Treatment of Post-menopausal Obesity and Associated Disease by PDE9 Inhibitors

Unmet Need
Obesity is a serious health problem both globally and in the United States. Obesity is associated with numerous comorbidities including type-2 diabetes, cardiovascular disease, and certain types of cancers. In particular, obesity is commonly seen in the post-menopausal population as 74% of American women over the age of 60 are considered overweight. Post-menopausal women gain an average of 5 pounds with up to 20% gaining 10 pounds or more of weight that is often resistant to diet and exercise. As such, there is a great healthcare need for a treatment to help restore normal weight levels independent of activity and diet. This treatment would increase the quality of life and reduce obesity comorbidities in the post-menopausal population.
 
Technology Overview
Johns Hopkins researchers have discovered a method to treat obesity by inhibiting phosphodiesterase type 9A (PDE9) activity in post-menopausal women who have reduced estrogen levels due to natural or medical causes. In women, a decline in estrogen levels is associated with depressed nitric oxide (NO) signaling – an important pathway implicated in maintaining metabolic homeostasis, body weight, and insulin sensitivity. NO efficacy has been shown to be restored with PDE9 inhibition. To this end, investigators challenged female mice that had undergone ovariectomies and had been exposed to a high-fat diet with a selective PDE9 inhibitor. Results showed that, with treatment, body weight declined by 20% due to a decrease in fat and increase in lean mass. In addition to the metabolic effects, the PDE9 inhibitor also significantly reduced cardiac mass (hypertrophy) and improved heart function ameliorating cardiac disease. This was accompanied by an increase in metabolic activity that decreased fat mass without regard to food intake or total activity.
 
Stage of Development
Animal model data are available.

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