We are a Team of young and eclectic Scientists interested in exploiting gene-engineering tools to study biological functions and solve problems with a direct impact on human health. One of our primary goal is to bring the potential of the new emerging site-specific genome editing technologies within the reach of gene and cell therapy.
In 2007, we demonstrated for the first time the power of the artificial nucleases technology to direct the integration of exogenous DNA sequences into a predetermined genomic locus of several human cell types. We then extended our knowledge and skills on this technology exploiting it for the development of two challenging but highly rewarding new therapeutic strategies: i) genetic redirection of T cell specificity, improving both safety and efficacy of cancer immunotherapy; and ii) targeted integration in human hematopoietic stem/progenitor cells (HSPC), providing safer stem cell gene therapy approaches for monogenic diseases. With the first application, in collaboration with the group of Chiara Bonini, we have established the proof-of-principle of TCR editing as a novel means of T-cell therapy, in which a new biological function is instructed to an immune effector cell by genetically re-writing its endogenous antigen specificity. These studies allow for the first time to effectively re-direct the specificity of CD8 T cell against a tumor-associated antigen without the risks associated with TCR mispairing. (Provasi*, Genovese*, Nat Med 2012). More recently, we aimed at applying genome editing in human HSPC, the target of choice for the treatment of hematologic hereditary diseases but for long time only an elusive target for the gene editing applications. By tailoring delivery platforms and culture conditions we successfully overcame the barriers that constrain homologous recombination and provide stringent evidence of targeted integration in human long-term repopulating HSC. The tools that we developed, which are already well recognized as state-of-the-art technologies in the field, may offer radical solutions to overcome some major hurdles that have hindered progress of gene therapy. Indeed, targeted integration strongly alleviates concerns for insertional mutagenesis and may ensure robust and predicable expression of a therapeutic transgene. When directed downstream its own endogenous promoter, it may not only restore the function of a diseased gene but also its physiological expression control, coming close to the long-sought Holy Grail of gene therapy (Genovese, Nature 2014).
PIETRO GENOVESE, Ph.D.
San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan, Italy
|INSTITUTION||DEGREE||YEAR(s)||FIELD OF STUDY|
|University of Modena and Reggio Emilia||B.Sc.
(Summa cum Laude)
|“Vita Salute San Raffaele” University||M.Sc.
(Summa cum Laude)
|2008||Site-Specific Genome editing|
|“Vita Salute San Raffaele” University||Ph.D.||2013||Gene Editing for Adoptive Immunotherapy|
EMPLOYMENT AND EXPERIENCE
2004-05 _ Lab training at the laboratory of Molecular Oncology, coordinated by Prof. Bruno Calabretta at University of Modena and Reggio Emilia, Dept. of Biomedical Sciences, Sect. of General Pathology.
2005 _ Thesis Internship at the laboratory of Molecular Biology and Gene Therapy, coordinated by Prof. Fulvio Mavilio, at University of Modena and Reggio Emilia, Dept. of Biomedical Sciences, Sect. of Biological Chemistry.
2005-08 _ Internship at the laboratory of Molecular and Cell Biology of Gene Transfer, of Prof. Luigi Naldini, at the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan.
2008-09 _ Fellowship at the laboratory of Molecular and Cell Biology of Gene Transfer, of Prof. Luigi Naldini, at the HSR-TIGET, Milan.
2009-13 _ Ph.D. student at the laboratory of Molecular and Cell Biology of Gene Transfer, of Prof. Luigi Naldini, at the HSR-TIGET Milan.
2013-16 _ Post-doctoral fellow at the laboratory of Molecular and Cell Biology of Gene Transfer, of Prof. Luigi Naldini, at the SR-TIGET Milan.
Since 2016 _ Project Leader, San Raffaele Telethon Institute for Gene Therapy, Milan, Italy
Principal Investigator (PI) of the Grant “Giovani Ricercatori 2013” (GR‐2013‐02358956) and of the SR-Tiget Core Grant 2016-Project E4 (Telethon).
Co-Principal Investigator of the SR-Tiget Core Grant 2016-Project E1 (Telethon).
Author on 9 peer-reviewed articles in international scientific journals (total Impact Factor = 217.21; average IF per paper = 24.1; total number of Citations = 1217; h-index = 8). Full list of publications available at: http://www.ncbi.nlm.nih.gov/pubmed/?term=Pietro+genovese. Bibliometric parameters available at: (http://www.scopus.com/authid/detail.url?authorId=22957867100)
Inventor of 2 international patents families on Targeted disruption of T cell receptor genes (US20110158957 A1; WO2014153470) and Delivery methods and compositions for nuclease-mediated genome engineering in hematopoietic stem cells (US20150174169A1 and WO2015057976;).
Associate Member of the American Society of Gene and Cell Therapy (ASGCT), the European Society of Gene and Cell Therapy (ESGCT) from 2009 to now and of the American Association for Cancer Research in 2010.
