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Intrapituitary Adenoviral Administration of 7B2 Can Extend Life Span and Reverse Endocrinological Deficiencies in 7B2 Null Mice

Department of Biochemistry and Molecular Biology (M.S.S., I.L.), Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112; Molecular Medicine and Gene Therapy Unit (S.W.), School of Medicine, University of Manchester, Manchester M13 9PT, United Kingdom; and Gene Therapeutics Research Institute (M.G.C.), Cedars Sinai Medical Center, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Iris Lindberg, Ph.D., Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, Louisiana 70112. E-mail: . ilindb{at}lsuhsc.edu

The prohormone convertase PC2 requires the aid of a helper protein, known as 7B2, for production of active enzyme. Deletion of 7B2 results in a lethal phenotype resembling Cushing’s disease. In this study, we have investigated the effect of a single low dose of recombinant adenovirus vector encoding 7B2 and delivered directly to the pituitary of 7B2 nulls on pituitary ACTH, plasma ACTH, corticosterone, MSH and glucose, and survival time. We show that after injection of recombinant adenovirus encoding 27-kDa 7B2 into 7B2 nulls, transgene expression, as measured by RIA for 7B2, exhibits a transient elevation in the pituitary and blood, with a slight but significant elevation of PC2 activity in pituitaries of 7B2 nulls and a drop in the level of circulating ACTH concomitant with a small increase in circulating MSH. The level of circulating blood glucose was increased, and that of corticosterone was decreased. Lastly, slight but significantly prolonged survival times were observed. These data showing partial rescue of 7B2 nulls support the idea that adenoviral administration of 7B2 will represent an effective means to study the role of this interesting neuroendocrine protein on endocrine function in vivo.

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