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Considerations of unintended effects in genome editing applications - Marie-Bérengere Troadec

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Considerations of unintended effects in genome editing applications - Marie-Bérengere Troadec

  1. 1. Risk  and  safety  considera0ons  :       Considera0ons  of  unintended  effects     in  genome  edi0ng  applica0ons     Opinion  from  the  French     High  Council  for  Biotechnology   OECD  Conference  on  Genome  Edi0ng:  Applica0ons  in  Agriculture     –  Implica0ons  for  Health,  Environment  and  Regula0on  –   28th-­‐29th  June  2018,  Paris     Marie-­‐Bérengère  TROADEC   for  the  Scien0fic  CommiHee  of  High  Council  for  Biotechnology   FRANCE    
  2. 2. •  This   talk   is   based   on   work   made   by   the   High   Council   for   Biotechnology.   •  It  does  not  reflect  a  posi0on  of  the  French  government.   •  Conflict  of  interest:  none  to  declare.     Disclosure  
  3. 3. HCB  is  an  independent  body     in  charge  of  advising  the  French  government     on  issues  rela0ng  to  GMOs  and  other  types  of  biotechnology.   What  is  the  High  Council  for     Biotechnology  (HCB)  ?  
  4. 4. Board Economic, Ethical and Social Committee Scientific Committee 40 scientific experts > provide a science-based analysis of the potential risks to the environment and public health associated with any biotechnology. 30 members Stakeholders, representatives of civil society, experts in social sciences > provide an analysis of the impacts of biotechnologies with respect to social, economic and ethical issues. President Scientific opinion Recommendation HCB opinion French  High  Council  for  Biotechnology  (HCB)  
  5. 5. Opinion  by  the     High  Council  for  Biotechnology   •  Opinion  on  New  Plant  Breeding  Techniques   •  Including  genome  edi0ng  techniques  (e.g.  CRISPR-­‐edi0on)   •  Assessment  methods,  risk  considera0on,  management,  regulatory   measures     •  Upon  request  of  the  Minister  of  Agriculture  and  the  Minister  of   Environment   •  Published  in  November  2017     http://www.hautconseildesbiotechnologies.fr/en/avis/
  6. 6. •  Genome editing and other crop modification techniques •  The questions INTRODUCTION UNINTENDED EFFECTS CONCLUSION
  7. 7. Genome  edi0ng     refers  to  techniques  in  which     specialized  enzymes  which  have  been  modified,     can  insert,  replace,  or  remove  DNA  from  a  genome     with  a  high  degree  of  specificity.     GENOME  EDITING     defini0on  by  OECD  
  8. 8. Genome  edi0ng  rela0ve  to  other  genome   modifica0on  breeding  techniques   MUTAGENESIS   TRANSGENESIS   RANDOM   STANDARD   GMO  plant  Physically            ex:  gamma  irradia0on   Chemically        ex:  base-­‐analog,  alkyla0ng  agents,  intercala0ng  agent   Biologically      ex:  transposon-­‐mediated    
  9. 9. Genome  edi0ng  rela0ve  to  other  genome   modifica0on  breeding  techniques   MUTAGENESIS   TRANSGENESIS   RANDOM   SITE-­‐DIRECTED   STANDARD  SITE-­‐DIRECTED   SDN1 SDN3 SDN: site-directed nuclease
  10. 10. The  intended  effects  of  genome  edi0ng   TARGETING CUTTING UNBIASED FROM TEMPLATE REPAIRING HERITABLE AND TARGETED MODIFICATION
  11. 11. specificity ≥ 33-35 bp Protein recognition one-to-one rule specificity ≥ 24 bp Protein recognition no obvious code specificity 19 bp RNA recognition one-to-one rule CONTINUOUS IMPROVEMENT OF THE SPECIFICITY TARGETING CUTTING Dimer nuclease Dimer nuclease Monomer nuclease 3-nt upstream of the PAM site DOUBLE STRAND BREAK
  12. 12. Adapted from Alexander Agrotis A et al. Front. Genet., 24 September 2015; doi.org/10.3389/fgene.2015.00300 UNBIASED TEMPLATED SDN2 (allele conversion) SDN3 (targeted integration) REPAIRING WITH OR WITHOUT A TEMPLATE
