NON-COMMUNICABLE DISEASES / Molecular Genetics
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 study of disease mechanisms of metabolic genetic diseases, and in 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 projects aim at developing efficacious therapies for severe pediatric liver diseases, for which there are no therapeutic alternatives except for liver transplantation, a very risky procedure with several limitations. We are concentrating our efforts in 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 very 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 addressing the mechanisms at the basis of bilirubin neurotoxicity and the possible therapeutic approaches to cure the disease. We are studying mechanisms of diseases and therapies, including genes that modify the severity of bilirubin-induced neurological damage, bilirubin-mediated inflammation and cell death, DNA damage, testing pharmacological therapies, gene therapy and gene editing approaches, which are being developed and tested in a CNSI mouse model.
The gene therapy experiments in mouse models have the final aim of transferring the methodologies to the clinics. We are currently participating to a network composed of several laboratories and clinical centers in Europe to perform a phaseI/II clinical trial for Crigler-Najjar syndrome patients, using AAV-vector mediated liver gene transfer.
We are also applying gene therapy approaches to other liver diseases, such as ornithine transcarbamylase deficiency and citrullinemia, two very severe disorders of the urea cycle.
Recently, the Group demonstrated the potential of blocking bilirubin production to treat neonatal hyperbilirubinemia (Antioxidants 2021, 10, 2029.). The inactivation of biliverdin reductase resulted in non-toxic hyperbiliverdinemia and full rescue of bilirubin-induced neonatal toxicity, thereby opening the way for future therapeutic applications. Also reported was a genome-targeting treatment for the permanent cure of hemophila B with long-term safety and efficacy (Front. Genome Ed. doi: 10.3389/fgeed.2022.785698).
Bortolussi G, Muro AF. 2020. Experimental models assessing bilirubin neurotoxicity. Pediatr Res 87:17-25.
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
De Caneva A, Porro F, Bortolussi G, Sola R, Lisjak M, Barzel A, Giacca M, Kay MA, Vlahovicek K, Zentilin L, Muro AF. 2019. Coupling AAV-mediated promoterless gene targeting to SaCas9 nuclease to efficiently correct liver metabolic diseases. JCI Insight 5
Malara A, Gruppi C, Abbonante V, Cattaneo D, De Marco L, Massa M, Iurlo A, Gianelli U, Balduini CL, Tira ME, Muro AF, Chauhan AK, Rosti V, Barosi G, Balduini A. 2019. EDA fibronectin-TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis. J Exp Med 216:587-604.
Vodret S, Bortolussi G, Iaconcig A, Martinelli E, Tiribelli C, Muro AF. 2018. Attenuation of neuro-inflammation improves survival and neurodegeneration in a mouse model of severe neonatal hyperbilirubinemia. Brain Behav Immun 70:166-178 PubMed link
Porro F, Bortolussi G, Barzel A, De Caneva A, Iaconcig A, Vodret S, Zentilin L, Kay MA, Muro AF. 2017. Promoterless gene targeting without nucleases rescues lethality of a Crigler-Najjar syndrome mouse model. EMBO Mol Med 9:1346-1355 PubMed link