rdf:type |
|
lifeskim:mentions |
umls-concept:C0036043,
umls-concept:C0086022,
umls-concept:C0086418,
umls-concept:C0231441,
umls-concept:C0442335,
umls-concept:C0443252,
umls-concept:C0449943,
umls-concept:C0678812,
umls-concept:C0679058,
umls-concept:C1136102,
umls-concept:C1366464,
umls-concept:C1412056,
umls-concept:C1547699,
umls-concept:C1705099,
umls-concept:C1705338,
umls-concept:C2700640
|
pubmed:issue |
5
|
pubmed:dateCreated |
2011-5-2
|
pubmed:abstractText |
Adeno-associated virus vectors (AAV) show promise for liver-targeted gene therapy. In this study, we examined the long-term consequences of a single intravenous administration of a self-complementary AAV vector (scAAV2/ 8-LP1-hFIXco) encoding a codon optimized human factor IX (hFIX) gene in 24 nonhuman primates (NHPs). A dose-response relationship between vector titer and transgene expression was observed. Peak hFIX expression following the highest dose of vector (2 × 10(12) pcr-vector genomes (vg)/kg) was 21 ± 3 µg/ml (~420% of normal). Fluorescent in-situ hybridization demonstrated scAAV provirus in almost 100% of hepatocytes at that dose. No perturbations of clinical or laboratory parameters were noted and vector genomes were cleared from bodily fluids by 10 days. Macaques transduced with 2 × 10(11) pcr-vg/kg were followed for the longest period (~5 years), during which time expression of hFIX remained >10% of normal level, despite a gradual decline in transgene copy number and the proportion of transduced hepatocytes. All macaques developed serotype-specific antibodies but no capsid-specific cytotoxic T lymphocytes were detected. The liver was preferentially transduced with 300-fold more proviral copies than extrahepatic tissues. Long-term biochemical, ultrasound imaging, and histologic follow-up of this large cohort of NHP revealed no toxicity. These data support further evaluation of this vector in hemophilia B patients.
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pubmed:grant |
|
pubmed:commentsCorrections |
|
pubmed:language |
eng
|
pubmed:journal |
|
pubmed:citationSubset |
IM
|
pubmed:chemical |
|
pubmed:status |
MEDLINE
|
pubmed:month |
May
|
pubmed:issn |
1525-0024
|
pubmed:author |
pubmed-author:AllayJamesJ,
pubmed-author:BronsonRoderickR,
pubmed-author:ColemanJohnJ,
pubmed-author:DavidoffAndrew MAM,
pubmed-author:DonahueRobert ERE,
pubmed-author:GrayJohn TJT,
pubmed-author:HighKatherine AKA,
pubmed-author:JacksonScottS,
pubmed-author:McCarvilleM BethMB,
pubmed-author:McIntoshJennyJ,
pubmed-author:MingozziFedericoF,
pubmed-author:NathwaniAmit CAC,
pubmed-author:NathwaniDevhrutD,
pubmed-author:NawatheSushmitaS,
pubmed-author:NgCatherine Y CCY,
pubmed-author:NienhuisArthur WAW,
pubmed-author:RajDeepakD,
pubmed-author:RastegarlariGhasemG,
pubmed-author:RosalesCeciliaC,
pubmed-author:SleepSusanS,
pubmed-author:SpenceYunyuY,
pubmed-author:ValentineMarcM,
pubmed-author:WaddingtonSimon NSN,
pubmed-author:ZhouJunfangJ
|
pubmed:issnType |
Electronic
|
pubmed:volume |
19
|
pubmed:owner |
NLM
|
pubmed:authorsComplete |
Y
|
pubmed:pagination |
876-85
|
pubmed:meshHeading |
pubmed-meshheading:21245849-Animals,
pubmed-meshheading:21245849-Capsid Proteins,
pubmed-meshheading:21245849-Dependovirus,
pubmed-meshheading:21245849-Factor IX,
pubmed-meshheading:21245849-Gene Expression,
pubmed-meshheading:21245849-Gene Therapy,
pubmed-meshheading:21245849-Genetic Vectors,
pubmed-meshheading:21245849-HEK293 Cells,
pubmed-meshheading:21245849-Hemophilia B,
pubmed-meshheading:21245849-Humans,
pubmed-meshheading:21245849-In Situ Hybridization, Fluorescence,
pubmed-meshheading:21245849-Liver,
pubmed-meshheading:21245849-Macaca,
pubmed-meshheading:21245849-Mice
|
pubmed:year |
2011
|
pubmed:articleTitle |
Long-term safety and efficacy following systemic administration of a self-complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins.
|
pubmed:affiliation |
Department of Hematology, University College London Cancer Institute, London, UK. a.nathwani@ucl.ac.uk
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
|