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Nicola Brunetti-Pierri

Associate Investigator, TIGEM

Associate Professor, Department of Translational Medicine, University of Naples "Federico II', Italy

Hepatocyte Gene Therapy

The overall goal of our research is to provide solutions to biologically relevant questions and to generate preclinical data that will lead to the development of new clinical therapies for patients with inborn errors of metabolism. Gene transfer and small molecules are hopeful strategies for future therapies, and our research focuses on investigating both of these approaches.

The liver is an attractive organ for gene therapy; hepatocyte genes have long been appreciated because their long-term expression provides a major opportunity for treatment, or perhaps, even a cure for several inborn errors of metabolism. Our efforts are currently focused on developing safe and effective gene therapy for primary hyperoxaluria type 1, Crigler-Najjar syndrome, and alpha1-antitrypsin (AAT) deficiency. To achieve these goals, we are investigating multiple gene therapy platforms, including helper-dependent adenoviral (HDAd) and adeno associated viral (AAV) vectors.

Small Molecules for Inborn Errors of Metabolism

Another one of our laboratory’s research interests is investigation of small molecules, orally bioavailable drugs, for the treatment of inborn errors of metabolism. We are evaluating the use of small molecules for the treatment of two diseases, AAT deficiency, one of the most common genetic causes of liver disease in children, and pyruvate dehydrogenase complex (PDHC) deficiency.

The most common genetic lesion in AAT deficiency results in a mutant protein, which forms aggregates that accumulate within the endoplasmic reticulum, ultimately causing liver injury. We are investigating drugs to increase the cellular clearance of toxic undegraded proteins. For PDHC deficiency, we are currently testing drugs acting on PDHC regulation to enhance the residual enzymatic activity. In collaboration with Dr. di Bernardo we are also searching for candidate drugs for both disorders by using a novel systems biology approach based on the analysis of drug expression profiles




Ferriero R, Nusco E, De Cegli R, Carissimo A, Manco G, Brunetti-Pierri N. Pyruvate dehydrogenase complex and lactate dehydrogenase are targets for therapy of acute liver failure. J Hepatol. 2018 Mar 24. pii: S0168-8278(18)30210-1.

Soria LR, Allegri G, Melck D, Pastore N, Annunziata P, Paris D, Polishchuk E, Nusco E, Thöny B, Motta A, Häberle J, Ballabio A, Brunetti-Pierri N. Enhancement of hepatic autophagy increases ureagenesis and protects against hyperammonemia. Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):391-396. 

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

Pastore N, Attanasio S, Granese B, Castello R, Teckman J, Wilson AA, Ballabio A, Brunetti-Pierri N. Activation of the c-Jun N-terminal kinase pathway aggravates proteotoxicity of hepatic mutant Z alpha1-antitrypsin. Hepatology. 2017 Jun;65(6):1865-1874. 

Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, Brunetti-Pierri N. Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med. 2013 Mar 6;5(175):175ra31.

Nicola Brunetti-Pierri MD

Molecular Therapy

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