Hypothalamic AAV-BDNF gene therapy improves metabolic function and behavior in the Magel2-null mouse model of Prader-Willi syndrome

Individuals with Prader-Willi syndrome (PWS) display devel-opmental delays, cognitive impairment, excessive hunger, obesity, and various behavioral abnormalities. Current PWS treatments are limited to strict supervision of food intake and growth hormone therapy, highlighting the need for new thera-peutic strategies. Brain-derived neurotrophic factor (BDNF) functions downstream of hypothalamic feeding circuitry and has roles in energy homeostasis and behavior. In this preclinical study, we assessed the translational potential of hypothalamic adeno-associated virus (AAV)-BDNF gene therapy as a thera-peutic for metabolic dysfunction in the Magel2-null mouse model of PWS. To facilitate clinical translation, our BDNF vec-tor included an autoregulatory element allowing for transgene titration in response to the host's physiological needs. Hypotha-lamic BDNF gene transfer prevented weight gain, decreased fat mass, increased lean mass, and increased relative energy expen-diture in female Magel2-null mice. Moreover, BDNF gene therapy improved glucose metabolism, insulin sensitivity, and circulating adipokine levels. Metabolic improvements were maintained through 23 weeks with no adverse behavioral effects, indicating high levels of efficacy and safety. Male Magel2-null mice also responded positively to BDNF gene ther-apy, displaying improved body composition, insulin sensitivity, and glucose metabolism. Together, these data suggest that regu-lating hypothalamic BDNF could be effective in the treatment of PWS-related metabolic abnormalities.