  13. 13. UNBIASED FROM TEMPLATE Adapted from Alexander Agrotis A et al. Front. Genet., 24 September 2015; doi.org/10.3389/fgene.2015.00300 REPAIRING WITH OR WITHOUT A TEMPLATE
  14. 14. UNBIASED FROM TEMPLATE Homology-directed repair (HDR) occurs at low frequency, and Non-homology end joining (NHEJ) is the dominant DSB repair mechanism requires delivery of repair templates in large amounts to outcompete NHEJ still a challenge Adapted from Caixia Gao, Nat Rev Mol Cell Biol 2018 > REPAIRING WITH OR WITHOUT A TEMPLATE
  15. 15. SDN1 SDN2 (allele conversion) SDN3 (targeted integration) SDN: site-directed nuclease UNBIASED FROM TEMPLATE REPAIRING WITH OR WITHOUT A TEMPLATE
  16. 16. A  specific  feature  of  genome  edi0ng  techniques   TARGETING CUTTING UNBIASED FROM TEMPLATE REPAIRING HERITABLE AND TARGETED MODIFICATION n targets at once = MULTIPLEXING (at one locus, at multiple loci)
  17. 17. •  Are  we  expec0ng  unintended  effects?  If  yes,  what  kind?   •  How  to  assess  those  effects?   •  What  safety  considera0ons  are  raised?   •  What  management  measures  can  we  propose  to  prevent   or  limit  poten0al  effects?   •  FOCUS  ON  PLANT  APPLICATION   •  FOCUS  ON  DIRECT  RISKS   The  ques0ons  
  18. 18. INTRODUCTION UNINTENDED EFFECTS CONCLUSION
  19. 19. GENOME  and  CELL   PLANT   Novelty  of  desired  traits   FIELD   HEALTH     GENOME  EDITION:   THE  QUESTION  OF  UNINTENDED  EFFECTS     FOR  HEALTH  (FOOD  AND  FEED  SAFETY)  AND  THE  ENVIRONMENT   q  UNINTENDED  EFFECTS   q  ASSESSMENTS   q  RISKS  ANS  SAFETY  CONSIDERATIONS   q  MANAGEMENT  TO  LIMIT  OR  PREVENT  RISKS   Direct  technological  limits   Accelera0on  and  adop0on  
  20. 20. GENOME  and  CELL   GENOME  EDITION:   THE  QUESTION  OF  UNINTENDED  EFFECTS     Direct  technological  limits   Type   of   risks   due   to   unintended   effects   inherent  to  the  genome  edi0ng  technique  :   (1)   unintended   effects   associated   with   effector  persistence     (2)   risks   associated   with   off-­‐target   modifica0ons  
  21. 21. GENOME  and  CELL   GENOME  EDITION:   THE  QUESTION  OF  UNINTENDED  EFFECTS     Direct  technological  limits   Type   of   risks   due   to   unintended   effects   inherent  to  the  genome  edi0ng  technique  :   (1)   unintended   effects   associated   with   effector  persistence     (2)   risks   associated   with   off-­‐target   modifica0ons  
  22. 22. The  effectors:   •  CAS9  nuclease  (DNA,  RNA,  protein)   •  Guide  RNA  (DNA,  RNA)     (1)  Risks  due  to  the  presence  of  the  effectors     From HCB’ scientific opinion, nov 2017 The  stable  or  transient  presence  of  the  effectors     depends  on  the  chemistry  of  the  support  of  expression     (DNA,  RNA  or  protein)      and  the  delivery  system.  
  23. 23. The  effectors:   •  CAS9  nuclease  (DNA,  RNA,  protein)   •  Guide  RNA  (DNA,  RNA)     (1)  Risks  due  to  the  presence  of  the  effectors     From HCB’ scientific opinion, nov 2017 PERSISTANCE  OF:   guide  RNA   guide  RNA  +  nuclease   nuclease   guide  RNA   Upon  crossing   x   may  result  in  gene0c  modifica0ons  in  offspring   SPECIFIC  RISKS  :   Nuclease  alone   may  result  in  a  larger  number  of  off-­‐target  cuts   does  not  seem  to  be  associated  to  any  risks   does  not  seem  to  be  associated  to  any  risks  
  24. 24.   The  Scien0fic  Commiaee  of  HCB  recommends   verifying  that  effector  coding  genes  are  absent.       It  is  technically  possible  (e.g.  PCR,  RT-­‐PCR,  sequencing).         (1)  Risks  due  to  the  presence  of  the  effectors     If effectors are genetically present and stably transmitted: the plant is transgenic, and EU GMO regulation applies.
