Stem cells and neurogenesis
Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.
Our lab has a strong interest in developing novel technologies in stem cells, genetic cell reprogramming and CRISPR/Cas9 gene editing for better modeling and treating neurological disorders. Patient’s derived iPS cells (iPSCs) offer a superior cellular model to recapitulate the key pathophysiological defects underlying the disease. In addition, CRISPR/Cas9 gene-editing provides a fast and efficient system to prove the direct association between a gene mutation and a specific cellular trait. The group has established numerous strategies for direct cell reprogramming to generate induced neuronal and glial cells for accelerating cellular modeling of human disorders. Moreover, we have established iPSCs from patients suffering from various diseases including Dravet, Rett and ASD syndromes, NBIA and Parkinson’s disease. CRISPR/Cas9 gene editing is a crucial tool in the lab to generate isogenic control iPSCs or to introduce targeted gene mutations. Lately, we have conceived and validated new approaches for correcting mutated genes or modulating their expression by CRISPR technology in vitro and in vivo. To vehiculate these tools in the brain and set up strategies of in vivo gene-therapy, this lab is producing new variants of adeno-associated viruses (AAV) that combined high targeting efficiency, tissue spreading and safety.
- Modelling cellular pathological defects of Parkinson’s disease with patient-derived iPSCs
- Developing new approaches of AAV-based gene-therapy to limit dopaminergic neuronal death and dysfunctions in Parkinson’s disease
- Validating new gene and pharmacological therapeutic approaches for Dravet syndrome based on CRISPR/Cas9 technology
- Understanding the molecular bases of infantile autism-spectrum disorders caused by mutations in chromatin factors and generation of patients derived iPSC models
- Technical development of new AAV variants for the gene therapy of brain disorders
- Validating gene-therapy procedures for incurable neuroinfantile disorders
Mazzara PG, Massimino L, Pellegatta M, Ronchi G, Ricca A, Iannielli A, Giannelli SG, Cursi M, Cancellieri C, Sessa A, Del Carro U, Quattrini A, Geuna S, Gritti A, Taveggia C, Broccoli V. Two factor-based reprogramming of rodent and human fibroblasts into Schwann cells. Nat Commun. 2017 Feb 7;8:14088.
Meneghini V, Frati G, Sala D, De Cicco S, Luciani M, Cavazzin C, Paulis M, Mentzen W, Morena F, Giannelli S, Sanvito F, Villa A, Bulfone A, Broccoli V, Martino S, Gritti A. Generation of human induced pluripotent stem cell-derived bona fide neural stem cells for ex vivo gene therapy of metachromatic leukodystrophy. Stem Cells Transl Med. 2017 Feb;6(2):352-368.
Rubio A, Luoni M, Giannelli SG, Radice I, Iannielli A, Cancellieri C, Di Berardino C, Regalia G, Lazzari G, Menegon A, Taverna S, Broccoli V. Rapid and efficient CRISPR/Cas9 gene inactivation in human neurons during human pluripotent stem cell differentiation and direct reprogramming. Sci Rep. 2016 Nov 18;6:37540.
Vasconcelos FF, Sessa A, Laranjeira C, Raposo AA, Teixeira V, Hagey DW, Tomaz DM, Muhr J, Broccoli V, Castro DS. MyT1 counteracts the neural progenitor program to promote vertebrate neurogenesis. Cell Rep. 2016 Oct 4;17(2):469-483.
Orellana DI, Santambrogio P, Rubio A, Yekhlef L, Cancellieri C, Dusi S, Giannelli SG, Venco P, Mazzara PG, Cozzi A, Ferrari M, Garavaglia B, Taverna S, Tiranti V, Broccoli V, Levi S. Coenzyme A corrects pathological defects in human neurons of PANK2-associated neurodegeneration. EMBO Mol Med. 2016 Oct 4;8(10):1197-1211.
Colasante G, Lignani G, Rubio A, Medrihan L, Yekhlef L, Sessa A, Massimino L, Giannelli SG, Sacchetti S, Caiazzo M, Leo D, Alexopoulou D, Dell'Anno MT, Ciabatti E, Orlando M, Studer M, Dahl A, Gainetdinov RR, Taverna S, Benfenati F, Broccoli V. Rapid conversion of fibroblasts into functional forebrain GABAergic interneurons by direct genetic reprogramming. Cell Stem Cell. 2015 Dec 3;17(6):719-34.
Broccoli V, Colasante G, Sessa A, Rubio A. Histone modifications controlling native and induced neural stem cell identity. Curr Opin Genet Dev. 2015 Oct;34:95-101.
Broccoli V, Rubio A, Taverna S, Yekhlef L. Overcoming the hurdles for a reproducible generation of human functionally mature reprogrammed neurons. Exp Biol Med (Maywood). 2015 Jun;240(6):787-94.
Dell'Anno MT, Caiazzo M, Leo D, Dvoretskova E, Medrihan L, Colasante G, Giannelli S, Theka I, Russo G, Mus L, Pezzoli G, Gainetdinov RR, Benfenati F, Taverna S, Dityatev A, Broccoli V. Remote control of induced dopaminergic neurons in parkinsonian rats. J Clin Invest. 2014 Jul;124(7):3215-29.
Caiazzo M, Dell'Anno MT, Dvoretskova E, Lazarevic D, Taverna S, Leo D, Sotnikova TD, Menegon A, Roncaglia P, Colciago G, Russo G, Carninci P, Pezzoli G, Gainetdinov RR, Gustincich S, Dityatev A, Broccoli V. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 2011 Jul 3;476(7359):224-7.
Pietro Giuseppe Mazzara
Alicia Rubio Garrido