbilirubinemia in Crigler-Najjar syndrome mice. Molecular therapy Methods & clinical development. 2023;31:101161
De Caneva A, Porro F, Bortolussi G, Sola R, Lisjak M, Barzel A, Giacca M, Kay MA, Vlahoviček K, Zentilin L, and Muro AF. Coupling AAV-mediated promoterless gene targeting to SaCas9 nuclease to efficiently correct liver metabolic diseases. JCI insight. 2019;4(15)
Collaud F, Bortolussi G, Guianvarc’h L, Aronson SJ, Bordet T, Veron P, Charles S, Vidal P, Sola MS, Rundwasser S, Dufour DG, Lacoste F, Luc C, Wittenberghe LV, Martin S, Le Bec C, Bosma PJ, Muro AF, Ronzitti G, Hebben M, Mingozzi F. 2019. Preclinical Development of an AAV8-hUGT1A1 Vector for the Treatment of Crigler-Najjar Syndrome. Mol Ther Methods Clin Dev 12:157-174
Porro F, Bortolussi G, Barzel A, De Caneva A, Iaconcig A, Vodret S, Zentilin L, Kay MA, and Muro AF. Promoterless gene targeting without nucleases rescues lethality of a Crigler‐Najjar syndrome mouse model. EMBO Molecular Medicine. 2017;9(10):1346-55
Group Leader
Andrés Muro
ICGEB Trieste, Italy
E-mail: [email protected]
Tel: +39-040-3757369/12
Group Leader CV
Group Members
Giulia Bortolussi, Research Associate
Giulia Romano, Research Scientist
Alessandra Iaconcig, Research Technician
Anantha Padmanabhan S.P., PhD Student
Sara Solaro, Undergraduate student