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BACULOGENES Use of baculovirus as a vector for gene therapy Summary Keywords | Baculovirus | gene delivery | insect cells | vertebrate cells | adeno-associated virus (AAV) | prostate cancer | age-related macular degeneration (AMD) | muscular disorders (MD) | Gene therapy is a technique to deliver therapeutic nucleic acids into somatic cells and is one of the most promising therapeutic methods under development for treating a large scope of pathologies, ranging from genetic disorders (e.g. myopathies) to degeneration syndromes or cancers. The potential of gene therapy is still not fully exploited mainly because of signifi cant limitations related to the safety, gene delivery capacities and some other properties of the currently used vectors. Baculoviruses (BVs) are insect pathogenic DNA viruses and are not known to replicate in mammalian cells giving them an advantage in terms of safety over classical mammalian viruses currently used as vectors such as adeno-associated virus (AAV), adenovirus, murine retroviruses and lentiviruses. The most promising baculovirus for gene therapy is the well known Autographa californica multiple nucleopolyhedrovirus (AcMNPV). It is inherently safe and can deliver large pieces of DNA on its genome (≥50 Kbp). BV replication and virus production does not occur in mammalian cells and BV is not known to be associated with any human disease. However, by using a vertebrate active expression cassette as a part of baculovirus genome, effi cient gene expression can also be directed in non-target cells. A large range of vertebrate cells has been shown to be permissive for AcMNPV transduction in vitro and in vivo. BV technology has been used for years for producing recombinant proteins and thus large scale production technology is readily adaptable for the exploitation of gene therapy approaches. In addition, BV vectors can be used effi ciently for producing other gene therapy vectors such as AAVs. The BV genome is well-known and several selective targeting approaches engineered into the virus envelope and capsid have been developed. The BACULOGENES project aims to develop clinically suitable methods for the development, production, testing and validation of next generation stabilised and selective BV vectors for gene therapy applications as well as to optimize production of new AAV serotype vectors. Target diseases for in vivo gene delivery with selectively targeted BV include muscle disorders, age-related macular degeneration and prostate cancer. The BACULO- GENES consortium consists of 8 partners from 6 countries, including pioneers in the use of BVs for mammalian gene transfer applications and 2 major established gene therapy vector producing companies in EU. The consortium will devote its eff orts not only to BV gene therapy applications, but also to the development of large scale production, downstream processing, purifi cation and analysis methods. The quality control and validation assays, and all issues related to regulatory aspects required for the clinical exploitation of BV technology will be covered. Problem Validation of BV as a vector for gene therapy and AAV production implies meeting several challenges including solving production issues. In fact, the use of BVs to be used as new effi cient and adapted vectors for gene therapy fully lies on the demonstration of their ability to: • carry large and/or multiple genes; • exclusively target selected tissues; • deliver the therapeutic gene with a high effi ciency; • generate an acceptable immunological and toxicological response; • show high stability; • be able to be produced and purifi ed in large quantities. The BACULOGENES project precisely addresses these issues. Aim The innovative strategy of BACULOGENES relies on the original engineering of BVs (AcMNPV) to make them safe, specifi c and effi cient vectors for gene therapy. BACULO- GENES approach consists in stabilizing the BV genome through deletion and insertion of specifi c sequences in combination with transgenes relevant to the disease targeted. The ‘stabilized’ BVs will then be engineered to: • enhance the capacity to deliver the therapeutic gene(s) to the right cells; • optimize the therapeutic gene expression in the right cells; • make BVs less immunogenic and potentially invisible for the immune system (stealth virus). Such improvements of the BV will be obtained through envelope protein, capsid and genome modifi cations. In parallel, the baculovirus expression system will be optimized for the production of diff erent serotypes of AAV by using stabilized constructs. In addition, the development of baculovirus constructs allowing the production of recombinant AAV without the concomitant production of baculovirus is planned. 170 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Expected results The BACULOGENES project will strengthen the European leadership, knowledge and competitiveness in BV technology through the delivery of novel and validated effi cient vectors and platform technology for the exploitation of potential clinical applications of gene therapy. This project will thus pave the way for the BVs to clinical applications, which has never been experimented as of yet and will provide an optimized BV based AAV platform for gene therapy purposes. The project will also provide the biotech community with a highly effi cient manufacturing process and associated QC methods for BVs processing. Potential applications Optimized production platform for next generation baculoviruses have wide applications in gene delivery, protein production and virus particle generation. Coordinator David Kombi ACIES SAS Lyon, France baculo@acies.fr Annsi Mähonen Ark Therapeutics Limited London, United Kingdom anssi.mahonen@arktherapeutics.com TREATMENT Partners Nick Hunt Altonabiotec Hamburg, Germany Paula Alves Instituto de Biologica Experimentale e Tecnololgica – IBET Oeiras, Portugal Monique van Oers Laboratory of Virology Wageningen University Wageningen, The Netherlands Kari Airenne University of Kuopio Kuopio, Finland Lindsay Georgopoulos YCR <strong>Cancer</strong> <strong>Research</strong> Unit University of York York, United Kingdom Otto-Wilhelm Merten Genethon Evry Cedex, France Project number LHSB-CT-2006-037541 EC contribution € 2 499 746 Duration 36 months Starting date 01/01/2007 Instrument STREP Project website under preparation 171
