Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results.

Hdl Handle:
http://hdl.handle.net/10147/230652
Title:
Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results.
Authors:
Flotte, Terence R; Trapnell, Bruce C; Humphries, Margaret; Carey, Brenna; Calcedo, Roberto; Rouhani, Farshid; Campbell-Thompson, Martha; Yachnis, Anthony T; Sandhaus, Robert A; McElvaney, Noel G; Mueller, Christian; Messina, Louis M; Wilson, James M; Brantly, Mark; Knop, David R; Ye, Guo-jie; Chulay, Jeffrey D
Affiliation:
University of Massachusetts Medical School, 55 Lake Avenue North,Worcester, MA 01655, USA. Terry.Flotte@umassmed.edu
Citation:
Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results. 2011, 22 (10):1239-47 Hum. Gene Ther.
Journal:
Human gene therapy
Issue Date:
Oct-2011
URI:
http://hdl.handle.net/10147/230652
DOI:
10.1089/hum.2011.053
PubMed ID:
21609134
Abstract:
Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α(1)-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×10(11), 1.9×10(12), and 6.0×10(12) vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with only mild injection site reactions and no serious adverse events. Serum creatine kinase was transiently elevated on day 30 in five of six subjects in the two higher dose groups and normalized by day 45. As expected, all subjects developed anti-AAV antibodies and interferon-γ enzyme-linked immunospot responses to AAV peptides, and no subjects developed antibodies to AAT. One subject in the mid-dose group developed T cell responses to a single AAT peptide unassociated with any clinical effects. Muscle biopsies obtained on day 90 showed strong immunostaining for AAT and moderate to marked inflammatory cell infiltrates composed primarily of CD3-reactive T lymphocytes that were primarily of the CD8(+) subtype. These results support the feasibility and safety of AAV gene therapy for AAT deficiency, and indicate that serum levels of vector-derived normal human AAT >20 μg/ml can be achieved. However, further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations.
Item Type:
Article
Language:
en
MeSH:
Antibodies; Creatine Kinase; Dependovirus; Dose-Response Relationship, Drug; Drug Toxicity; Enzyme-Linked Immunospot Assay; Gene Therapy; Genetic Vectors; Humans; Immunophenotyping; Injections, Intramuscular; Interferon-gamma; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency
ISSN:
1557-7422

Full metadata record

DC FieldValue Language
dc.contributor.authorFlotte, Terence Ren_GB
dc.contributor.authorTrapnell, Bruce Cen_GB
dc.contributor.authorHumphries, Margareten_GB
dc.contributor.authorCarey, Brennaen_GB
dc.contributor.authorCalcedo, Robertoen_GB
dc.contributor.authorRouhani, Farshiden_GB
dc.contributor.authorCampbell-Thompson, Marthaen_GB
dc.contributor.authorYachnis, Anthony Ten_GB
dc.contributor.authorSandhaus, Robert Aen_GB
dc.contributor.authorMcElvaney, Noel Gen_GB
dc.contributor.authorMueller, Christianen_GB
dc.contributor.authorMessina, Louis Men_GB
dc.contributor.authorWilson, James Men_GB
dc.contributor.authorBrantly, Marken_GB
dc.contributor.authorKnop, David Ren_GB
dc.contributor.authorYe, Guo-jieen_GB
dc.contributor.authorChulay, Jeffrey Den_GB
dc.date.accessioned2012-06-25T16:04:16Z-
dc.date.available2012-06-25T16:04:16Z-
dc.date.issued2011-10-
dc.identifier.citationPhase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results. 2011, 22 (10):1239-47 Hum. Gene Ther.en_GB
dc.identifier.issn1557-7422-
dc.identifier.pmid21609134-
dc.identifier.doi10.1089/hum.2011.053-
dc.identifier.urihttp://hdl.handle.net/10147/230652-
dc.description.abstractRecombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α(1)-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×10(11), 1.9×10(12), and 6.0×10(12) vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with only mild injection site reactions and no serious adverse events. Serum creatine kinase was transiently elevated on day 30 in five of six subjects in the two higher dose groups and normalized by day 45. As expected, all subjects developed anti-AAV antibodies and interferon-γ enzyme-linked immunospot responses to AAV peptides, and no subjects developed antibodies to AAT. One subject in the mid-dose group developed T cell responses to a single AAT peptide unassociated with any clinical effects. Muscle biopsies obtained on day 90 showed strong immunostaining for AAT and moderate to marked inflammatory cell infiltrates composed primarily of CD3-reactive T lymphocytes that were primarily of the CD8(+) subtype. These results support the feasibility and safety of AAV gene therapy for AAT deficiency, and indicate that serum levels of vector-derived normal human AAT >20 μg/ml can be achieved. However, further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Human gene therapyen_GB
dc.subject.meshAntibodies-
dc.subject.meshCreatine Kinase-
dc.subject.meshDependovirus-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshDrug Toxicity-
dc.subject.meshEnzyme-Linked Immunospot Assay-
dc.subject.meshGene Therapy-
dc.subject.meshGenetic Vectors-
dc.subject.meshHumans-
dc.subject.meshImmunophenotyping-
dc.subject.meshInjections, Intramuscular-
dc.subject.meshInterferon-gamma-
dc.subject.meshalpha 1-Antitrypsin-
dc.subject.meshalpha 1-Antitrypsin Deficiency-
dc.titlePhase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results.en_GB
dc.typeArticleen
dc.contributor.departmentUniversity of Massachusetts Medical School, 55 Lake Avenue North,Worcester, MA 01655, USA. Terry.Flotte@umassmed.eduen_GB
dc.identifier.journalHuman gene therapyen_GB
dc.description.provinceLeinsteren

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