Endocrine Abstracts (2019) 65 P270 | DOI: 10.1530/endoabs.65.P270

Antisense oligonucleotides as a novel medical therapy for Cushing's disease

Jacob Whatmore, Ahmed Alzahrani, Julie Porter, Helen Kemp & John Newell-Price

University of Sheffield, Sheffield, UK

Introduction: Cushing’s disease (CD) is a rare but devastating condition, caused by hypersecretion of adrenocorticotropic hormone (ACTH) from a corticotroph adenoma in the anterior pituitary. CD is associated with a five-fold excess mortality and clinical features including hypertension, diabetes mellitus, osteoporosis, and depression. First-line treatment is transsphenoidal surgery, but this is effective in only 65% of cases and the relapse rate is high. Other treatment options are limited. Antisense therapy is a technique for inducing post-transcriptional gene silencing by the use of antisense oligonucleotides (ASOs), which target specific sequences on mRNAs leading to RNase-H degradation or steric blocking of ribosomal machinery. We hypothesised that ASOs against POMC, which encodes ACTH, could be an effective treatment for CD by silencing POMC expression and thus decreasing the secretion of ACTH.

Methodology: Two POMC-specific ASOs were used to transfect AtT-20 cells, which hyper-secrete ACTH. ASOs unrelated to POMC provided control data, and untreated cells gave baseline ACTH secretion. Modified ASOs contained a phosphorothioate backbone and 2’-O-methoxy nucleotides at the ends of the molecule. Changes in secreted ACTH levels in culture medium were measured by immunoassay, and were compared by ANOVA.

Results: ASOs specifically targeting POMC mRNA caused a sustained (up to five days) reduction (>65%) of ACTH secretion by AtT-20 cells compared to untreated cells (P values <0.05). ASO modifications resulted in a significant decrease in ACTH expression compared with the equivalent unmodified ASOs (P values <0.05). Control ASOs had no significant effect upon the secretion of ACTH.

Conclusions: ASOs targeting POMC mRNA reduced the secretion of ACTH by AtT-20 cells. Chemical modifications to the ASOs resulted in an increase in their efficacy. POMC ASOs could be a novel medical therapy for CD.

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