Currently Mentoring a Ph.D (International Graduate School in Molecular Medicine, “Vita Salute San Raffaele” University) and 3 M.Sc. students (“Vita Salute San Raffaele” University, University of Groningen). Mentor of a M.Sc. and a B.Sc. students (Medical Biotechnology, “Vita Salute San Raffaele” University) to successful completion of their studies and defence of the thesis, all to top grades. Supervised more than 4 undergraduate M.D. and M.Sc. students. Served as external member of the examiners panel for the Ph.D. Thesis defence at the Universidad Autónoma de Madrid (2015).
Served as Ad hoc reviewer for international grant applications (DEBRA International, Vienna; French National Research Agency, ANR) and contributed to the revision of scientific manuscripts for Nature journals.
Invited speaker at international meetings (Annual Meeting of the French society of cellular and gene therapy, SFTCG; 18th Annual Meeting of the American Society of Gene and Cell Therapy, ASGCT).
Lecturer at the GlaxoSmithKline (Genome Editing Symposium, 2015, Stevenage, UK), St. Jude Children’s Research Hospital (Invited Speaker for a Faculty position, 2015), G. Gaslini Institute (Genome Editing Science Club, 2016, Genoa, Italy).
Presentation of 16 proffered abstracts at international meeting including the Annual Meetings of the American Society of Gene and Cell Therapy (ASGCT), the European Society of Gene and Cell Therapy (ESGCT), the CELL-PID & PERSIST, the American Association for Cancer Research (AACR), San Raffaele Scientific Retreat, Telethon Tri-retreat.
Recipient of the 3 year Grant “Giovani Ricercatori 2013” (GR‐2013‐02358956), sponsored by the Italian Minister of Health.
Principal Investigator (PI) of the SR-Tiget Core Grant 2016-Project E4 (Telethon).
Co-Principal Investigator of the SR-Tiget Core Grant 2016-Project E1 (Telethon).
Recipient of the “Nicolò Copernico Award for Biomedical Science” from the Promoting Committee of the Awards «Giulio Natta and Nicolò Copernico» for the Scientific Research and Technology Innovation of Ferrara granted to an Italian young researcher that published an article in a Scientific Journal with an impact factor over 10, December 2014 (link1, link2).
Recipient of the “Cecilia Cioffrese award” from the Fondazione Carlo Erba for the best research followed by Italian young graduates on the field of cancer, December 2014.
Recipient of the “Van Bekkum award” from the European Society of Bone Marrow Transplantation (EBMT) for the best abstract submitted to the physician’s programme at the EBMT annual congress, April 2012.
Recipient of the “Jon Van Rood Award” from the European Federation for Immunogenetics (EFI) for Best Abstract submitted to the EFI annual congress, 2012.
Recipient of the “Leslie Fairbairn Runner Up Award” from the PERSIST European Research Consortium, January 2010.
Recipient of four Meritorious Travel Grant Award from the American Society of Gene and Cell Therapy, May 2010, May 2012, May 2013 and May 2014.
Recipient of three Meritorious Travel Grant Award from the European Society of Gene and Cell Therapy, November 2011, October 2013, October 2014.
Our research activities are aimed to develop more precise HSC Gene Engineering strategies based on targeted genome editing in order to stringently reconstitute gene function and expression control by in situ gene correction and abrogate any residual risk of insertional mutagenesis by targeted integration.
We will undertake the following activities:
- Focus initial application of gene editing on diseases for which gene correction is associated with growth advantage (SCID-X1, CD40LG deficiency, RAG-1 deficiency) in order to compensate for the current low efficiency of gene editing in HSC. We will:
- design suitable preclinical safety and efficacy studies, including in mouse disease models
- scale-up and qualify the HSC editing protocol for GMP use
- eventually progress to what might be the first-in-human testing of corrective gene editing in HSC
- Increase the efficiency of editing and the purity and yield of edited HSC in order to support safe and effective application also when there is no growth advantage associated with gene correction. We will pursue these aims by:
- assessing new RNA-based nuclease technologies and emerging improvements, in partnership with biotech companies
- monitoring DNA damage response and exhaustion of edited HSC, and investigating strategies to attenuate or revert them
- adopting emerging HSC ex vivo strategies aimed to select and expand edited HSC
Overall, these studies may position gene editing as new golden standard for precise HSC engineering. They will enable our Team to continue being at the forefront of technological advances and leading their translation towards the next generation of gene therapy, exploiting the capacity of the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) for developing early phase clinical trials of HSC-based therapy for inherited diseases, such as primary immunodeficiencies.
