PMID- 38445045
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240403
IS  - 2329-0501 (Print)
IS  - 2329-0501 (Electronic)
IS  - 2329-0501 (Linking)
VI  - 32
IP  - 1
DP  - 2024 Mar 14
TI  - Biodistribution and safety of a single rAAV3B-AAT vector for silencing and 
      replacement of alpha-1 antitrypsin in Cynomolgus macaques.
PG  - 101200
LID - 10.1016/j.omtm.2024.101200 [doi]
LID - 101200
AB  - Alpha-1 antitrypsin deficiency (AATD) is characterized by both chronic lung 
      disease due to loss of wild-type AAT (M-AAT) antiprotease function and liver 
      disease due to toxicity from delayed secretion, polymerization, and aggregation 
      of misfolded mutant AAT (Z-AAT). The ideal gene therapy for AATD should therefore 
      comprise both endogenous Z-AAT suppression and M-AAT overexpression. We designed 
      a dual-function rAAV3B (df-rAAV3B) construct, which was effective at transducing 
      hepatocytes, resulting in a considerable decrease of Z-AAT levels and safe M-AAT 
      augmentation in mice. We optimized df-rAAV3B and created two variants, AAV3B-E12 
      and AAV3B-G3, to simultaneously enhance the concentration of M-AAT in the 
      bloodstream to therapeutic levels and silence endogenous AAT liver expression in 
      cynomolgus monkeys. Our results demonstrate that AAV3b-WT, AAV3B-E12, and 
      AAV3B-G3 were able to transduce the monkey livers and achieve high M-AAT serum 
      levels efficiently and safely. In this nondeficient model, we did not find 
      downregulation of endogenous AAT. However, the dual-function vector did serve as 
      a potentially "liver-sparing" alternative for high-dose liver-mediated AAT gene 
      replacement in the context of underlying liver disease.
CI  - (c) 2024 The Authors.
FAU - Blackwood, Meghan
AU  - Blackwood M
AD  - Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 
      Worcester, MA 01605, USA.
FAU - Gruntman, Alisha M
AU  - Gruntman AM
AD  - Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 
      Worcester, MA 01605, USA.
AD  - Department of Pediatrics, University of Massachusetts Chan Medical School, 
      Worcester, MA 01605, USA.
AD  - Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts 
      University, North Grafton, MA 01536, USA.
FAU - Tang, Qiushi
AU  - Tang Q
AD  - Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 
      Worcester, MA 01605, USA.
FAU - Pires-Ferreira, Debora
AU  - Pires-Ferreira D
AD  - Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 
      Worcester, MA 01605, USA.
FAU - Reil, Darcy
AU  - Reil D
AD  - Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 
      Worcester, MA 01605, USA.
FAU - Kondratov, Oleksandr
AU  - Kondratov O
AD  - Division of Cellular and Molecular Therapy, Department of Pediatrics, University 
      of Florida, Gainesville, FL 32611, USA.
FAU - Marsic, Damien
AU  - Marsic D
AD  - Division of Cellular and Molecular Therapy, Department of Pediatrics, University 
      of Florida, Gainesville, FL 32611, USA.
AD  - MaiBo Biotech, Suzhou Industrial Park, Jiangsu, China.
FAU - Zolotukhin, Sergei
AU  - Zolotukhin S
AD  - Division of Cellular and Molecular Therapy, Department of Pediatrics, University 
      of Florida, Gainesville, FL 32611, USA.
FAU - Gernoux, Gwladys
AU  - Gernoux G
AD  - Nantes Universite, CHU de Nantes, INSERM, TaRGeT-Translational Research in Gene 
      Therapy, UMR 1089, 44200 Nantes, France.
FAU - Keeler, Allison M
AU  - Keeler AM
AD  - Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 
      Worcester, MA 01605, USA.
AD  - Department of Pediatrics, University of Massachusetts Chan Medical School, 
      Worcester, MA 01605, USA.
AD  - NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, 
      MA 01605, USA.
FAU - Mueller, Christian
AU  - Mueller C
AD  - Genomic Medicine Unit, Sanofi, Waltham, MA 02451, USA.
FAU - Flotte, Terence R
AU  - Flotte TR
AD  - Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 
      Worcester, MA 01605, USA.
AD  - Department of Pediatrics, University of Massachusetts Chan Medical School, 
      Worcester, MA 01605, USA.
LA  - eng
GR  - P01 HL131471/HL/NHLBI NIH HHS/United States
GR  - P01 HL158506/HL/NHLBI NIH HHS/United States
GR  - R01 DK098252/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20240130
PL  - United States
TA  - Mol Ther Methods Clin Dev
JT  - Molecular therapy. Methods & clinical development
JID - 101624857
PMC - PMC10914479
OTO - NOTNLM
OT  - AAV gene therapy
OT  - AAV3B
OT  - alpha-1 antitrypsin deficiency
OT  - biodistribution
OT  - gene silencing
OT  - miRNA
OT  - preclinical
COIS- T.R.F., A.G., C.M., and A.K. report financial support was provided by National 
      Heart Lung and Blood Institute. T.R.F. and A.G. report equipment, drugs, or 
      supplies was provided by National Heart Lung and Blood Institute Gene Therapy 
      Resource Program. C.M. reports a relationship with Sanofi that includes: 
      employment. C.M. reports a relationship with Apic Bio that includes: board 
      membership and equity or stocks. T.R.F. and C.M. have a patent pending to Apic 
      Bio. T.R.F. is Chair of the NHLBI Gene Therapy Resource Program Advisory 
      Committee. C.M. is a named inventor on the patent for the dual function AAT 
      construct; D.M., S.Z., and C.M. are named inventors on the patent for the AAV3B 
      variants.
EDAT- 2024/03/06 06:43
MHDA- 2024/03/06 06:44
PMCR- 2024/01/30
CRDT- 2024/03/06 03:59
PHST- 2023/09/12 00:00 [received]
PHST- 2024/01/24 00:00 [accepted]
PHST- 2024/03/06 06:44 [medline]
PHST- 2024/03/06 06:43 [pubmed]
PHST- 2024/03/06 03:59 [entrez]
PHST- 2024/01/30 00:00 [pmc-release]
AID - S2329-0501(24)00016-0 [pii]
AID - 101200 [pii]
AID - 10.1016/j.omtm.2024.101200 [doi]
PST - epublish
SO  - Mol Ther Methods Clin Dev. 2024 Jan 30;32(1):101200. doi: 
      10.1016/j.omtm.2024.101200. eCollection 2024 Mar 14.