Antisense oligonucleotide-induced inhibition of adrenocorticotropic hormone release from cultured human corticotrophs

Object. Available therapies for Gushing's disease are often inadequate or i nvolve the risk of significant morbidity. Accordingly, the need arises for the development of novel treatments, especially for cases caused by cortico troph hyperplasia, a condition difficult to treat using standard therapies. In this study, the authors investigated the use of phosphorothioate antise nse oligonucleotides as a potential treatment for Gushing's disease. Methods. Corticotrophs, obtained from a patient with Gushing's disease in w hom pathological findings showed multifocal areas of corticotroph adenoma a nd hyperplasia, were grown in tissue culture. By assessing cell viability a nd using immunoradiometric assay techniques, it was determined that these c ells grew autonomously and secreted adrenocorticotropic hormone (ACTH) in v itro. A fully phosphorothioated antisense oligonucleotide was constructed t o be complementary to the first 25 bp of the region coding for ACTH in exon 3 of the proopiomelanocortin precursor. After incubation of the corticotro phs with liposome-coated phosphorothioate antisense oligonucleotides, a gre ater than 90% decrease in ACTH release was noted on Days 3 and 6, compared with nonsense-treated controls (p < 0.05). Conclusions. Antisense oligonucleotides may prove to be a useful adjunct in treating Gushing's disease by targeting one of its fundamental problems, A CTH hypersecretion.