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PROJECT SYNOPSES CANCER RESEARCH PR
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CANCER RESEARCH PROJECTS FUNDED UND
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TABLE OF CONTENTS FOREWORD - CANCER
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Prevention 97 EPIC 98 EUROCADET 100
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CANCER: COMBATING A COMPLEX DISEASE
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Biology Cancer is a disease ethat t
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p53 activators ASPP Partner 5 NFkap
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Keywords | Angiogenesis | vasculoge
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Keywords | Tumour-host interactions
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Keywords | Breast | metastasis | ge
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Keywords | Identifi cation of novel
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Keywords | Systems biology | modell
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Keywords | Oncology | anticancer th
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• public health research coupled
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Expected results We will construct
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Potential applications Our DNA is u
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Microscopic examination of tissue s
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Pluripotent embryonic stem cells ar
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• Decryption of the leukaemia cel
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• identifi cation of molecular ta
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A B C LT-HSC CSC The Cancer Stem Ce
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X-ray diff raction of target drug c
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using pathway-specifi c reporter ce
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Keywords | Kinases | pediatric panc
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Keywords | Lymphangiogenesis | angi
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Keywords | Breast cancer | metastas
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Keywords | Mitosis | phosphorylatio
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Keywords | Therapy | genome | telom
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Keywords | Multiple myeloma | cance
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Keywords | p53 tumour suppressor |
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Development of eff ective anti-canc
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Coordinator Patrick A. Curmi INSERM
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Drosophila as a model system for tu
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Normal cell growth and epithelial l
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effi ciently with cancer cell proli
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A high-throughput assay of transcri
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Coordinator Ewa Sikora Nencki Insti
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Expected results The SIROCCO consor
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Keywords | Epigenetics | gene regul
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Keywords | Hereditary | tricarboxyl
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Keywords | HSV-1 | hepatocellular c
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Keywords | Apoptosis | autophagy |
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Keywords | Tumour | host | signalli
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Aetiology The uncontrolled cell gro
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Coordinator Rosalind Eeles Reader i
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The parallelogram approach in CARCI
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Keywords | Melanoma | genetics | na
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Keywords | Virus | bacteria | HPV |
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Keywords | Breast | prostate | gene
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Prevention The fact that preventing
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Coordinator Elio Riboli Imperial Co
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Coordinator Jan Willem Coebergh Joh
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Coordinator Jose M a Benlloch Conse
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BAMOD Breath-Gas Analysis for Molec
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BioCare Molecular Imaging for Biolo
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These centres of excellence will in
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Expected results Optimise the benef
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114 Cell proliferation and apoptosi
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COBRED Colon and Breast cancer Diag
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DASIM Diagnostic Applications of Sy
Page 122 and 123: Expected results Primarily, the res
Page 124 and 125: Coordinator John A. Foekens Dept. o
Page 126 and 127: 124 Aim Drop-Top has two major obje
Page 128 and 129: Coordinator Gorka Ochoa Progenika B
Page 130 and 131: Expected results The E.E.T.-Pipelin
Page 132 and 133: e developed by eTUMOUR is likely to
Page 134 and 135: Coordinator Angel Porgador Ben-Guri
Page 136 and 137: • the design of a compact assembl
Page 138 and 139: Potential applications We believe t
Page 140 and 141: Tumor initiation, progression to ma
Page 142 and 143: MolDiag-Paca Novel Molecular Diagno
Page 144 and 145: NEMO Nano based capsule-Endoscopy w
Page 146 and 147: OVCAD Ovarian Cancer - Diagnosis of
Page 148 and 149: P-MARK Validation of recently devel
Page 150 and 151: POC4life Multiparametric quantum do
Page 152 and 153: PROMET Prostate cancer molecular-or
Page 154 and 155: Micrometastasis in the bone marrow.
