Erythropoietin Gene Transfer and Expression in Adult Normal Mice: Use of an Adenovirus Vector

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Abstract
A hormonal model of erythropoietin (Epo) delivery by use of an adenovirus vector was investigated. We constructed a replication-defective adenovirus carrying the monkey (cynomolgus) Epo cDNA under control of the Rous sarcoma virus long terminal repeat promoter. Fifty 8-week-old mice were injected with escalating doses of the recombinant virus from 106 to 1010 plaque-forming units (pfu). Different modes of administration were studied. Intravenous (i.v.) injection was the most effective mode of administration and exhibited a dose-dependent response. After a single i.v. injection with high doses (5 × 109 and 1010 pfu), a dramatic increase in hematocrit (Hct) and long-term Epo expression (6 months at this time) were observed. Intravenous administration with lower doses and intramuscular (i.m.) administration were inefficient or had a very transient effect. A localized muscle attrition prior to i.m. administration of 1010 pfu enhanced Hct response. This initial study opens the way for high level and durable Epo therapy by gene transfer. Moreover, this recombinant virus provides a convenient means to study the efficacy, duration, and safety aspects of hormonal delivery by an adenoviral vector. It seems important to study alternative modes for administering Epo because of the rapid expansion of its clinical applications and the high doses and durations required. The delivery of therapeutic levels of a hormone in the serum could be achieved by use of a recombinant adenovirus. The present paper reports the effectiveness of a single i.v. injection of a replication-defective adenovirus encoding the Epo cDNA in producing a long-term rise in hematocrits in the infected mice. These results represent a first step toward in vivo Epo therapy by gene transfer. Aspects concerning the stability and control of the level of expression are to be addressed before this approach can be considered in disorders benefiting from continuous Epo administration.