  25. 25. GENOME  and  CELL   GENOME  EDITION:   THE  QUESTION  OF  UNINTENDED  EFFECTS     Direct  technological  limits   Type   of   risks   due   to   unintended   effects   inherent  to  the  genome  edi0ng  technique  :   (1)   unintended   effects   associated   with   effector  persistence     (2)   risks   associated   with   off-­‐target   modifica0ons  
  26. 26. •  Off-­‐target   modifica0on   does   not   necessarily   mean   off-­‐target   effects.   (2)  Risks  associated  with  off-­‐target  modifica0ons   From HCB’ scientific opinion, nov 2017 genome modification DIFFERENT FROM the modification originally desired Site-directed genome editing OFF-TARGET MODIFICATIONS Not targeted techniques UNINTENDED MODIFICATIONS
  27. 27. (2)  Risks  associated  with  off-­‐target  modifica0ons   NATURAL GENETIC VARIATION plant Rate of spontaneous mutation 1 mutation for approximately 100 million base pairs per generation in A. thaliana A. thaliana: roughly 1 mutation per seed Wheat: theoretically roughly 120 mutations per seed Lynch M, Trends Genet 2010 August ; 26(8): 345–352. doi:10.1016/j.tig.2010.05.003
  28. 28. (2)  Risks  associated  with  off-­‐target  modifica0ons   OFF-TARGET CUTS IN SDN1/SDN2/SDN3 Off-­‐target  cuts  from  SDN1/SDN2/SDN3  will  probably  have   the  same  consequence,   since  the  probability  of  the  template  DNA     to  recombine  in  the  area  of  the  DNA  break,    which  is  expected  to  differ  widely,     is  very  small.  
  29. 29. (2)  Risks  associated  with  off-­‐target  modifica0ons   NATURAL VARIATION IN PLANT GERM CELLS OFF-TARGET CUTS IN SDN1/SDN2/SDN3 UNINTENDED CUTS in CHEMICAL or RADIATION MUTAGENESIS much fewer than << -  few -  close frequencies same biochemistry (physiological repair system)
  30. 30.   •  If  guide  RNAs  are  not  specific  enough.   •  If  CAS9  enzyme  is  stably  expressed.     •  It  seems  that  the  off-­‐targets  are  limited  to  restricted  sites,   homologous  to  the  guide  RNA    (up  to  5  mismatches).        Puta0ve  off-­‐target  regions     When  do  off-­‐target  modifica0ons  appear?   In  silico  predictable   in  known  genomes  
  31. 31. Iden0fying  off-­‐target  modifica0ons   Iden0fica0on  of  off-­‐target  modifica0on  for  crop  plant +  targeted  sequencing  of  in  silico  predictable  off-­‐target  regions                in  known  genomes   +  can  be  iden0fied  by  whole-­‐genome  sequencing     with  large  genome -­‐  size  and  diversity  of  sequence  repeats  in  these  genomes -­‐  reference  sequences  will  not  necessarily  match  the  sequence  of  the   variety  under  considera0on -­‐  hard  to  rou0nely  quan0fy  precisely    Off-­‐target  muta0ons  are  not  easily  dis0nguishable     from  the  natural  muta0ons  found  in  plants.    
  32. 32. Elimina0ng  off-­‐target  modifica0ons    If  a  phenotype  is  associated  with  off-­‐target  cuts      +  Backcrossing  during  the  selec0on  process             -­‐      apart  from  those  that  may  be  gene0cally  linked  to  the  desired  trait. -­‐  technically  difficult  to  use  for  perennials  such  as  fruit  trees      or  for  plants  that  reproduce  mainly  through  vegeta0ve  propaga0on.  
  33. 33. Preven0ng  off-­‐target  modifica0ons   Specificity  of  guide  RNA Cas9  and  guide  RNA  dosage   OPTIMAL  CHOICE +  Towards  a  high  specificity  guideRNA  design     Absence  of  off-­‐target  muta0ons  have  been  reported     in  zebrafish,  mice,  chicken,  Arabidopsis,  and  rice.  
