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Blood, 1 March 2001, Vol. 97, No. 5, pp. 1258-1265
GENE THERAPY
Factors influencing in vivo transduction by recombinant
adeno-associated viral vectors expressing the human factor
IX cDNA
Amit C. Nathwani,
Andrew Davidoff,
Hideki Hanawa,
Jun-Fang Zhou,
Elio F. Vanin, and
Arthur W. Nienhuis
From the Division of Experimental Hematology, Department
of Hematology/ Oncology, and Department of Surgery, St Jude
Children's Research Hospital, Memphis, TN.
Long-term expression of coagulation factor IX (FIX) has been
observed in murine and canine models following administration of
recombinant adeno-associated viral (rAAV) vectors into either the
portal vein or muscle. These studies were designed to evaluate factors
that influence rAAV-mediated FIX expression. Stable and persistent
human FIX (hFIX) expression (> 22 weeks) was observed from 4 vectors
after injection into the portal circulation of immunodeficient mice.
The level of expression was dependent on promoter with the highest
expression, 10% of physiologic levels, observed with a vector
containing the cytomegalovirus (CMV) enhancer/ -actin promoter
complex (CAGG). The kinetics of expression after injection of vector
particles into muscle, tail vein, or portal vein were similar with hFIX
detectable at 2 weeks and reaching a plateau by 8 weeks. For a given
dose, intraportal administration of rAAV CAGG-FIX resulted in a
1.5-fold or 4-fold higher level of hFIX compared to tail vein or
intramuscular injections, respectively. Polymerase chain reaction
analysis demonstrated predominant localization of the rAAV FIX genome
in liver and spleen after tail vein injection with a higher proportion
in liver after portal vein injection. Therapeutic levels of hFIX were
detected in the majority of immunocompetent mice (21 of 22) following
intravenous administration of rAAV vector without the development of
anti-hFIX antibodies, but hFIX was not detected in 14 immunocompetent
mice following intramuscular administration, irrespective of strain.
Instead, neutralizing anti-hFIX antibodies were detected in all the
mice. These observations may have important implications for hemophilia
B gene therapy with rAAV vectors.
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