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Hematopoietic stem cell gene therapy for lysosomal storage disorders

SR-Tiget Unit
Alessandra Biffi, Head of Unit

biffi.alessandra@hsr.it



Lysosomal storage disorders (LSDs) comprise a class of inherited diseases characterized by disruption of normal lysosomal function and accumulation of undegraded substrates. Despite sharing a similar pathogenic mechanism, the over 40 different described LSDs differ for disease-specific features. The main differences are represented by the pattern of visceral organ involvement and by the presence and severity of nervous system (NS) involvement. Hematopoietic stem cells transplantation (HCT) is an effective treatment for some LSDs. Its efficacy relies on the migration of donor cells of the monocyte lineage into disease target organs, where they replace the resident enzyme-deficient population, thus becoming a local and steady source of the functional enzyme. In the case of LSDs with NS involvement, HCT efficacy has been limited and the patients eligible for such procedure are a minority. The main reason for HCT failure in LSD patients with overt neurological symptoms or in those with early onset or aggressive infantile forms is the likely slow pace of replacement of resident tissue macrophages/histiocytes and microglia populations by the transplanted hematopoietic cell progeny as compared with the rapid progression of the primary disease. Due to this lag period, which is expected to be in the range of 12–24 months before initial disease stabilization, the more severe the phenotype and the longer the interval from onset of first symptoms to allogeneic HCT, the poorer the outcome. Hematopoietic stem cell (HSC)-mediated gene therapy has long been considered an attractive option for the treatment of LSDs, and in particular for NS manifestations. Firstly, it may substantially reduce allogeneic HCT side effects since the autologous procedure is expected to be associated to a reduced transplant-related morbidity and mortality, and avoids the risks of GvHD. Besides safety, the main and critical advantage of the use of genetically corrected autologous HSC as respect to their allogeneic counterpart resides in the possible improvement of the therapeutic potential of HCT in refractory LSDs by means of gene transfer. Indeed, autologous HSCs can be genetically modified to constitutively express higher than normal levels of the therapeutic enzyme and become a quantitatively more effective source of enzyme than normal donors’ cells, possibly also at the level of the affected CNS. Our preclinical and clinical research activity on Type I Mucopolysaccharidosis (MPS I), Glodoid Leukodystrophy (GLD, also known as Krabbe disease) and in Metachromatic Leukodystrophy (MLD), respectively, is devoted to the proof of feasibility and therapeutic relevance of this approach using as gene transfer vehicles advanced generation lentiviral vectors (LVs). Moreover, we are exploring the therapeutic mechanisms underlying disease correction in order to establish novel dynamic principles of therapy uniquely afforded by gene therapy, such as the advantages of enzyme overexpression and the modalities of its biodistribution, while at the same time providing new insights into biological processes of tissue homeostasis, such as microglia turnover at baseline and upon myeloablative conditioning.

Curriculum vitae

Born 10/12/1973 in Milano, Italy.

Education

Institution and location Degree
(if applicable)
Year(s) Field of Study
University of Milan, Italy M.D. 1998 Medicine
University of Milan, Dept. of Pharmacology Specialty 2002 Clinical Pharmacology
Vita Salute San Raffaele University, Dept. of Pediatrics Specialty 2008 Pediatrics

 

Professional experience and appointments

Research activity

  • Since 09/2014: Tenure position as Head of Clinical Unit (“Therapies for lysosomal storage disorders”) at the Pediatric Immunohematology Unit, San Raffaele Scientific Institute
  • Since 04/2014: Tenure position as Head of Unit (“Hematopoietic stem cell gene therapy for lysosomal storage disorders”) at HSR-TIGET, San Raffaele Scientific Institute
  • 09/2012-03/2014: Tenure position as Senior Physician Scientist at HSR-TIGET “Hematopoietic stem cell gene therapy for lysosomal storage disorders” Research Unit and Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute
  • 09/2009-08/2012: Physician Scientist at HSR-TIGET “Hematopoietic stem cell gene therapy for lysosomal storage disorders” Research Unit and Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute
  • 11/2008-08/2009: Group Leader and Staff Pediatrician, HSR-TIGET “Hematopoietic stem cell gene therapy for lysosomal storage disorders” Research Unit and Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute
  • 01/2006-10/2008: Project Leader, HSR-TIGET “Hematopoietic stem cell gene therapy for lysosomal storage disorders” Research Unit and Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute
  • 01/2003 to 06/2003: Visiting Scientist (with Prof David Wenger), Jefferson Medical College. Department of Neurology, Philadelphia
  • 03/2001-12/2005: Post-Doctoral Resident Fellow, HSR-TIGET “Hematopoietic stem cell gene therapy for lysosomal storage disorders” Research Unit and Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute
  • 09/1999-06/2000: Visiting Scientist (with Dr Bruno Peault), Institut d’Embryologie Cellulaire et Moleculaire du CNRS et du College de France, Nogent-sur-Marne, France
  • 10/1998-2/2001: Clinical Fellow and (since 11/1998) Resident Fellow, Cystic Fibrosis unit and 1° Infanzia, Clinica Pediatrica De Marchi, University of Milano School of Medicine and San Raffaele Telethon Institute for Gene Therapy (SR-Tiget)/ Institute for Experimental Treatment of Cystic Fibrosis, San Raffaele Scientific Institute
  • 09/1996-09/1997: Intern, Internal Medicine Department, San Raffaele Scientific Institute and University of Milan, School of Medicine

