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Pasquale Piccolo

Assistant Investigator, TIGEM

Hepatocyte-directed gene therapy for inherited disorders with liver fibrosis

Gene therapy for inherited liver disorders has undergone tremendous development. Recombinant adeno-associated viral vectors (rAAVs) are actually considered as the vector of choice for the treatment of inherited liver diseases and have recently achieved remarkable successes in clinics. Nevertheless, integrity of liver architecture is considered prerequisite for efficient gene transfer using rAAVs and patient with clinically relevant liver fibrosis are excluded from clinical trials. In our lab we develop novel gene therapy approaches to achieve clinically effective levels of liver transduction in presence of fibrosis.
Several liver genetic disorders are characterized by advanced fibrosis or cirrhosis. Among these, Wilson Disease (WD) is the most frequent and is caused by mutations in ATP7B, encoding for a P-type copper transporting ATPase expressed in the hepatocytes. Our efforts are focused on the development of a liver-directed gene therapy for WD using rAAV bearing engineered ATP7B, size-optimized expression cassettes or dual rAAV vector systems. We are combining these gene replacement approaches with anti-fibrotic therapy using microRNAs to reduce fibrosis and achieve clinically effective transduction levels.

Piccolo P, Annunziata P, Soria LR, Attanasio S, Barbato A, Castello R, Carissimo A, Quagliata L, Terracciano LM, Brunetti-Pierri N. Downregulation of HNF-4α and defective zonation in livers expressing mutant Z α1-antitrypsin. Hepatology, 2017 Jul;66(1):124-135

Piccolo P, Attanasio S, Secco I, Sangermano R, Strisciuglio C, Limongelli G, Miele E, Mutarelli M, Banfi S, Nigro V, Pons T, Valencia A, Zentilin L, Campione S, Nardone G, Lynnes TC, Celestino-Soper PBS, Spoonamore KG, D'Armiento FP, Giacca M, Staiano A, Vatta M, Collesi C, Brunetti-Pierri N. MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Ménétrier-like gastropathy. Hum Mol Genet 2017 Jan 1;26(1):33-43.

Piccolo P, Annunziata P, Mithabokar P, Brunetti-Pierri N. SR-A and SREC-I blocking peptides increase HDAd-mediated liver transduction. Gene Ther. 2014 Nov; 21(11):950-7.

Piccolo P, Mithbaokar P, Sabatino V, Tolmie J, Melis D, Schiaffino MC, Filocamo M, Andria G, Brunetti-Pierri N. SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan. Eur J Hum Genet. 2014 Aug;22(8):988-94

Piccolo P, Vetrini F, Mithbaokar P, Grove NC, Bertin T, Palmer D, Ng P, Brunetti-Pierri N. SR-A and SREC-I are Kupffer and endothelial cell receptors for helper-dependent adenoviral vectors. Mol Ther. 2013 Apr;21(4):767-74.

Pasquale Piccolo PHD

Molecular Therapy

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