PMID- 31502485
OWN - NLM
STAT- MEDLINE
DCOM- 20200327
LR  - 20200327
IS  - 1557-7422 (Electronic)
IS  - 1043-0342 (Print)
IS  - 1043-0342 (Linking)
VI  - 30
IP  - 10
DP  - 2019 Oct
TI  - Prevalence and Relevance of Pre-Existing Anti-Adeno-Associated Virus Immunity in 
      the Context of Gene Therapy for Crigler-Najjar Syndrome.
PG  - 1297-1305
LID - 10.1089/hum.2019.143 [doi]
AB  - Adeno-associated virus (AAV) vector-mediated gene therapy is currently evaluated 
      as a potential treatment for Crigler-Najjar syndrome (CN) (NCT03466463). 
      Pre-existing immunity to AAV is known to hinder gene transfer efficacy, 
      restricting enrollment of seropositive subjects in ongoing clinical trials. We 
      assessed the prevalence of anti-AAV serotype 8 (AAV8) neutralizing antibodies 
      (NAbs) in subjects affected by CN and investigated the impact of low NAb titers 
      (<1:5) on liver gene transfer efficacy in an in vivo passive immunization model. 
      A total of 49 subjects with a confirmed molecular diagnosis of CN were included 
      in an international multicenter study (NCT02302690). Pre-existing NAbs against 
      AAV8 were detected in 30.6% (15/49) of screened patients and, in the majority of 
      positive cases, cross-reactivity to AAV2 and AAV5 was detected. To investigate 
      the impact of low NAbs on AAV vector-mediated liver transduction efficiency, 
      adult wild-type C57BL/6 mice were passively immunized with pooled human 
      donor-derived immunoglobulins to achieve titers of up to 1:3.16. After 
      immunization, animals were injected with different AAV8 vector preparations. 
      Hepatic vector gene copy number was unaffected by low anti-AAV8 NAb titers when 
      column-purified AAV vector batches containing both full and empty capsids were 
      used. In summary, although pre-existing anti-AAV8 immunity can be found in about 
      a third of subjects affected by CN, low anti-AAV8 NAb titers are less likely to 
      affect liver transduction efficiency when using AAV vector preparations 
      manufactured to contain both full and empty capsids. These findings have 
      implications for the design of liver gene transfer clinical trials and for the 
      definition of inclusion criteria related to seropositivity of potential 
      participants.
FAU - Aronson, Sem J
AU  - Aronson SJ
AD  - Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology 
      and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The 
      Netherlands.
FAU - Veron, Philippe
AU  - Veron P
AD  - Genethon, Evry, France.
FAU - Collaud, Fanny
AU  - Collaud F
AD  - Genethon, Evry, France.
FAU - Hubert, Aurelie
AU  - Hubert A
AD  - Department of Hereditary Diseases of Hepatic Metabolism, Hopital Antoine Beclere, 
      Clamart, France.
FAU - Delahais, Virginie
AU  - Delahais V
AD  - Genethon, Evry, France.
FAU - Honnet, Geraldine
AU  - Honnet G
AD  - Genethon, Evry, France.
FAU - de Knegt, Robert J
AU  - de Knegt RJ
AD  - Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, 
      The Netherlands.
FAU - Junge, Norman
AU  - Junge N
AD  - Department of Paediatric Gastroenterology and Hepatology, Hannover Medical 
      School, Hannover, Germany.
AD  - Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical 
      School, Hannover, Germany.
FAU - Baumann, Ulrich
AU  - Baumann U
AD  - Department of Paediatric Gastroenterology and Hepatology, Hannover Medical 
      School, Hannover, Germany.
AD  - Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical 
      School, Hannover, Germany.
FAU - Di Giorgio, Angelo
AU  - Di Giorgio A
AD  - Department of Paediatric Hepatology, Gastroenterology and Transplantation, Papa 
      Giovanni XXIII Hospital, Bergamo, Italy.