  34. 34. Preven0ng  off-­‐target  modifica0ons   Specificity  of  guide  RNA Cas9  and  guide  RNA  dosage   OPTIMAL  CHOICE +  Towards  a  high  specificity  guideRNA  design     +  Gene0cally  modified  Cas  with  high  specificity              are  now  available     +  Guidelines  for  minimizing  CRISPR/Cas9  off-­‐target  effects     -­‐  Good  knowledge  of  plant’s  genome  sequence  
  35. 35. The  Scien0fic  Commiaee  of  the  HCB     has  discussed  the  possibility  of       sequencing  the  puta0ve  off-­‐target  regions  iden0fied  in  silico   in  rou0ne,  for  a  few  years,     to  collect  data  on  the  frequency  of  off-­‐target  cuts     when  using  SDNs.     (2)  Risks  associated  with  off-­‐target  modifica0ons   Major  difficulty:   To  know  the  full  sequence  of  the  variety  grown     rather  than  the  model  variety  for  the  species.  
  36. 36. GENOME  and  CELL   PLANT   Novelty  of  desired  traits   FIELD   GENOME  EDITION:   THE  QUESTION  OF  UNINTENDED  EFFECTS     Direct  technological  limits   Accelera0on  and  adop0on  
  37. 37. GENOME  and  CELL   PLANT   Novelty  of  desired  traits   FIELD   GENOME  EDITION:   THE  QUESTION  OF  UNINTENDED  EFFECTS     Direct  technological  limits   No   puta0ve   risks   specific   to   genome   edi0ng  
  38. 38. •  A  TRAIT  IS  NOT  ALWAYS  NOVEL     Risks  arising  from  desired  traits,     2  remarks   Introduction of allele into different varieties In just a few steps
  39. 39. •  A  TRAIT  IS  NOT  ALWAYS  NOVEL   •  SOME   TRAITS   OBTAINED   BY   GENOME   EDITING   COULD   BE   OBTAINED  BY  OTHER  TECHNIQUES   Risks  arising  from  desired  traits,     2  remarks   Techniques not covered by GMO regulations Regulated techniques Genome edition
  40. 40. Risks  arising  from  desired  traits  are  common  to  all   genome  modifica0on  and  plant  breeding  techniques   DIRECT RISKS TO HUMAN HEALTH potential toxicity, nutritional balance, allergic phenomena, … DIRECT RISKS TO ECOSYSTEM HEALTH - dispersal and risk of invasion - modification of ecological and particularly trophic interactions -  … DIRECT COMMON RISKS GENOME EDITING AND THE OTHER PLANT BREEDING TECHNIQUES
  41. 41. Risks  arising  from  desired  traits  are  common  to  all   genome  modifica0on  and  plant  breeding  techniques   -  changes in farming practice, - modification of habitats due to the multiplication of “modified” varieties, -  spreading of the trait into wild species sexually compatible with the crop varieties -  … INDIRECT COMMON RISKS may arise from potential: GENOME EDITING AND THE OTHER PLANT BREEDING TECHNIQUES
  42. 42. Risks  arising  from  desired  traits  are  common  to  all   genome  modifica0on  and  plant  breeding  techniques   Trait’s novelty Uncertainty of the risks GENOME EDITING AND THE OTHER PLANT BREEDING TECHNIQUES
  43. 43. Risks  arising  from  desired  traits  are  common  to  all   genome  modifica0on  and  plant  breeding  techniques   DIRECT AND INDIRECT COMMON RISKS: The potential risks arising out of desired traits are different for each individual TRAIT and are NOT affected by the TECHNIQUE used to obtain it. GENOME EDITING AND THE OTHER PLANT BREEDING TECHNIQUES
  44. 44. GENOME  and  CELL   PLANT   Novelty  of  desired  traits   FIELD   GENOME  EDITION:   THE  QUESTION  OF  UNINTENDED  EFFECTS     FOR  HEALTH  (FOOD  AND  FEED  SAFETY)  AND  THE  ENVIRONMENT   Direct  technological  limits   Accelera0on  and  adop0on  
  45. 45. FIELD   GENOME  EDITION:   THE  QUESTION  OF  UNINTENDED  EFFECTS     Accelera0on  and  adop0on   (1)   unintended   effects   associated   with   combining   targeted   modifica0ons   (mul0plex   gene  edi0ng)  to  derive  new  traits       (2)   risks   associated   with   poten0al   accelera0on   of   breeding   owing   to   efficiency   and  technical  ease  of  use  of  genome  edi0ng:   related   to   agricultural   prac0ces   and   ground   alloca0on.    
