Ablation of Hepatic Production of the Acid Labile Subunit in the Bovine-GH Transgenic Mice

Presentation Number: OR18-5
Date of Presentation: April 2nd, 2017

Zhongbo Liu1, Tianzhen Han2, Shannon Fishman3, James Butler3, Tracy S. Zimmermann3, Frederic Tremblay4, John J Kopchick5 and Shoshana Yakar*6
1New York University College of Dentistry New York, New York, 2New York University College of Dentistry, New York, NY, 32. Alnylam Pharmaceuticals, Inc., Cambridge, MA, 4Alnylam Pharmaceuticals, Inc., Cambridge, MA, 5Ohio University, Athens, OH, 6New York University COLLEGE OF D, New York, NY


Acromegaly is a chronic, multisystem, progressive disorder caused by uncontrolled secretion of growth hormone (GH) most commonly by a pituitary adenoma. GH hypersecretion leads to a slew of medical problems among them is increased somatic growth, which leads to acral, maxillofacial changes and debilitating arthritis. The management of patients with acromegaly is complex multidisciplinary and requires a tailored approach to each patient. A major biochemical characteristic of acromegaly is the increased production of liver-derived insulin like growth factor-1 (IGF-1). In fact, most of the systemic complications associated with acromegaly can be attributed to the effects of IGF-1, which mediates a significant portion of the somatic and metabolic effects of GH. We hypothesized that targeting specifically the liver-derived acid labile subunit (ALS), which stabilizes IGF-1 in circulation, will reduce serum IGF-1 levels and alleviate the metabolic and somatic growth symptoms associated with GH hypersecretion. We used the bovine GH (bGH) transgenic mice that express the bGH ubiquitously under the metallothionine promoter and ablated hepatic ALS using 1) siRNA gene target approach, or 2) by crossing the bGH with the ALS knockout (ALSKO) to generate bGH/ALSKO mice. We found that in both models ablation of the ALS significantly decreased body weight (bGH/ALSKO 28.595±1.810, bGH/siRNA-ALS 31.925±1.725 as compared to bGH 38.240±2.857g) serum IGF-1 (bGH/ALSKO 112.78±26.35, bGH/siRNA-ALS 107.32±13.92 as compared to bGH 1725.90±971.79ng/ml), serum IGF-binding protein-3 and serum ALS levels. However, targeting ALS in the bGH mice did not alleviate the hyperinsulinemia of the bGH mice. Lastly, only genetic ablation of ALS (bGH/ALSKO), and not siRNA-ALS reduced long bone linear and radial growth, suggesting that extrahepatic ALS sources play a role in skeletal regulation.


Disclosure: SF: Employee, Alnylam. JB: Employee, Alnylam. TSZ: Employee, Alnylam. FT: Employee, Alnylam. Nothing to Disclose: ZL, TH, JJK, SY