Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for α-1-antitrypsin deficiency
Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder α-1-antitrypsin (AAT) deficiency. Results from phase I and II studies have shown relatively stable and dose-dependent increases in transgene-derived wild-type AAT after local intra...
Saved in:
| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 7; pp. 1655 - 1659 |
|---|---|
| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
14.02.2017
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0027-8424 1091-6490 |
| DOI | 10.1073/pnas.1617726114 |
Cover
| Abstract | Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder α-1-antitrypsin (AAT) deficiency. Results from phase I and II studies have shown relatively stable and dose-dependent increases in transgene-derived wild-type AAT after local intramuscular vector administration. In this report we describe the appearance of transgene-specific T-cell responses in two subjects that were part of the phase II trial. The patient with the more robust T-cell response, which was associated with a reduction in transgene expression, was characterized more thoroughly in this study. We learned that the AAT-specific T cells in this patient were cytolytic in phenotype, mapped to a peptide in the endogenous mutant AAT protein that contained a common polymorphism not incorporated into the transgene, and were restricted by a rare HLA class I C alleles present only in this patient. These human studies illustrate the genetic influence of the endogenous gene and HLA haplotype on the outcome of gene therapy. |
|---|---|
| AbstractList | The use of adeno-associated virus (AAV)-mediated gene therapy to treat monogenic disorders is currently being tested in phase I, II, and III clinical trials. An immune response to the newly introduced gene product remains a potential problem because of the patient’s lack of central and peripheral tolerance to foreign epitopes. In this study, we show the induction of a T-cell response to the therapeutic product in a α-1-antitrypsin (AAT)-deficient subject receiving AAV1-AAT treatment. The response was directed to an AAT epitope upstream of the mutation and was associated with a polymorphism present in the subject but not in the wild-type AAT therapeutic product. Our study highlights the importance of considering polymorphisms in the targeted population when designing a transgene.
Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder α-1-antitrypsin (AAT) deficiency. Results from phase I and II studies have shown relatively stable and dose-dependent increases in transgene-derived wild-type AAT after local intramuscular vector administration. In this report we describe the appearance of transgene-specific T-cell responses in two subjects that were part of the phase II trial. The patient with the more robust T-cell response, which was associated with a reduction in transgene expression, was characterized more thoroughly in this study. We learned that the AAT-specific T cells in this patient were cytolytic in phenotype, mapped to a peptide in the endogenous mutant AAT protein that contained a common polymorphism not incorporated into the transgene, and were restricted by a rare HLA class I C alleles present only in this patient. These human studies illustrate the genetic influence of the endogenous gene and HLA haplotype on the outcome of gene therapy. Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder α-1-antitrypsin (AAT) deficiency. Results from phase I and II studies have shown relatively stable and dose-dependent increases in transgene-derived wild-type AAT after local intramuscular vector administration. In this report we describe the appearance of transgene-specific T-cell responses in two subjects that were part of the phase II trial. The patient with the more robust T-cell response, which was associated with a reduction in transgene expression, was characterized more thoroughly in this study. We learned that the AAT-specific T cells in this patient were cytolytic in phenotype, mapped to a peptide in the endogenous mutant AAT protein that contained a common polymorphism not incorporated into the transgene, and were restricted by a rare HLA class I C alleles present only in this patient. These human studies illustrate the genetic influence of the endogenous gene and HLA haplotype on the outcome of gene therapy. Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder a-1-antitrypsin (AAT) deficiency. Results from phase I and II studies have shown relatively stable and dose-dependent increases in transgene-derived wild-type AAT after local intramuscular vector administration. In this report we describe the appearance of transgene-specific T-cell responses in two subjects that were part of the phase II trial. The patient with the more robust T-cell response, which was associated with a reduction in transgene expression, was characterized more thoroughly in this study. We learned that the AAT-specific T cells in this patient were cytolytic in phenotype, mapped to a peptide in the endogenous mutant AAT protein that contained a common polymorphism not incorporated into the transgene, and were restricted by a rare HLA class I C alleles present only in this patient. These human studies illustrate the genetic influence of the endogenous gene and HLA haplotype on the outcome of gene therapy. |
| Author | Betts, Michael R. Rech, Andrew J. Qin, Qiuyue Vonderheide, Robert H. Flotte, Terence R. Mueller, Christian Wilson, James M. Calcedo, Roberto Somanathan, Suryanarayan |
| Author_xml | – sequence: 1 givenname: Roberto surname: Calcedo fullname: Calcedo, Roberto organization: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 – sequence: 2 givenname: Suryanarayan surname: Somanathan fullname: Somanathan, Suryanarayan organization: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 – sequence: 3 givenname: Qiuyue surname: Qin fullname: Qin, Qiuyue organization: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 – sequence: 4 givenname: Michael R. surname: Betts fullname: Betts, Michael R. organization: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 – sequence: 5 givenname: Andrew J. surname: Rech fullname: Rech, Andrew J. organization: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 – sequence: 6 givenname: Robert H. surname: Vonderheide fullname: Vonderheide, Robert H. organization: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 – sequence: 7 givenname: Christian surname: Mueller fullname: Mueller, Christian organization: Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655 – sequence: 8 givenname: Terence R. surname: Flotte fullname: Flotte, Terence R. organization: Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655 – sequence: 9 givenname: James M. surname: Wilson fullname: Wilson, James M. organization: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28137880$$D View this record in MEDLINE/PubMed |
| BookMark | eNqNkk1rFTEUhoNU7G117UrJ0s20-ZiPZCPIxWqh4KZdh0zmTG_K3CQmucIs-qP8I_6mZrit1UKhmwTOed-HNyfnCB047wCh95ScUNLx0-B0OqEt7TrWUlq_QitKJK3aWpIDtCKEdZWoWX2IjlK6IYTIRpA36JAJyjshyArdriedEj6vIqQcrckw4MvKwDThUgneJUg4e6xx8NO89TFsrMEBQrYDYOtK4xoc4LyBqMOMzWSdNXrCBVbO0Uf853dFK-2yzXEOqVgGGK2x4Mz8Fr0e9ZTg3f19jK7Ovl6uv1cXP76dr79cVKauRa5AalIL3mvdt7Ipr-BUghwZMC5aOpRaZ7Tp256QvusbpgmMRDAjNeuLQPNj9HnPDbt-C4MBl6OeVIh2q-OsvLbq_46zG3Xtf6mGMyKFKIBP94Dof-7KqNTWpmVK2oHfJUWFoN2Sjb9A2nJGpSQL9eO_sf7mefieImj2AhN9ShFGZWzW2folpZ0UJWpZA7WsgXpcg-I7feJ7QD_v-LB33KTs42OStu4kly2_A_wBwY0 |
| CitedBy_id | crossref_primary_10_3389_fimmu_2021_672449 crossref_primary_10_1038_s41577_022_00698_0 crossref_primary_10_1016_j_omtm_2021_02_003 crossref_primary_10_1177_01926233211041962 crossref_primary_10_1016_j_omtm_2023_02_004 crossref_primary_10_1016_j_ymthe_2020_01_001 crossref_primary_10_3390_cells8121586 crossref_primary_10_3390_v16101507 crossref_primary_10_1016_j_omtm_2025_101409 crossref_primary_10_1038_s41434_024_00490_w crossref_primary_10_1073_pnas_2307798120 crossref_primary_10_1002_bies_202200055 crossref_primary_10_1172_jci_insight_99052 crossref_primary_10_1038_s41434_023_00423_z crossref_primary_10_5483_BMBRep_2020_53_11_185 crossref_primary_10_3389_fimmu_2020_00670 crossref_primary_10_1016_j_ijcard_2023_131617 crossref_primary_10_1016_j_omtm_2018_11_002 crossref_primary_10_1016_j_bbrc_2020_04_037 crossref_primary_10_1016_j_ymthe_2022_03_004 crossref_primary_10_1186_s12987_024_00573_1 crossref_primary_10_1016_j_omtm_2022_09_009 crossref_primary_10_1016_j_omtm_2022_07_018 crossref_primary_10_1089_hgtb_2018_038 crossref_primary_10_1089_hum_2023_056 crossref_primary_10_1016_j_omtm_2017_11_007 crossref_primary_10_1002_jcph_2141 crossref_primary_10_1155_2024_5487973 crossref_primary_10_1007_s40259_023_00585_7 crossref_primary_10_1016_j_cellimm_2017_05_006 crossref_primary_10_3389_fimmu_2018_00554 crossref_primary_10_1089_hum_2019_109 crossref_primary_10_3389_fimmu_2021_674242 crossref_primary_10_1016_j_omtm_2019_12_008 crossref_primary_10_1016_j_ymthe_2019_12_010 crossref_primary_10_3389_fimmu_2021_658038 crossref_primary_10_1016_j_omtm_2018_10_012 crossref_primary_10_1146_annurev_virology_101416_041936 crossref_primary_10_1089_hum_2021_29193_amk crossref_primary_10_1089_hum_2023_227 crossref_primary_10_1038_nbt_4182 crossref_primary_10_1016_j_jaci_2019_08_029 crossref_primary_10_3389_fimmu_2021_753467 crossref_primary_10_3389_fbioe_2023_1138596 crossref_primary_10_3389_fphar_2022_1015926 crossref_primary_10_3389_fimmu_2021_655478 crossref_primary_10_3389_fimmu_2022_991832 crossref_primary_10_3390_vaccines6030035 crossref_primary_10_1016_j_cellimm_2018_03_004 crossref_primary_10_1146_annurev_virology_092818_015530 crossref_primary_10_3389_fimmu_2023_1094279 crossref_primary_10_1016_j_ymthe_2023_11_029 |
