Liver gene therapy
We are a young and dynamic group that focuses on the biotechnological aspects and translational applications of liver-directed gene transfer and editing. We investigate lentiviral vector (LV)-mediated liver gene transfer and its stability following post-natal liver growth, homeostatic turnover, tissue damage and evaluate different gene therapy strategies in preclinical models of hemophilia and liver metabolic diseases, with the ultimate goal of devising advanced gene therapy products as novel treatments for affected patients.
Our research focuses on three areas:
Gene therapy for hemophilia. The overall objectives of this area are: i) to bring LV-mediated liver gene therapy to first-in-human testing in people with severe hemophilia, ii) to continue development of improved LV and administration protocols for liver-directed gene therapy, iii) to support development of improved manufacturing processes.
Liver tissue dynamics. The overall objective of this area is to dissect the role of different liver cell populations in post-natal liver growth, homeostatic renewal and response to damage. Successful liver gene therapy for inherited monogenic diseases provides safe, therapeutic, life-long replacement of the missing function to pediatric patients. To achieve this goal, the therapeutic genetic modification needs to survive physiological post-natal growth, homeostatic turnover in adulthood and potentially regeneration following tissue damage. Thus, it is necessary to identify and target the therapy to the cell populations contributing to these processes in the liver.
Liver metabolic diseases. The overall goal of this area is to define and tailor the best gene therapy strategy for metabolic liver diseases. One aim is to further investigate which biological barriers limit in vivo liver gene transfer and how to overcome them. The second aim is to determine the threshold of genetically corrected hepatocytes required for disease correction and assess whether cross-correction or selective advantage occur in animal models of metabolic diseases. A third aim is to compare advanced LV-mediated gene delivery and site-specific nuclease mediated gene editing in terms of efficiency, therapeutic efficacy, safety and durability and define the most suitable therapeutic indication among metabolic liver diseases.
Milani M, Canepari C, Liu T, Biffi M, Russo F, Plati T, Curto R, Patarroyo-White S, Drager D, Visigalli I, Brombin C, Albertini P, Follenzi A, Ayuso E, Mueller C, Annoni A, Naldini L*, Cantore A*. Liver-directed lentiviral gene therapy corrects hemophilia A mice and achieves normal-range factor VIII activity in non-human primates. Nat Commun. 2022. *Co-last, co-corresponding authors.
Cesana D, Calabria A, Rudilosso L, Gallina P, Benedicenti F, Spinozzi G, Schiroli G, Magnani A, Acquati S, Fumagalli F, Calbi V, Witzel M, Bushman FD, Cantore A, Genovese P, Klein C, Fischer A, Cavazzana M, Six E, Aiuti A, Naldini L, Montini E. Retrieval of vector integration sites from cell-free DNA. Nat Med. 2021 Jun 17. Online ahead of print. PMID: 34140705
Vonada A, Tiyaboonchai A, Nygaard S, Posey J, Peters AM, Winn SR, Cantore A, Naldini L, Harding CO, Grompe M. Therapeutic liver repopulation by transient acetaminophen selection of gene-modified hepatocytes. Sci Transl Med. 2021 Jun 9;13(597):eabg3047. PMID: 34108249
Bénéchet AP, De Simone G, Di Lucia P, Cilenti F, Barbiera G, Le Bert N, Fumagalli V, Lusito E, Moalli F, Bianchessi V, Andreata F, Zordan P, Bono E, Giustini L, Bonilla WV, Bleriot C, Kunasegaran K, Gonzalez-Aseguinolaza G, Pinschewer DD, Kennedy PTF, Naldini L, Kuka M, Ginhoux F, Cantore A, Bertoletti A, Ostuni R, Guidotti LG, Iannacone M. Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming. Nature. 2019 Oct 2. PMID: 31582858
Milani M, Annoni A, Moalli F, Liu T, Cesana D, Calabria A, Bartolaccini S, Biffi M, Russo F, Visigalli I, Raimondi A, Patarroyo-White S, Drager D, Cristofori P, Ayuso E, Montini E, Peters R, Iannacone M, Cantore A*, Naldini L*. Phagocytosis-Shielded Lentiviral Vectors Improve Liver Gene Therapy in Non Human Primates. Sci Transl Med. 2019 May 22;11(493). pii: eaav7325. *Co-last, co-corresponding authors. PMID: 31118293
Milani M, Annoni A, Bartolaccini S, Biffi M, Russo F, Di Tomaso T, Raimondi A, Lengler J, Holmes MC, Scheiflinger F, Lombardo A, Cantore A*, Naldini L*. Genome editing for scalable production of alloantigen-free lentiviral vectors for in vivo gene therapy. EMBO Mol Med, 2017 Aug 23. *Co-last authors. PMID: 28835507
Cantore A*, Ranzani M*, Bartholomae C, Volpin M, Della Valle P, Sanvito F, Sergi Sergi L, Gallina P, Benedicenti F, Bellinger D, Raymer R, Merricks E, Bellintani F, Martin S, Doglioni C, D’Angelo A, VandenDriessche T. Chuah M, Schmidt M, Nichols T, Montini E, Naldini L. Liver-directed lentiviral gene therapy in a dog model of hemophilia B. Sci Transl Med, 2015 Mar 4;7(277):277ra28. *Equal contribution. PMID: 25739762
Annoni A*, Cantore A*, Della Valle P, Goudy K, Akbarpour M, Russo F, Bartolaccini S, D'Angelo A, Roncarolo MG, Naldini L. Liver gene therapy by lentiviral vectors reverses anti-factor IX pre-existing immunity in haemophilic mice. EMBO Mol Med. 2013 Nov;5(11):1684-97. *Equal contribution. PMID: 24106222
Cantore A*, Nair N*, Della Valle P, Di Matteo M, Màtrai J, Sanvito F, Brombin C, Di Serio C, D'Angelo A, Chuah M, Naldini L, Vandendriessche T. Hyperfunctional coagulation factor IX improves the efficacy of gene therapy in hemophilic mice. Blood. 2012 Nov 29;120(23):4517-20. *Equal contribution. PMID: 23043073
Mátrai J*, Cantore A*, Bartholomae CC*, Annoni A*, Wang W, Acosta-Sanchez A, Samara-Kuko E, De Waele L, Ma L, Genovese P, Damo M, Arens A, Goudy K, Nichols TC, von Kalle C, L Chuah MK, Roncarolo MG, Schmidt M, Vandendriessche T, Naldini L. Hepatocyte-targeted expression by integrase-defective lentiviral vectors induces antigen-specific tolerance in mice with low genotoxic risk. Hepatology. 2011 May;53(5):1696-707. *Equal contribution. PMID: 21520180
Cantore A, Naldini L. WFH State-of-the-art paper 2020: In vivo lentiviral vector gene therapy for haemophilia. Haemophilia. 2020 Jun 14. PMID: 32537776