Academic appointments

  • 01/2014: National board for Associate Professor in Pediatrics
  • 09/2012-present: Temporary Professor of Pediatrics, Medical School, ‘Vita-Salute’ University, Milano
  • Tutor, Histology and Tissue Biology (Medical School and School of Biotechnology, ‘Vita-Salute’ University, Milano, 2003-2005)
  • Supervised 6 PhD Students within the Institutional/External PhD Programs (Martina Cesani, Ilaria Visigalli, Alessia Capotondo – completed; Silvia Ungari, Stefania Delai, Rita Milazzo – on going), 4 Master degree students at School of Biotechnology, ‘Vita-Salute’ University (Silvia Ungari, Helena Anderson, Rita Milazzo – completed; Francesca Ferro, Eleonora Cavalca – on going, as “correlatore”), 5 Medical students at Medical School, ‘Vita-Salute’ University (Francesca Fumagalli, Daniela Ungaro, Laura Lorioli, the latter as “correlatore” – completed; Silene Casari and Camilla Caporali, on going, as “correlatore”) in their thesis work preparation; supervised a visiting Master degree student from Erasmus University – Rotterdam (Merel Stok) in the execution of her thesis work; acts as tutor of two Resident Fellows in Pediatrics (Laura Lorioli and Marta Frittoli) since 2010

Honors and Awards

  • December 2011: “Medaglia del Presidente della Repubblica Italiana” for scientific merit – “Bio e Nano WomenTech” price
  • June 2010: Recipient of the Outstanding New Investigator Award, American Society for Cell and Gene Therapy
  • October 2009: Recipient of the Young Investigator Award, European Society for Cell and Gene Therapy
  • June 2005: Recipient of the Excellence in Research Award, American Society of Gene Therapy Annual Meeting, 2005, St. Louise
  • June 2004: Recipient of the Excellence in Research Award, American Society of Gene Therapy Annual Meeting, 2004, Minneapolis

Scientific achievements

  • Authored 42 scientific papers (total impact factor 295; h index 20; citations 1425) of which 13 as first, 14 as last/senior and 20 as corresponding Author, including 2 Science; 2 Blood, 1 PNAS, 2 JCI; wrote a book chapter in “Lysosomal Storage Disorders”, ISBN 978-0-387-70908-6, Springer E., 2007 and a section dedicated to “Metachromatic leukodystrophy, multiple sulfatase deficiency, and sulfatideactivator deficiency” in Medlink Neurology (www.medlink.com)
  • Leads a research/clinical research group made of 15 researches/clinicians (5 postdoctoral fellows, 3 PhD students, 1 technician, 1 fellow, 1 clinical resident in pediatrics, 2 medical students and 2 master degree students)
  • Contributed to the preparation of the Dossier for granting the medicinal product “Autologous CD34+ cells transfected with lentiviral vector containing the human arylsulfatase A cDNA for treatment of metachromatic leukodystrophy” by the European Commission of Orphan Drug Designation (Orphan Drug Status granted on March 8, 2007 (EMEA/COMP 84536/2007)).
  • Principal Investigator of the Phase I/II Clinical Trial “TIGET-MLD: Autologous CD34+ cells transfected with lentiviral vector containing the human arylsulfatase A cDNA for treatment of metachromatic leukodystrophy”
  • Principal Investigator of an observational Clinical Trial on the natural history of Metachromatic Leukodystrophy, “LDM1: Studio clinico della Leucodistrofia Metacromatica”
  • Contributed to the establishment of Arylsulfatase A gene sequencing as Routine Diagnostic Test provided by LaboRaf (Analisi completa mutazioni del gene ARSA – MUARSA)
  • Wrote several funded research grants as PI and is actively participating to the Telethon-GSK alliance with direct responsibility of three research areas
  • Chair of the Gene & Cell Therapy of Genetic and Metabolic Diseases Committee of the American Society of Cell and Gene Therapy (2014-2015)
  • Referee for Human Gene Therapy, Molecular Therapy, The Journal of Gene Medicine, Current Gene Therapy, Neurobiology of Disease, Journal of Neuroscience, J Virology