  46. 46. FIELD   GENOME  EDITION:   THE  QUESTION  OF  UNINTENDED  EFFECTS     Accelera0on  and  adop0on   (1)   unintended   effects   associated   with   combining   targeted   modifica0ons   (mul0plex   gene  edi0ng)  to  derive  new  traits       (2)   risks   associated   with   poten0al   accelera0on   of   breeding   owing   to   efficiency   and  technical  ease  of  use  of  genome  edi0ng:   related   to   agricultural   prac0ces   and   ground   alloca0on.    
  47. 47. (1)  Risks  associated  with  combining   targeted  modifica0ons  to  derive  new  traits   GENE  FAMILY   or     METABOLIC  PATHWAY   Gene  1   Gene  2   Gene  3   Gene  n   MULTIPLEX   EDITING   CHANGE  EXPRESSION  OF   OTHER  GENES  or  METABOLIC   PATHWAYS   may  allow  emergence  of  :     -­‐  Novel  traits,   -­‐  Phenotypic  changes  that   might  not  be  detected  in  the   phenotypic  assessment  of  a   variety     -­‐  Expression  of  pleiotropic   effects.       DOES  NOT  NECESSARILY   PRODUCE  THE  SUM  OF  THEIR   INDIVIDUAL  PHENOTYPIC   MODIFICATIONS   (PHENOMENON  OF   EPISTASIS)   NEW TRAIT :
  48. 48. (1)  Risks  associated  with  combining   targeted  modifica0ons  to  derive  new  traits   GENE  FAMILY   or     METABOLIC  PATHWAY   Gene  1   Gene  2   Gene  3   Gene  n   MULTIPLEX   EDITING   CHANGE  EXPRESSION  OF   OTHER  GENES  or  METABOLIC   PATHWAYS   may  allow  emergence  of  :     -­‐  Novel  traits,   -­‐  Phenotypic  changes  that   might  not  be  detected  in  the   phenotypic  assessment  of  a   variety     -­‐  Expression  of  pleiotropic   effects.       DOES  NOT  NECESSARILY   PRODUCE  THE  SUM  OF  THEIR   INDIVIDUAL  PHENOTYPIC   MODIFICATIONS   (PHENOMENON  OF   EPISTASIS)   Monitoring  with  regard  to  ecological,  agro-­‐ecological,   economic  and  societal  impact NEW TRAIT :
  49. 49. FIELD   GENOME  EDITION:   THE  QUESTION  OF  UNINTENDED  EFFECTS     Accelera0on  and  adop0on   (1)   unintended   effects   associated   with   combining   targeted   modifica0ons   (mul0plex   gene  edi0ng)  to  derive  new  traits       (2)   risks   associated   with   poten0al   accelera0on   of   breeding   owing   to   efficiency   and  technical  ease  of  use  of  genome  edi0ng:   related   to   agricultural   prac0ce   and   ground   alloca0on.    
  50. 50. (2)  Risks  associated  with  poten0al   accelera0on  of  breeding   1. direct transfer of a knowledge from a model variety into other elite varieties of the same species 2. potential translation of an academic knowledge from a cultivated or wild species into other ones 3. multiplex gene modification of elite varieties for multi-traits faster pace of production and faster cultivation of varieties positively or negatively affect ecosystem functioning and dynamics POTENTIAL ACCELERATION OF BREEDING MAY BENEFIT TO : RELATIVE EFFICACY AND EASE OF USE OF GENOME EDITING
  51. 51. (2)  Risks  associated  with  poten0al   accelera0on  of  breeding   The  Scien0fic  commiaee  of  the  HCB  suggests:     q A  local  management  with,  if  necessary,     gradual  roll-­‐out  over  0me  and  space  of  plants  with  a  Novel  Trait  to   control  the  pace  of  agro-­‐ecosystem  change     that  might  result  from  use  of  these  plants.   q If  needed,  a  propor0onal  monitoring  with  regard  to  ecological,   agro-­‐ecological,  economic  and  societal  impact  
  52. 52. INTRODUCTION UNINTENDED EFFECTS •  Risks, danger and exposure •  Traceability document •  Take home message CONCLUSION
  53. 53. Risks,  danger  and  exposure   RISK EXPOSUREDANGER crop  area   (amplitude  and  novel  farmed  areas  due  to   farmers’  adop0on  of  the  modified  varie0es)   This  adop0on:   -­‐  is  oeen  hard  to  predict,     -­‐  varies  according  to  social  and  economic  parameters,  to  the  impact  of   climate  and  also  to  the  strategies  of  the  various  par0es  involved  in  the   supply  chains.     consump0on  of  products   (and  public  acceptance)   Ideally,  poten0al  risks  should  be  evaluated     rela0ve  to  adop0on  rate.      