FAU - D'Antiga, Lorenzo
AU  - D'Antiga L
AD  - Department of Paediatric Hepatology, Gastroenterology and Transplantation, Papa 
      Giovanni XXIII Hospital, Bergamo, Italy.
FAU - Ginocchio, Virginia M
AU  - Ginocchio VM
AD  - Telethon Institute of Genetics & Medicine (TIGEM), Pozzuoli, Italy.
AD  - Department of Translational Medicine, Federico II University of Naples, Naples, 
      Italy.
FAU - Brunetti-Pierri, Nicola
AU  - Brunetti-Pierri N
AD  - Telethon Institute of Genetics & Medicine (TIGEM), Pozzuoli, Italy.
AD  - Department of Translational Medicine, Federico II University of Naples, Naples, 
      Italy.
FAU - Labrune, Philippe
AU  - Labrune P
AD  - Department of Hereditary Diseases of Hepatic Metabolism, Hopital Antoine Beclere, 
      Clamart, France.
FAU - Beuers, Ulrich
AU  - Beuers U
AD  - Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology 
      and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The 
      Netherlands.
FAU - Bosma, Piter J
AU  - Bosma PJ
AD  - Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology 
      and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The 
      Netherlands.
FAU - Mingozzi, Federico
AU  - Mingozzi F
AD  - Genethon, Evry, France.
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Observational Study
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hum Gene Ther
JT  - Human gene therapy
JID - 9008950
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Antibodies, Viral)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - EC 2.4.1.- (UGT1A1 enzyme)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - RFM9X3LJ49 (Bilirubin)
RN  - YQE403BP4D (Phenobarbital)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Animals
MH  - Antibodies, Neutralizing/*biosynthesis
MH  - Antibodies, Viral/*biosynthesis
MH  - Bilirubin/immunology/metabolism
MH  - Capsid/immunology/metabolism
MH  - Child
MH  - Child, Preschool
MH  - Crigler-Najjar Syndrome/genetics/immunology/pathology/*therapy
MH  - Dependovirus/*genetics/immunology
MH  - Excitatory Amino Acid Antagonists/therapeutic use
MH  - Female
MH  - Gene Expression
MH  - Genetic Therapy/*methods
MH  - Glucuronosyltransferase/deficiency/*genetics/immunology
MH  - HEK293 Cells
MH  - Humans
MH  - Immunity, Innate
MH  - Immunization, Passive
MH  - Liver/immunology/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phenobarbital/therapeutic use
MH  - Phototherapy/methods
MH  - Plasmids/chemistry/metabolism
MH  - Transfection
PMC - PMC6763963
OTO - NOTNLM
OT  - AAV gene therapy
OT  - Crigler-Najjar syndrome
OT  - UGT1A1
OT  - anti-AAV neutralizing antibodies
OT  - pre-existing immunity
OT  - unconjugated hyperbilirubinemia
COIS- F.M. is an employee and equity holder of Spark Therapeutics. F.M. and F.C. are 
      inventors in patents describing liver gene transfer approaches for metabolic 
      diseases. L.D. has consultancy agreements with Alexion Biosciences and Vivet 
      Therapeutics. None of the other authors declare any conflicts of financial 
      interest.
EDAT- 2019/09/11 06:00
MHDA- 2020/03/28 06:00
PMCR- 2019/09/24
CRDT- 2019/09/11 06:00
PHST- 2019/09/11 06:00 [pubmed]
PHST- 2020/03/28 06:00 [medline]
PHST- 2019/09/11 06:00 [entrez]
PHST- 2019/09/24 00:00 [pmc-release]
AID - 10.1089/hum.2019.143 [pii]
AID - 10.1089/hum.2019.143 [doi]
PST - ppublish
SO  - Hum Gene Ther. 2019 Oct;30(10):1297-1305. doi: 10.1089/hum.2019.143.