Congenital virilizing adrenal hyperplasia (CAH) is caused by impaired adrenal steroidogenesis that results in reduced production of cortisol and aldosterone, and excessive production of androgens. Whereas there are consequences of reduced cortisol and aldosterone production, increased androgen is responsible for most of the adverse effects of this condition. In normal conditions and in CAH, excessive androgen production is regulated by pituitary ACTH, which acts via the melanocortin-2 receptor (MC2R) in the adrenal gland to stimulate steroid production. If activation of the MC2R can be inhibited, adrenal activity in CAH will be markedly reduced and management optimized. ? ? In this application we propose the development of a novel immunological approach for inducing adrenal insufficiency in patients with CAH by making a vaccine that inhibits ACTH-mediated activation of the MC2R. This application is based on preliminary studies showing that antibodies to the MC2R inhibit the ability of ACTH to activate MC2R function in adrenal cells. We also find that immunizing mice with synthetic peptides that correspond to small regions of the MC2R induces an immune response against the MC2R. Based on these observations, we hypothesize that it is possible to develop a """"""""vaccine"""""""" against the MC2R that blocks ACTH action. We also hypothesize that a vaccine against the MC2R will lead to improved treatment of CAH, To test these hypotheses we propose to (1) induce immunity against the MC2R by immunizing mice with modified peptides. (2) Determine if vaccinating mice with modified MC2R peptides leads to adrenal insufficiency. We anticipate that these studies will lead to the development of a novel approach for treating patients with CAH. If these phase I studies are effective, phase II studies will focus on preclinical trials in non-human primates. We also anticipate being able to extend this novel approach to the treatment of other receptor-mediated endocrine disorders, such as hyperthyroidism. ? ?