  54. 54. Traceability  document     for  genome-­‐edited  crop   Unlike GMOs, the trace of genetic modification will hardly be detected with SDN1 and SDN2 genome edition. q Species and variety q Breeding method q Delivery method (if applicable) q Tissues targeted by modification q Trait(s) modified or introduced q Phenotyping method q Target region sequences (before and after modification) and chromosome location; q Presence or absence of effectors needed for SDNs (if applicable); q Unique identifier, as per the standard, if possible.
  55. 55. presence of effectors GENOME  and  CELL   PLANT   Novelty  of  desired  traits   FIELD   GENOME  EDITION:  THE  QUESTION  OF  UNINTENDED  EFFECTS     FOR  HEALTH  (FOOD  AND  FEED  SAFETY)  AND  THE  ENVIRONMENT   Direct  technological  limits   Accelera0on  and  adop0on   q Check the absence q If effectors are still present, directive 2001/18/EC for transgenic plants applies. q Such plants shall be subject to assessment and appropriate management measures (including surveillance and post-market monitoring).
  56. 56. presence of effectors off-target modifications GENOME  and  CELL   PLANT   Novelty  of  desired  traits   FIELD   GENOME  EDITION:  THE  QUESTION  OF  UNINTENDED  EFFECTS     FOR  HEALTH  (FOOD  AND  FEED  SAFETY)  AND  THE  ENVIRONMENT   Direct  technological  limits   Accelera0on  and  adop0on   q Sequencing regions of interest q If needed: backcrosses
  57. 57. presence of effectors off-target modifications novel traits GENOME  and  CELL   PLANT   Novelty  of  desired  traits   FIELD   GENOME  EDITION:  THE  QUESTION  OF  UNINTENDED  EFFECTS     FOR  HEALTH  (FOOD  AND  FEED  SAFETY)  AND  THE  ENVIRONMENT   Direct  technological  limits   Accelera0on  and  adop0on   q Case-by-case study q Individual trait matters, more than the technique. q The assessment could be conducted, depending on the traits and the species, in a contained environment and/or in field trials. q After a period to be defined, and depending on the observations made, an assessment should be made as to whether the biomonitoring should be discontinued.
  58. 58. presence of effectors off-target modifications novel traits faster breeding q Local management q Biomonitoring q Taking in consideration the predicted adoption rate multiplex gene editing GENOME  and  CELL   PLANT   Novelty  of  desired  traits   FIELD   GENOME  EDITION:  THE  QUESTION  OF  UNINTENDED  EFFECTS     FOR  HEALTH  (FOOD  AND  FEED  SAFETY)  AND  THE  ENVIRONMENT   Direct  technological  limits   Accelera0on  and  adop0on  
  59. 59. GENOME  and  CELL   PLANT   Novelty  of  desired  traits   FIELD   HEALTH     GENOME  EDITION:   THE  QUESTION  OF  UNINTENDED  EFFECTS     FOR  HEALTH  (FOOD  AND  FEED  SAFETY)  AND  THE  ENVIRONMENT   Direct  technological  limits   Accelera0on  and  adop0on   presence of effectors off-target modifications novel traits faster breeding multiplex gene editing
  60. 60. Where  you  can  find     the  opinion  from     the  scien0fic  commiHee  of     the  High  Council  for  Biotechnology:     http://www.hautconseildesbiotechnologies.fr/en/avis/

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