| Cites_doi | 10.1016/S1474-4422(11)70039-4 10.1089/hum.2006.17.1177 10.1089/hum.2008.107 10.1002/ana.22251 10.1093/brain/awr342 10.1089/humc.2012.249 10.1074/jbc.271.30.17829 10.1073/pnas.0904514106 10.1056/NEJMoa1108046 10.1073/pnas.0807027105 10.1038/mt.2010.135 10.1161/ATVBAHA.108.175620 10.1089/hum.2009.060 10.1182/blood-2013-01-306647 10.1212/01.wnl.0000312381.29287.ff 10.1172/JCI70314 10.1038/mt.2010.250 10.1056/NEJMoa1407309 10.1016/S0021-9258(18)66664-5 10.1038/nm1358 10.1007/s00251-005-0781-7 10.1093/nar/gks438 10.1172/JCI68205 10.1056/NEJMoa0802315 10.1089/10430340460732490 10.1089/hum.2011.053 |
| ContentType | Journal Article |
| Copyright | Volumes 1–89 and 106–114, copyright as a collective work only; author(s) retains copyright to individual articles |
| Copyright_xml | – notice: Volumes 1–89 and 106–114, copyright as a collective work only; author(s) retains copyright to individual articles |
| DBID | AAYXX CITATION NPM 7X8 7T5 8FD FR3 H94 P64 RC3 5PM |
| DOI | 10.1073/pnas.1617726114 |
| DatabaseName | CrossRef PubMed MEDLINE - Academic Immunology Abstracts Technology Research Database Engineering Research Database AIDS and Cancer Research Abstracts Biotechnology and BioEngineering Abstracts Genetics Abstracts PubMed Central (Full Participant titles) |
| DatabaseTitle | CrossRef PubMed MEDLINE - Academic AIDS and Cancer Research Abstracts Genetics Abstracts Immunology Abstracts Engineering Research Database Technology Research Database Biotechnology and BioEngineering Abstracts |
| DatabaseTitleList | AIDS and Cancer Research Abstracts MEDLINE - Academic PubMed CrossRef |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Sciences (General) |
| DocumentTitleAlternate | Immune response to AAT transgene |
| EISSN | 1091-6490 |
| EndPage | 1659 |
| ExternalDocumentID | PMC5320988 28137880 10_1073_pnas_1617726114 26479396 |
| Genre | Research Support, U.S. Gov't, P.H.S Journal Article Research Support, N.I.H., Extramural |
| GrantInformation_xml | – fundername: NHLBI NIH HHS grantid: P01 HL059407 – fundername: NHLBI NIH HHS grantid: P01 HL131471 – fundername: FDA HHS grantid: R01 FD003896 – fundername: HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI) grantid: HL059407-16A1 |
| GroupedDBID | --- -DZ -~X .55 0R~ 123 29P 2AX 2FS 2WC 4.4 53G 5RE 5VS 85S AACGO AAFWJ AANCE ABBHK ABOCM ABPLY ABPPZ ABTLG ABXSQ ABZEH ACGOD ACHIC ACIWK ACNCT ACPRK ADQXQ ADULT AENEX AEUPB AEXZC AFFNX AFOSN AFRAH ALMA_UNASSIGNED_HOLDINGS AQVQM BKOMP CS3 D0L DCCCD DIK DU5 E3Z EBS EJD F5P FRP GX1 H13 HH5 HYE IPSME JAAYA JBMMH JENOY JHFFW JKQEH JLS JLXEF JPM JSG JST KQ8 L7B LU7 N9A N~3 O9- OK1 PNE PQQKQ R.V RHI RNA RNS RPM RXW SA0 SJN TAE TN5 UKR W8F WH7 WOQ WOW X7M XSW Y6R YBH YKV YSK ZCA ~02 ~KM AAYXX CITATION NPM 7X8 7T5 8FD FR3 H94 P64 RC3 5PM |
| ID | FETCH-LOGICAL-c448t-e9a0483baab695009319e9f2e23861d6957cacb6b00b7b52a0ef082c9a2b861a3 |
| ISSN | 0027-8424 |
| IngestDate | Thu Aug 21 18:08:39 EDT 2025 Thu Sep 04 18:19:06 EDT 2025 Thu Sep 04 19:56:25 EDT 2025 Thu Apr 03 07:08:28 EDT 2025 Tue Jul 01 03:19:29 EDT 2025 Thu Apr 24 22:59:30 EDT 2025 Fri May 30 11:47:02 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 7 |
