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  • Center for Cellular and Molecular Therapeutics at The Childrens Hospital of Philadelphia (CCMT/CHOP)

    AAV8-hFIX19

    Environmental Risk Assessment Dossier (In accordance with Schedule II, SI 500/2003)

    Final January 2013

  • CCMT/CHOP AAV8-hFIX19

    Final January 2013 1

    TABLE OF CONTENTS

    1. Objective ................................................................................................................... 4 2. General Principle ...................................................................................................... 4 3. Methodology ............................................................................................................. 4

    3.1. Intended Recipient ............................................................................................ 4 3.2. Parental organism ............................................................................................. 4 3.3. Genetic modification and characteristics of the GMO ..................................... 7 3.4. Intended release including scale ....................................................................... 9 3.5. Potential receiving environment ..................................................................... 10

    4. Identification of Characteristics which may cause adverse effects ........................ 12 4.1. Potential effects on the environment .............................................................. 12 4.2. Potential effects on human health ................................................................... 14 4.3. Conclusions ..................................................................................................... 15

    5. Evaluation of potential consequences / magnitude of effect .................................. 15 5.1. Direct effects ................................................................................................... 15

    5.1.1. Magnitude of effect ................................................................................... 16 5.1.2. Potential consequences ............................................................................. 16

    5.2. Indirect effects ................................................................................................ 20 5.2.1. Magnitude of effect ................................................................................... 20 5.2.2. Potential consequences ............................................................................. 21

    5.3. Conclusions ..................................................................................................... 21 6. Evaluation of likelihood of occurrence of identified adverse effect ....................... 21

    6.1. Likelihood of transmission of AAV8-hFIX19 to an unintended human recipient ...................................................................................................................... 22 6.2. Likelihood of transmission of wild type AAV to an unintended human recipient ...................................................................................................................... 23 6.3. Likelihood of exposure of the environment to residual plasmid sequences ... 24 6.4. Conclusions ..................................................................................................... 24

    7. Estimation of risk posed by each identified characteristic ..................................... 24 7.1. Risk associated with the parental organism (wild type AAV) ........................ 24 7.2. Risk associated with the transmission of AAV8-hFIX19 to an unintended recipient ...................................................................................................................... 27 7.3. Risk associated with transmission of wild type AAV to an unintended human recipient ...................................................................................................................... 28 7.4. Risk to the environment associated with residual plasmid DNA sequences .. 28

    8. Application of management strategies for risks ..................................................... 29 8.1. Design of viral construct ................................................................................. 29 8.2. Control of release ............................................................................................ 29 8.3. Dose preparation and administration precautions ........................................... 30 8.4. Waste treatment .............................................................................................. 34 8.5. Product Labelling ............................................................................................ 34 8.6. Monitoring activities ....................................................................................... 35

    8.6.1. Monitoring during treatment of patients ................................................... 35 8.6.2. Follow-up of patients after treatment ........................................................ 36 8.6.3. Monitoring of unintended recipients ......................................................... 37

    8.7. Conclusions ..................................................................................................... 37 9. Determination of overall risk of the GMO ............................................................. 37

  • CCMT/CHOP AAV8-hFIX19

    Final January 2013 2

    LIST OF ABBREVIATIONS

    AAV Adeno-associated virus AAV-hFIX Adeno-associated viral vector encoding human coagulation

    factor IX AAV2-hFIX9 Single-stranded adeno-associated viral vector, serotype 2,

    expressing human factor IX under control of the cytomegalovirus promoter (muscle-directed)

    AAV2-hFIX16 Single-stranded adeno-associated viral vector, serotype 2, encoding human factor IX under control of the human 1-antitrypsin promoter coupled to the human apolipoprotein E enhancer

    AAV8-hFIX19 Single-stranded adeno-associated viral vector, serotype 8, encoding human factor IX under control of the human 1-antitrypsin promoter coupled to the human apolipoprotein E enhancer (construct changes from hFIX16 to hFIX19 include codon-optimization, removal of alternate open reading frames of the factor IX gene, and replacement of amp with kan resistance in the plasmid used for vector generation)

    AAV8-LP1-hFIXco Self complementary AAV vector, serotype 8, encoding human factor IX

    Ad Adenovirus APH Aminoglycoside 3'-phosphotransferase ApoE Apolipoprotein E ARF Alternate open reading frame bp Base pair BSC BioSafety Cabinet BSL Biosafety Level CCMT Center for Cellular and Molecular Therapeutics at The

    Childrens Hospital of Philadelphia cDNA Complimentary deoxyribonucleic acid CHOP The Childrens Hospital of Philadelphia CRO Contract research organization DNA Deoxyribonucleic acid DSMB Data and Safety Monitoring Board ELISA Enzyme-linked immunosorbent assay EPA Environmental Protection Agency EU European Union FDA Food and Drug Administration FIX Coagulation factor IX GCP Good clinical practice GMO Genetically Modified Organism hAAT Human alpha 1 antitrypsin HCC Hepatocellular carcinomas HEK Human embryonic kidney epithelial cell line hFIX Human coagulation factor IX HPV Human papilloma virus HSV Herpes Simplex Virus IATA International Air Transport Association IBC Institutional Biosafety Committee IDDS Investigational Drug Data Sheet

  • CCMT/CHOP AAV8-hFIX19

    Final January 2013 3

    IM Intramuscular IMB Irish Medicines Board IND Investigational new drug application ITR Inverted terminal repeats IV Intravenous kan Kanamycin kb Kilobases kDa kiloDaltons LCA Lebers Congenital Amaurosis LOD Limit of Detection LOQ Limit of Quantitation LTFU Long Term Follow-Up MCB Master Cell Bank MSDS Material Safety Data Sheet Nab Neutalising antibodies NHP Non-human primate NPC Nuclear Pore Complex ORF Open reading frame PBMC Peripheral blood mononuclear cells PCR Polymerase chain reaction PPE Personal Protective Equipment QPCR Quantitative polymerase chain reaction rAAV Recombinant adeno-associated viral vectors RNA Ribonucleic acid SAE Serious adverse event ss Single stranded SUSAR Suspected Unexpected Serious Adverse Reaction vg Vector genome WBC T Whole blood clotting time WHO World Health Organisation

  • CCMT/CHOP AAV8-hFIX19

    Final January 2013 4

    1. OBJECTIVE

    The objective of this Environmental Risk Assessment (ERA) is to identify and evaluate potential adverse effects of AAV8-hFIX19 on human health and the environment which the deliberate release of the GMO may exert, in accordance with Schedule II of SI 500/2003. 2. GENERAL PRINCIPLE

    This ERA has been performed according to the precautionary principle using the methodology set down in Schedule II of SI 500/2003 and Commission Decision 2002/623/EC. These general principles are:

    Identified characteristics of the GMO and its use which have the potential to cause adverse effects should be compared to those presented by the non-modified organism from which it is derived and its use under corresponding situations

    The ERA should be carried out in a scientifically sound and transparent manner

    based on available scientific and technical data.

    The ERA should be carried out on a case-by-case basis. 3. METHODOLOGY

    This Environmental Risk Assessment takes into account the full Technical and Scientific Information on the GMO (AAV8-hFIX19) which are provided in a separate document in accordance with Schedule III of SI 500/2003. The characteristics of the GMO and the nature of the release are summarised below. 3.1. Intended Recipient

    AAV8-hFIX19 will be administered by a single peripheral intravenous infusion into eligible, consent

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