PMID- 38440160
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240309
IS  - 2329-0501 (Print)
IS  - 2329-0501 (Electronic)
IS  - 2329-0501 (Linking)
VI  - 32
IP  - 1
DP  - 2024 Mar 14
TI  - B cell focused transient immune suppression protocol for efficient AAV 
      readministration to the liver.
PG  - 101216
LID - 10.1016/j.omtm.2024.101216 [doi]
LID - 101216
AB  - Adeno-associated virus (AAV) vectors are used for correcting multiple genetic 
      disorders. Although the goal is to achieve lifelong correction with a single 
      vector administration, the ability to redose would enable the extension of 
      therapy in cases in which initial gene transfer is insufficient to achieve a 
      lasting cure, episomal vector forms are lost in growing organs of pediatric 
      patients, or transgene expression is diminished over time. However, AAV typically 
      induces potent and long-lasting neutralizing antibodies (NAbs) against capsid 
      that prevents re-administration. To prevent NAb formation in hepatic AAV8 gene 
      transfer, we developed a transient B cell-targeting protocol using a combination 
      of monoclonal Ab therapy against CD20 (for B cell depletion) and BAFF (to slow B 
      cell repopulation). Initiation of immunosuppression before (rather than at the 
      time of) vector administration and prolonged anti-BAFF treatment prevented immune 
      responses against the transgene product and abrogated prolonged IgM formation. As 
      a result, vector re-administration after immune reconstitution was highly 
      effective. Interestingly, re-administration before the immune system had fully 
      recovered achieved further elevated levels of transgene expression. Finally, this 
      immunosuppression protocol reduced Ig-mediated AAV uptake by immune cell types 
      with implications to reduce the risk of immunotoxicities in human gene therapy 
      with AAV.
CI  - (c) 2024 The Author(s).
FAU - Rana, Jyoti
AU  - Rana J
AD  - Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, 
      IN 46202, USA.
FAU - Herzog, Roland W
AU  - Herzog RW
AD  - Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, 
      IN 46202, USA.
FAU - Munoz-Melero, Maite
AU  - Munoz-Melero M
AD  - Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, 
      IN 46202, USA.
FAU - Yamada, Kentaro
AU  - Yamada K
AD  - Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, 
      IN 46202, USA.
FAU - Kumar, Sandeep R P
AU  - Kumar SRP
AD  - Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, 
      IN 46202, USA.
FAU - Lam, Anh K
AU  - Lam AK
AD  - Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, 
      IN 46202, USA.
FAU - Markusic, David M
AU  - Markusic DM
AD  - Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, 
      IN 46202, USA.
FAU - Duan, Dongsheng
AU  - Duan D
AD  - Department of Molecular Microbiology and Immunology, School of Medicine, 
      University of Missouri, Columbia, MO 65212, USA.
FAU - Terhorst, Cox
AU  - Terhorst C
AD  - Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215, USA.
FAU - Byrne, Barry J
AU  - Byrne BJ
AD  - Department of Pediatrics, University of Florida College of Medicine, Gainesville, 
      FL 32607, USA.
FAU - Corti, Manuela
AU  - Corti M
AD  - Department of Pediatrics, University of Florida College of Medicine, Gainesville, 
      FL 32607, USA.
FAU - Biswas, Moanaro
AU  - Biswas M
AD  - Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, 
      IN 46202, USA.
LA  - eng
GR  - R01 AI051390/AI/NIAID NIH HHS/United States
GR  - R21 HL170146/HL/NHLBI NIH HHS/United States
GR  - R01 HL131093/HL/NHLBI NIH HHS/United States
GR  - P30 CA082709/CA/NCI NIH HHS/United States
GR  - U54 DK106846/DK/NIDDK NIH HHS/United States
GR  - R01 AI177600/AI/NIAID NIH HHS/United States
GR  - P01 HL160472/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20240220
PL  - United States
TA  - Mol Ther Methods Clin Dev
JT  - Molecular therapy. Methods & clinical development
JID - 101624857
PMC - PMC10911854
OTO - NOTNLM
OT  - AAV
OT  - BAFF
OT  - CD20
OT  - capsid
OT  - gene therapy
OT  - immune suppression
OT  - re-administration
OT  - redosing
OT  - transgene
COIS- R.W.H. serves on the scientific advisory boards and committees of Regeneron 
      Pharmaceuticals, Pfizer, Biomarin, Spark Therapeutics, Hoffman-La Roche, and 
      Prevail Therapeutics. D.D. serves on the scientific advisory boards of Solid 
      Biosciences and Sardocor Corporation. M.B. serves on the steering committee of 
      Pfizer.
EDAT- 2024/03/05 06:44
MHDA- 2024/03/05 06:45
PMCR- 2024/02/20
CRDT- 2024/03/05 03:51
PHST- 2023/08/09 00:00 [received]
PHST- 2024/02/18 00:00 [accepted]
PHST- 2024/03/05 06:45 [medline]
PHST- 2024/03/05 06:44 [pubmed]
PHST- 2024/03/05 03:51 [entrez]
PHST- 2024/02/20 00:00 [pmc-release]
AID - S2329-0501(24)00032-9 [pii]
AID - 101216 [pii]
AID - 10.1016/j.omtm.2024.101216 [doi]
PST - epublish
SO  - Mol Ther Methods Clin Dev. 2024 Feb 20;32(1):101216. doi: 
      10.1016/j.omtm.2024.101216. eCollection 2024 Mar 14.