| Keywords | gene therapy a-1-antitrypsin adeno-associated virus polymorphism immune response |
| Language | English |
| LinkModel | OpenURL |
| MergedId | FETCHMERGED-LOGICAL-c448t-e9a0483baab695009319e9f2e23861d6957cacb6b00b7b52a0ef082c9a2b861a3 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Kenneth I. Berns, University of Florida College of Medicine, Gainesville, FL, and approved December 27, 2016 (received for review October 27, 2016) 1R.C. and S.S. contributed equally to this paper. Author contributions: R.C., S.S., C.M., T.R.F., and J.M.W. designed research; R.C., S.S., Q.Q., and M.R.B. performed research; R.C., S.S., A.J.R., R.H.V., and J.M.W. analyzed data; and R.C., S.S., A.J.R., R.H.V., T.R.F., and J.M.W. wrote the paper. |
| OpenAccessLink | https://www.pnas.org/content/pnas/114/7/1655.full.pdf |
| PMID | 28137880 |
| PQID | 1863219908 |
| PQPubID | 23479 |
| PageCount | 5 |
| ParticipantIDs | pubmedcentral_primary_oai_pubmedcentral_nih_gov_5320988 proquest_miscellaneous_1881769503 proquest_miscellaneous_1863219908 pubmed_primary_28137880 crossref_citationtrail_10_1073_pnas_1617726114 crossref_primary_10_1073_pnas_1617726114 jstor_primary_26479396 |
| ProviderPackageCode | CITATION AAYXX |
| PublicationCentury | 2000 |
| PublicationDate | 2017-02-14 |
| PublicationDateYYYYMMDD | 2017-02-14 |
| PublicationDate_xml | – month: 02 year: 2017 text: 2017-02-14 day: 14 |
| PublicationDecade | 2010 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | Proceedings of the National Academy of Sciences - PNAS |
| PublicationTitleAlternate | Proc Natl Acad Sci U S A |
| PublicationYear | 2017 |
| Publisher | National Academy of Sciences |
| Publisher_xml | – name: National Academy of Sciences |
| References | e_1_3_3_17_2 e_1_3_3_16_2 e_1_3_3_19_2 e_1_3_3_18_2 e_1_3_3_13_2 e_1_3_3_12_2 e_1_3_3_15_2 e_1_3_3_14_2 e_1_3_3_11_2 e_1_3_3_10_2 e_1_3_3_6_2 e_1_3_3_5_2 e_1_3_3_8_2 e_1_3_3_7_2 e_1_3_3_9_2 e_1_3_3_27_2 e_1_3_3_24_2 e_1_3_3_23_2 Takahashi H (e_1_3_3_26_2) 1990; 47 e_1_3_3_25_2 e_1_3_3_2_2 e_1_3_3_20_2 e_1_3_3_1_2 e_1_3_3_4_2 e_1_3_3_22_2 e_1_3_3_3_2 e_1_3_3_21_2 18401019 - Neurology. 2008 May 20;70(21):1980-3 23790242 - Hum Gene Ther Clin Dev. 2013 Sep;24(3):108-15 21419704 - Lancet Neurol. 2011 Apr;10(4):309-19 8663374 - J Biol Chem. 1996 Jul 26;271(30):17829-36 24231351 - J Clin Invest. 2013 Dec;123(12):5310-8 22149959 - N Engl J Med. 2011 Dec 22;365(25):2357-65 18774912 - Hum Gene Ther. 2008 Oct;19(10):979-90 21031578 - Ann Neurol. 2010 Nov;68(5):629-38 21609134 - Hum Gene Ther. 2011 Oct;22(10):1239-47 23596044 - Blood. 2013 Jul 4;122(1):23-36 17115945 - Hum Gene Ther. 2006 Dec;17(12):1177-86 18441370 - N Engl J Med. 2008 May 22;358(21):2240-8 14965381 - Hum Gene Ther. 2004 Jan;15(1):93-128 3491072 - J Biol Chem. 1986 Dec 5;261(34):15989-94 16474400 - Nat Med. 2006 Mar;12(3):342-7 22610854 - Nucleic Acids Res. 2012 Jul;40(Web Server issue):W525-30 21119617 - Mol Ther. 2011 Jan;19(1):16-27 20606642 - Mol Ther. 2010 Sep;18(9):1731-5 22240777 - Brain. 2012 Feb;135(Pt 2):483-92 23778142 - J Clin Invest. 2013 Jul;123(7):2994-3001 15744535 - Immunogenetics. 2005 Apr;57(1-2):33-41 18809924 - Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15112-7 18802015 - Arterioscler Thromb Vasc Biol. 2008 Dec;28(12):2303-4 19441963 - Hum Gene Ther. 2009 Sep;20(9):930-42 1975477 - Am J Hum Genet. 1990 Sep;47(3):403-13 25409372 - N Engl J Med. 2014 Nov 20;371(21):1994-2004 19706466 - Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16363-8 |
