PMID- 35211638
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220226
IS  - 2329-0501 (Print)
IS  - 2329-0501 (Electronic)
IS  - 2329-0501 (Linking)
VI  - 24
DP  - 2022 Mar 10
TI  - Differential T cell immune responses to deamidated adeno-associated virus vector.
PG  - 255-267
LID - 10.1016/j.omtm.2022.01.005 [doi]
AB  - Despite the high safety profile demonstrated in clinical trials, the 
      immunogenicity of adeno-associated virus (AAV)-mediated gene therapy remains a 
      major hurdle. Specifically, T-cell-mediated immune responses to AAV vectors are 
      related to loss of efficacy and potential liver toxicities. As post-translational 
      modifications in T cell epitopes have the potential to affect immune reactions, 
      the cellular immune responses to peptides derived from spontaneously deamidated 
      AAV were investigated. Here, we report that highly deamidated sites in AAV9 
      contain CD4 T cell epitopes with a Th1 cytokine pattern in multiple human donors 
      with diverse human leukocyte antigen (HLA) backgrounds. Furthermore, some 
      peripheral blood mononuclear cell (PBMC) samples demonstrated differential T cell 
      activation to deamidated or non-deamidated epitopes. Also, in vitro and in silico 
      HLA binding assays showed differential binding to the deamidated or 
      non-deamidated peptides in some HLA alleles. This study provides critical 
      attributes to vector-immune-mediated responses, as AAV deamidation can impact the 
      immunogenicity, safety, and efficacy of AAV-mediated gene therapy in some 
      patients.
FAU - Bing, So Jin
AU  - Bing SJ
AD  - Division of Cellular and Gene Therapies, Center for Biologics Evaluation and 
      Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
FAU - Justesen, Sune
AU  - Justesen S
AD  - Immunitrack ApS, Copenhagen, Denmark.
FAU - Wu, Wells W
AU  - Wu WW
AD  - Facility for Biotechnology Resources, Center for Biologics Evaluation and 
      Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
FAU - Sajib, Abdul Mohin
AU  - Sajib AM
AD  - Division of Cellular and Gene Therapies, Center for Biologics Evaluation and 
      Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
FAU - Warrington, Stephanee
AU  - Warrington S
AD  - Division of Cellular and Gene Therapies, Center for Biologics Evaluation and 
      Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
FAU - Baer, Alan
AU  - Baer A
AD  - Division of Cellular and Gene Therapies, Center for Biologics Evaluation and 
      Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
FAU - Thorgrimsen, Stephan
AU  - Thorgrimsen S
AD  - Immunitrack ApS, Copenhagen, Denmark.
FAU - Shen, Rong-Fong
AU  - Shen RF
AD  - Facility for Biotechnology Resources, Center for Biologics Evaluation and 
      Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
FAU - Mazor, Ronit
AU  - Mazor R
AD  - Division of Cellular and Gene Therapies, Center for Biologics Evaluation and 
      Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
LA  - eng
PT  - Journal Article
DEP - 20220118
PL  - United States
TA  - Mol Ther Methods Clin Dev
JT  - Molecular therapy. Methods & clinical development
JID - 101624857
PMC - PMC8829777
OTO - NOTNLM
OT  - T cell epitopes
OT  - adeno-associated virus vector
OT  - deamidation
OT  - gene therapy
OT  - immunogenicity
COIS- The authors declare no competing interests.
EDAT- 2022/02/26 06:00
MHDA- 2022/02/26 06:01
PMCR- 2022/01/18
CRDT- 2022/02/25 05:39
PHST- 2021/11/03 00:00 [received]
PHST- 2022/01/16 00:00 [accepted]
PHST- 2022/02/25 05:39 [entrez]
PHST- 2022/02/26 06:00 [pubmed]
PHST- 2022/02/26 06:01 [medline]
PHST- 2022/01/18 00:00 [pmc-release]
AID - S2329-0501(22)00006-7 [pii]
AID - 10.1016/j.omtm.2022.01.005 [doi]
PST - epublish
SO  - Mol Ther Methods Clin Dev. 2022 Jan 18;24:255-267. doi: 
      10.1016/j.omtm.2022.01.005. eCollection 2022 Mar 10.