Abstract:
:Integration site analysis was performed on six dogs with canine leukocyte adhesion deficiency (CLAD) that survived greater than 1 year after infusion of autologous CD34+ bone marrow cells transduced with a gammaretroviral vector expressing canine CD18. A total of 387 retroviral insertion sites (RIS) were identified in the peripheral blood leukocytes from the six dogs at 1 year postinfusion. A total of 129 RIS were identified in CD3+ T-lymphocytes and 102 RIS in neutrophils from two dogs at 3 years postinfusion. RIS occurred preferentially within 30 kb of transcription start sites, including 40 near oncogenes and 52 near genes active in hematopoietic stem cells. Integrations clustered around common insertion sites more frequently than random. Despite potential genotoxicity from RIS, to date there has been no progression to oligoclonal hematopoiesis and no evidence that vector integration sites influenced cell survival or proliferation. Continued follow-up in disease-specific animal models such as CLAD will be required to provide an accurate estimate of the genotoxicity using gammaretroviral vectors for hematopoietic stem cell gene therapy.
journal_name
Gene Therjournal_title
Gene therapyauthors
Hai M,Adler RL,Bauer TR Jr,Tuschong LM,Gu YC,Wu X,Hickstein DDdoi
10.1038/gt.2008.52subject
Has Abstractpub_date
2008-07-01 00:00:00pages
1067-71issue
14eissn
0969-7128issn
1476-5462pii
gt200852journal_volume
15pub_type
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