Original Research Articles
- Targeted genome editing in human repopulating haematopoietic stem cells. GenoveseP, Schiroli G, Escobar G, Di Tomaso T, Firrito C, Calabria A, Moi D, Mazzieri R, Bonini C, Holmes MC, Gregory PD, van der Burg M, Gentner B, Montini E, Lombardo A, Naldini Nature. 2014 Jun 12;510(7504):235-40. doi: 10.1038/nature13420. Epub 2014 May 28. PMID: 24870228. 2015 Impact Factor: 38.138
News & Views: Fischer A. Nature. 2014. 12;510(7504):226-7
Research Highlights: Koch L. Nature Reviews Genetics. 2014. 15, 442-442
- Cytokine-Induced Killer (CIK) cells engineered with exogenous T cell receptors directed against melanoma antigens: enhanced efficacy of effector cells endowed with a double mechanism of tumor recognition. Elia A, Circosta P, Sangiolo D, Bonini C, Gammaitoni L, Mastaglio S, Genovese P, Geuna M, Avolio F, Inghirami G, Tarella C, Cignetti A. Hum Gene Therapy. 2015 Mar 10. [Epub ahead of print] PMID: 25758764. 2015 Impact Factor: 062
- Targeted gene therapy and cell reprogramming in Fanconi anemia. Rio P, Baños R, Lombardo A, Quintana-Bustamante O, Alvarez L, Garate Z, GenoveseP, Almarza E, Valeri A, Díez B, Navarro S, Torres Y, Trujillo JP, Murillas R, Segovia JC, Samper E, Surralles J, Gregory PD, Holmes MC, Naldini L, Bueren JA. EMBO Molecular Medicine, 2014 May 23;6(6):835-48. doi: 10.15252/emmm.201303374. PMID: 24859981. 2015 Impact Factor: 9.547
- CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Casucci M, Nicolis di Robilant B, Falcone L, Camisa B, Norelli M, GenoveseP, Gentner B, Gullotta F, Ponzoni M, Bernardi M, Marcatti M, Saudemont A, Bordignon C, Savoldo B, Ciceri F, Naldini L, Dotti G, Bonini C, Bondanza A. Blood. 2013 Nov 14;122(20):3461-72. doi: 10.1182/blood-2013-04-493361. Epub 2013 Sep 9. PMID: 24016461. 2015 Impact Factor: 11.841
- Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Provasi E*, GenoveseP*, Lombardo A, Magnani Z, Liu PQ, Reik A, Chu V, Paschon DE, Zhang L, Kuball J, Camisa B, Bondanza A, Casorati G, Ponzoni M, Ciceri F, Bordignon C, Greenberg PD, Holmes MC, Gregory PD, Naldini L, Bonini C. *Equal contribution. Nature Medicine, 2012 May;18(5):807-15. doi: 10.1038/nm.2700. PMID: 22466705. 2015 Impact Factor: 30.357
Research Highlights: Kreisberg J. Nature Biotechnology. 2012 May; 30(5):411
- Site-specific integration and tailoring of cassette design for sustainable gene transfer. Lombardo A, Cesana D*, GenoveseP*, Di Stefano B*, Provasi E*, Colombo DF*, Neri M, Magnani Z, Cantore A, Lo Riso P, Damo M, Pello OM, Holmes MC, Gregory PD, Gritti A, Broccoli V, Bonini C,Naldini *Equal contribution. Nature Methods, 2011 Aug 21;8(10):861-9. doi: 10.1038/nmeth.1674. PMID: 21857672. 2014 Impact Factor: 25.328
Perspective: Sadelain M, Papapetrou EP, Bushman FD. Nature Reviews in Cancer. 2011. Dec 1;12:51-8
- An unbiased genome-wide analysis of zinc-finger nuclease specificity. Gabriel R, Lombardo A, Arens A, Miller JC, Genovese P, Kaeppel C, Nowrouzi A, Bartholomae CC, Wang J, Friedman G, Holmes MC, Gregory PD, Glimm H, Schmidt M, NaldiniL, von Kalle C. Nature Biotechnology, 2011 Aug 7;29(9):816-23. doi: 10.1038/nbt.1948. PMID:21822255. 2014 Impact Factor: 43.113
- Hepatocyte-targeted expression by integrase-defective lentiviral vectors induces antigen-specific tolerance in mice with low genotoxic risk. Mátrai J, Cantore A, Bartholomae CC, Annoni A, Wang W, Acosta-Sanchez A, Samara-Kuko E, De Waele L, Ma L, GenoveseP, Damo M, Arens A, Goudy K, Nichols TC, von Kalle C, L Chuah MK, Roncarolo MG, Schmidt M, Vandendriessche T, Naldini Hepatology. 2011 May;53(5):1696-707. doi: 10.1002/hep.24230. PMID: 21520180. 2014 Impact Factor: 11.711
- Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Lombardo A, Genovese P, Beausejour CM, Colleoni S, Lee YL, Kim KA, Ando D, Urnov FD, Galli C, Gregory PD, Holmes MC, Naldini Nature Biotechnology, 2007 Nov;25(11):1298-306. Epub 2007 Oct 28. PMID: 17965707. 2014 Impact Factor: 43.113
Preview: Ptaszek L.M., Cowan C.A. Cell Stem Cell. 1 (6), pp. 600-602; 2007
Research Highlight: Flintoft L. Nature Reviews in Genetics. 2007 Dec 8, 908-909