Current research interests

  • Assessment of the efficacy and safety of HSC gene therapy in MLD patients based on biochemical, molecular and clinical assessments
  • Pre-clinical and clinical development of hematopoietic stem cell gene therapy approaches for the treatment of different lysosomal storage disorders (LSD), including globoid cell leukodystrophy and type I mucopolysaccharidosis
  • Study of the mechanisms of microglia reconstitution following hematopoietic stem cell transplantation
  • Analysis of the role of the lysosomal enzyme galactocerebrosidase in regulating hematopoietic stem cell survival
  • Characterization of novel arylsulfatase A gene mutations and identification of genotype-phenotype correlations in metachromatic leukodystrophy

Clinical activity

  • Acts as Principal Investigator of the Phase I/II Clinical Trial “TIGET-MLD”: clinical protocol design, patients’ recruitment, assessment on eligibility, patients’ treatment, clinical monitoring during and post-transplant, reporting of AE/SAE and other regulatory duties
  • Acts as Principal Investigator of the observational clinical study LDM1, dedicated to the definition of the natural history of Metachromatic Leukodystrophy: patients’ recruitment and regular clinical and instrumental follow up (in/out-patient)
  • Daily activity and wards (reperibilità) for pediatric patients affected by genetic diseases (lysosomal storage disorders, immunodeficiencies, hematological disorders including thalassemia) undergoing gene therapy and/or allogeneic hematopoietic cell transplantation within the Pediatric Immunohematology and Bone Marrow Transplantation Unit and SR-Tiget Pediatric Clinical Research Unit (inpatient and outpatient services)
  • Outpatient service for pediatric patients with metabolic disorders

Invited lectures (last 5 years)

  • XXII Annual Congress of the European Society of Gene and Cell Therapy, Le Haugue – October 2014
  • EBMT/ESID IEWP 17th Meeting, Munich – October 2014
  • XII CONGRESSO AINR DI NEURORADIOLOGIA PEDIATRICA, Milan – October 2014
  • XXIV European Congress of Perinatal Medicine, Florence – June 2014
  • ESHG Conference, Milan – June 2014
  • Le applicazioni delle cellule staminali in medicina rigenerativa: III incontro del ciclo “Scienza, Innovazione e Salute” c/o Senato della Repubblica, Rome – April 2014
  • ELA Scientific Day, Paris – March 2014-08-20
  • XXVIII Congresso AIMPS, Senago – March 2014
  • V Congresso Nazionale Congiunto SIMMESN e SIMGePeD, Naples – November 2013
  • RiMED Foundation Meeting, Rome – October 2013
  • 7th Stem Cell Clonality and Genome Stability Retreat, Madrid – October 2013
  • XXI Annual Congress of the European Society of Gene and Cell Therapy, Madrid – October 2013
  • XI Annual Meeting of the International Society for Stem Cell Research, Boston – June 2013
  • XVI Annual Congress of the American Society of Gene and Cell Therapy, Salt Lake City – May 2013
  • 39th Annual Meeting of the European Group for Blood and Marrow Transplantation, London – April 2013
  • XV Congresso Nazionale SIGU (Società Italiana di Genetica Umana) – Sorrento, November 2012
  • EBMT Working Party “Inborn Errors” Meeting, Barcellona – November 2012
  • XX Annual Congress of the European Society of Gene and Cell Therapy, Versailles – October 2012
  • XII International Symposium on MPS and Related Diseases, Noordwijkerhout – July 2012
  • XV Annual Congress of the American Society of Gene and Cell Therapy, Philadelphia – May 2012
  • XIX Annual Congress of the European Society of Gene and Cell Therapy, Brigthon – October 2011
  • EBMT Working Party “Inborn Errors” Meeting, Belgrade – September 2011
  • XIV Annual Congress of the American Society of Gene and Cell Therapy, Seattle – May 2011
  • XVIII Annual Congress of the European Society of Gene and Cell Therapy, Milano – October 2010
  • 2010 Annual Symposium of the Society for the Study of Inborn Errors of Metabolism, Istanbul – September 2010
  • XIII Annual Congress of the American Society of Gene and Cell Therapy, Washington – May 2010
  • XVII Annual Congress of the European Society of Gene and Cell Therapy, Hannover – November 2009
  • Myelin Project Annual Meeting, Toronto – October 2009
  • EBMT Working Party “Inborn Errors” Meeting, Cambridge – September 2009
  • International Society for Lysosomal Storage Disorders Meeting, Frankfurth – April 2009
  • II ELA Foundation Scientific Meeting, Luxembourg – March 2009

 

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