| References_xml | – ident: e_1_3_3_7_2 doi: 10.1016/S1474-4422(11)70039-4 – ident: e_1_3_3_15_2 doi: 10.1089/hum.2006.17.1177 – ident: e_1_3_3_2_2 doi: 10.1089/hum.2008.107 – ident: e_1_3_3_22_2 doi: 10.1002/ana.22251 – ident: e_1_3_3_21_2 doi: 10.1093/brain/awr342 – ident: e_1_3_3_25_2 doi: 10.1089/humc.2012.249 – ident: e_1_3_3_23_2 doi: 10.1074/jbc.271.30.17829 – ident: e_1_3_3_14_2 doi: 10.1073/pnas.0904514106 – ident: e_1_3_3_6_2 doi: 10.1056/NEJMoa1108046 – ident: e_1_3_3_3_2 doi: 10.1073/pnas.0807027105 – ident: e_1_3_3_5_2 doi: 10.1038/mt.2010.135 – ident: e_1_3_3_8_2 doi: 10.1161/ATVBAHA.108.175620 – ident: e_1_3_3_11_2 doi: 10.1089/hum.2009.060 – ident: e_1_3_3_24_2 doi: 10.1182/blood-2013-01-306647 – ident: e_1_3_3_4_2 doi: 10.1212/01.wnl.0000312381.29287.ff – ident: e_1_3_3_18_2 doi: 10.1172/JCI70314 – ident: e_1_3_3_9_2 doi: 10.1038/mt.2010.250 – ident: e_1_3_3_12_2 doi: 10.1056/NEJMoa1407309 – ident: e_1_3_3_20_2 doi: 10.1016/S0021-9258(18)66664-5 – ident: e_1_3_3_13_2 doi: 10.1038/nm1358 – ident: e_1_3_3_19_2 doi: 10.1007/s00251-005-0781-7 – ident: e_1_3_3_27_2 doi: 10.1093/nar/gks438 – ident: e_1_3_3_10_2 doi: 10.1172/JCI68205 – ident: e_1_3_3_1_2 doi: 10.1056/NEJMoa0802315 – ident: e_1_3_3_16_2 doi: 10.1089/10430340460732490 – ident: e_1_3_3_17_2 doi: 10.1089/hum.2011.053 – volume: 47 start-page: 403 year: 1990 ident: e_1_3_3_26_2 article-title: Alpha 1-antitrypsin Null(isola di procida): An alpha 1-antitrypsin deficiency allele caused by deletion of all alpha 1-antitrypsin coding exons publication-title: Am J Hum Genet – reference: 22610854 - Nucleic Acids Res. 2012 Jul;40(Web Server issue):W525-30 – reference: 3491072 - J Biol Chem. 1986 Dec 5;261(34):15989-94 – reference: 18809924 - Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15112-7 – reference: 18774912 - Hum Gene Ther. 2008 Oct;19(10):979-90 – reference: 22240777 - Brain. 2012 Feb;135(Pt 2):483-92 – reference: 8663374 - J Biol Chem. 1996 Jul 26;271(30):17829-36 – reference: 21609134 - Hum Gene Ther. 2011 Oct;22(10):1239-47 – reference: 18441370 - N Engl J Med. 2008 May 22;358(21):2240-8 – reference: 14965381 - Hum Gene Ther. 2004 Jan;15(1):93-128 – reference: 23596044 - Blood. 2013 Jul 4;122(1):23-36 – reference: 25409372 - N Engl J Med. 2014 Nov 20;371(21):1994-2004 – reference: 21031578 - Ann Neurol. 2010 Nov;68(5):629-38 – reference: 23778142 - J Clin Invest. 2013 Jul;123(7):2994-3001 – reference: 21119617 - Mol Ther. 2011 Jan;19(1):16-27 – reference: 16474400 - Nat Med. 2006 Mar;12(3):342-7 – reference: 19441963 - Hum Gene Ther. 2009 Sep;20(9):930-42 – reference: 24231351 - J Clin Invest. 2013 Dec;123(12):5310-8 – reference: 17115945 - Hum Gene Ther. 2006 Dec;17(12):1177-86 – reference: 1975477 - Am J Hum Genet. 1990 Sep;47(3):403-13 – reference: 15744535 - Immunogenetics. 2005 Apr;57(1-2):33-41 – reference: 23790242 - Hum Gene Ther Clin Dev. 2013 Sep;24(3):108-15 – reference: 21419704 - Lancet Neurol. 2011 Apr;10(4):309-19 – reference: 20606642 - Mol Ther. 2010 Sep;18(9):1731-5 – reference: 18802015 - Arterioscler Thromb Vasc Biol. 2008 Dec;28(12):2303-4 – reference: 22149959 - N Engl J Med. 2011 Dec 22;365(25):2357-65 – reference: 19706466 - Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16363-8 – reference: 18401019 - Neurology. 2008 May 20;70(21):1980-3 |
