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Blood, 15 January 2001, Vol. 97, No. 2, pp. 410-418
GENE THERAPY
Second generation knockout sickle mice: the effect of
HbF
Mary E. Fabry,
Sandra M. Suzuka,
Rona S. Weinberg,
Christine Lawrence,
Stephen M. Factor,
John G. Gilman,
Frank Costantini, and
Ronald L. Nagel
From the Departments of Medicine and Pathology, Albert
Einstein College of Medicine/Montefiore Medical Center, Bronx, NY;
Mount Sinai School of Medicine, New York, NY; and Columbia University,
New York, NY.
Sickle transgenic mice expressing exclusively human globins are
desirable for studying pathophysiology and testing gene therapy strategies, but they must have significant pathology and show evidence
of amelioration by antisickling hemoglobins. Mice were generated that
expressed exclusively human sickle hemoglobin with 3 levels
of HbF using their previously described sickle constructs (cointegrated
human miniLCR 2 and miniLCR S [PNAS 89:12150, 1992]),
mouse - and -globin-knockouts, and 3 different human
 -transgenes. It was found that, at all 3 levels of HbF expression,
these mice have balanced chain synthesis, nearly normal mean
corpuscular hemoglobin, and, in some cases, F cells. Mice with
the least adult HbF expression were the most severe. Progressive
increase in HbF from less than 3% to 20% to 40% correlated with
progressive increase in hematocrit (22% to 34% to 40%) and progressive decrease in reticulocyte count (from 60% to 30% to 13%).
Urine concentrating ability was normalized at high HbF, and tissue
damage detected by histopathology and organ weight were ameliorated by
increased HbF. The -transgene that produces intermediate levels
of HbF was introduced into knockout sickle mice described by
Pàszty and coworkers that express the
miniLCR1GA S
transgene and have fetal but not adult expression of HbF. It was found
that the level of HbF required to ameliorate low hematocrit and
normalize urine concentrating defect was different for the miniLCR2S and
miniLCR1GAS mice.
We conclude that knockout mice with the
miniLCR2S transgene and postnatal expression of HbF
have sufficiently faithful sickle pathology to serve as a platform for
testing antisickling interventions.
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