Background. Anemia is a significant problem in many disease states. Erythropoietin (Epo) has been used in the treatment of anemia associated with numerous chronic diseases. This study investigates the dose-response profiles of a single intramuscular (im) injection of a recombinant adeno-associated virus vector (rAAV) containing the Epo gene with the goal of achieving a sustained elevation of hematocrit (Hct). Methods. Cynomolgus (cm) monkeys were given single injections of different doses of rAAV-cm-Epo. The biological effect of Epo gene expression was monitored by determining the Hct levels and circulating hormone levels by ELISA. Antibody to the rAAV capsid protein was also measured over the 41-week period of the experiment. Results. Epo expression was noted only when 2 x 1011 or more particles were injected. Epo was noted to be increased as soon as 1 week postinjection and was maximum in 6 to 8 weeks. This level of expression remained constant for nearly 20 weeks. Animals given the highest dose of rAAV developed a higher Hct over the first 8 weeks postinjection than those given an intermediate dose. However, the maximum levels of hemoglobin were the same. There was a weak correlation between amount of rAAV injected and capsid antibody response. Conclusions. AAV vectors are able to transduce skeletal muscle and are capable of achieving sustained expression and systemic delivery of a therapeutic protein following a single in administration. Dose responses to rAAV-Epo are achievable, although a threshold inoculum of virus is necessary to produce an effect and the therapeutic window is narrow. (C) 2000 Academic Press.
- Adeno-associated virus vector
- Cynomolgus monkeys
- Gene therapy
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