| SSID | ssj0009580 |
| Score | 2.451335 |
| Snippet | Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder α-1-antitrypsin (AAT) deficiency.... The use of adeno-associated virus (AAV)-mediated gene therapy to treat monogenic disorders is currently being tested in phase I, II, and III clinical trials.... Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder a-1-antitrypsin (AAT) deficiency.... |
| SourceID | pubmedcentral proquest pubmed crossref jstor |
| SourceType | Open Access Repository Aggregation Database Index Database Enrichment Source Publisher |
| StartPage | 1655 |
| SubjectTerms | Biological Sciences |
| Title | Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for α-1-antitrypsin deficiency |
| URI | https://www.jstor.org/stable/26479396 https://www.ncbi.nlm.nih.gov/pubmed/28137880 https://www.proquest.com/docview/1863219908 https://www.proquest.com/docview/1881769503 https://pubmed.ncbi.nlm.nih.gov/PMC5320988 |
| Volume | 114 |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1bb9MwFLbKeOEFMWBQbjISk4ailKS52H4c1WAgUW1SJ_WtshNXVBpJ1aYPReJHwQ_hN3GO7Vw6NgS8RG3iJJXPV_uco-98h5BXPJ6nLI6Vn6go8mMhpS94EPl5lGsZg8cQSsx3fBqnpxfxx2ky7fV-dFhLm0oNsq_X1pX8j1XhHNgVq2T_wbLNQ-EEfAb7whEsDMe_srHpaOl98LG_Bqxn6DxOfEzFeytLfbX6DRJbMUCMD1O6yLwl8lhyoxUisYGy9mwN1ratkrStPJCAeDg6OXwbQgAosZx3tV2uDXsWZSewZrPr2p41W-G6Jh6M60zjcVu34haTted7Z-O2C_JIXmY6L1uyd9nkfkpk2GKG37KIVlv4upLbFtbnVgfhfLHZblqSgK6qdacwwDEjXYIDNk1st2KTDNouyuDT-Gls24o2q7YbYuHJOmtwmFrh3982B1jNsKNxIdcDjOoYBI_2IR2oLL8YrAx5iEL7QbtLNtzF-tItcnvImKEGvJ-GHaFnHtQSUix6c-VtqD3t7t9xhCwX9roo5ypZt-P9TO6Ruy5soccWg_ukp4v7ZL-2JT1y6uWvH5BvBpS0C0pqQUkbUNKqpJJ2QEkdKOmigAsISupASWtQUgNKCqCkP7_vApK2gHxILt6dTEanvuvx4WdxzCtfC4lNDZSUKhUJ5tdCocV8qMGVTMMczrFMZiqF3UExlQxloOfgtWZCDhUMkNEB2SvKQj8mlOVKJCoJwjwL40RAKMRTMc85Bxc_14Hqk0E94bPMCeBjH5bLmSFisGiGxpq1xuqTo-aGpdV-uXnogbFgMw7iDNj5RNonL2uTzmDhxtmWhS43cDNPI3AX4Hf-aQwPGc5L1CePLAzaNzgc9QnbAUgzAIXjd68Ui89GQB6bwQjOn9z4zKfkTvtPfEb2qtVGPwfnu1IvDNp_AUva3lo |
| linkProvider | Geneva Foundation for Medical Education and Research |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Class+I-restricted+T-cell+responses+to+a+polymorphic+peptide+in+a+gene+therapy+clinical+trial+for+%CE%B1-1-antitrypsin+deficiency&rft.jtitle=Proceedings+of+the+National+Academy+of+Sciences+-+PNAS&rft.au=Calcedo%2C+Roberto&rft.au=Somanathan%2C+Suryanarayan&rft.au=Qin%2C+Qiuyue&rft.au=Betts%2C+Michael+R&rft.date=2017-02-14&rft.eissn=1091-6490&rft.volume=114&rft.issue=7&rft.spage=1655&rft_id=info:doi/10.1073%2Fpnas.1617726114&rft_id=info%3Apmid%2F28137880&rft.externalDocID=28137880 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0027-8424&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0027-8424&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0027-8424&client=summon |