Page 156 and 157: and pharmaco-kinetics studies. This
Page 158 and 159: Coordinator Raffaella Giavazzi Isti
Page 160 and 161: • Development of tools for diagno
Page 163 and 164: Treatment Two major problems when t
Page 165 and 166: Coordinator Lluis M. Mir UMR 8121 C
Page 167 and 168: Potential applications ANGIOSTOP ha
Page 169 and 170: Green-fl uorescence protein- expres
Page 171: Coordinator Robert Hawkins Universi
Page 175 and 176: descriptors of the molecules to be
Page 177 and 178: Keywords | Therapeutic vaccine | im
Page 179 and 180: Keywords | Cancer chemotherapy | dr
Page 181 and 182: Keywords | Children | cancer | leuk
Page 183 and 184: Chimaeric TCR shown in context of n
Page 185 and 186: Andrea Splendiani Leaf Bioscience s
Page 187 and 188: Coordinator Anne O’Garra The Medi
Page 189 and 190: Coordinator Jacques Bartholeyns IDM
Page 191 and 192: Structure Driven Drug Design The in
Page 193 and 194: • acquire fundamental knowledge a
Page 195 and 196: Terry Jones Victoria University of
Page 197 and 198: Potential applications The use of t
Page 199 and 200: groups and management structures. T
Page 201 and 202: T. Barbui Azienda Ospedaliera-Osped
Page 203 and 204: Keywords | Mantle cell lymphoma | t
Page 205 and 206: Keywords | Hypoxia | HIF | pericell
Page 207 and 208: Keywords | Radiation-induced compli
Page 209 and 210: Keywords | Gene therapy | adenoviru
Page 211 and 212: Keywords | Dependence receptors | a
Page 213 and 214: Keywords | Photodynamic therapy | a
Page 215 and 216: Keywords | Ovarian cancer | thymidy
Page 217 and 218: Keywords | Quality assurance | clin
Page 219 and 220: Keywords | Circadian | clocks | cel
Page 221 and 222: Keywords | Anticancer therapy | onc
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Coordinator Monika Lusky Transgene
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6 000 women over a three-year perio
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Keywords | Solid tumours | apoptosi
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Keywords | Lymphoma | leukaemia | v
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Coordinator Riccardo Dolcetti Centr
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CCPRB Cancer Control using Populati
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EPCRC The European Palliative Care
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EUROCAN+PLUS Feasibility Study for
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EUSTIR A European strategy for the
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NORMOLIFE Development of new therap
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Scientifi c Model Systems The compl
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Performance of benchmarking exercis
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• markers correlating with the im
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Indices - Keywords Indices - Partne
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● disease markers 131 ● DNA dam
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● renal 77 ● replication 219
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Bos, Nico A. 56 Boskovic, Darinka 2
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Geley, Stephan 159 Georgopoulos, Li
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Lingner, Joachim 54 Linial, Michal
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Ragno, Pia 115 Rainford, Martyn 92
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Vernos, Isabelle 22 Veronesi, Umber
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● Centre Hospitalier Universitair
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● IFOM - Fondazione Istituto FIRC
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● National University of Ireland
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● University of Bari 174 ● Univ
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HOW TO OBTAIN EU PUBLICATIONS Our p
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