Sustained intravesical interferon protein exposure is achieved using an adenoviral-mediated gene delivery system: a study in rats evaluating dosing regimens.
OBJECTIVE
To evaluate whether a recombinant replication-deficient adenovirus containing the secreted human interferon alpha-2b gene (rAd-IFN) could improve the tissue and urine levels of IFN protein by transducing the urothelium with the secreted human IFN-alpha gene. We also assessed whether varying the interval between rAd-IFN/Syn3 treatments would improve the duration and levels of gene expression.


METHODS
The rats received intravesical administration of rAd-IFN at varying concentrations in a formulation containing Syn3, an agent identified that facilitates passage of the adenovirus through the protective barrier of the bladder. Urine was collected daily for 7 days, and human IFN was measured in the urine by enzyme-linked immunosorbent assay. For the redosing studies, the animals received a second dose at varying intervals ranging from 1 to 7 days after the first dose or at longer intervals (30, 60, or 90 days).


RESULTS
Rats that received intravesical administration of rAd-IFN in a Syn3 formulation expressed levels of human IFN protein in their urine at peak concentrations of 50,000 to 100,000 pg/mL, but were undetectable by 7 days. Expression was localized to the bladder with only minimal systemic exposure to IFN. Short-term redosing marginally improved the IFN urine concentrations, with maximal levels achieved when a second dose was administered 3 days after a first dose. Although gene expression was attenuated when a second dose was given 5 to 7 days after the first treatment, the levels and duration of IFN expression recovered when the interval was increased to 90 days.


CONCLUSIONS
Intravesical treatment with rAd-IFN facilitates high levels of IFN transgene exposure and may be a new approach to treating superficial bladder cancer.
Canji, Incorporated, San Diego, California 92121, USA. robert.conner@canji.com
Robert J
RJ
Connor
Jennifer M
JM
Anderson
Todd
T
Machemer
Daniel C
DC
Maneval
Heidrun
H
Engler
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005260:Female; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D001743:Urinary Bladder
D004337:Drug Carriers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins