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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 1882-1894
Transduction of Primitive Human Marrow and Cord Blood-Derived
Hematopoietic Progenitor Cells With Adeno-Associated Virus Vectors
Saswati Chatterjee,
Wei Li,
Christie Ann Wong,
Grace Fisher-Adams,
Di Lu,
Mausumee Guha,
James A. Macer,
Stephen J. Forman, and
K.K. Wong Jr
From the Division of Pediatrics, Department of Hematology and Bone
Marrow Transplantation, City of Hope National Medical Center, Duarte,
CA; and the Department of Obstetrics and Gynecology, School of
Medicine, University of Southern California and Huntington Memorial
Hospital, Pasadena, CA.
We evaluated the capacity of adeno-associated virus
(AAV) vectors to transduce primitive human myeloid
progenitor cells derived from marrow and cord blood in long-term
cultures and long-term culture-initiating cell (LTC-IC)
assays. Single-colony analyses showed that AAV vectors transduced
CD34+ and CD34+38 clonogenic
cells in long-term culture. Gene transfer was readily observed in
LTC-ICs derived from 5-, 8-, and 10-week cultures. Recombinant AAV
(rAAV) transduction was observed in every donor analyzed,
although a wide range of gene transfer frequencies (5% to 100%) was
noted. AAV transduction of LTC-ICs was stable, with week-8 and -10 LTC-ICs showing comparable or better transduction relative to week-5
LTC-ICs. Fluorescence in situ hybridization (FISH)
analyses performed to determine the fate of AAV vectors in transduced
cells showed that 9% to 28% of CD34+ and
CD34+38 cells showed stable vector
integration as evidenced by chromosome-associated signals in metaphase
spreads. Comparisons of interphase and metaphase FISH suggested that a
fraction of cells also contained episomal vector at early time points
after transduction. Despite the apparent loss of the episomal forms
with continued culture, the number of metaphases containing integrated
vector genomes remained stable long term. Transgene transcription and
placental alkaline phosphatase (PLAP) expression was
observed in CD34+, CD34+38
LTC-ICs in the absence of selective pressure. These results suggest that primitive myeloid progenitors are amenable to genetic modification with AAV vectors.
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