SUN-687 - Metabolic and skeletal outcomes of a novel AAV serotype-mediated hypothalamic BDNF gene therapy in the Magel2-null mouse model of Prader-Willi syndrome

Introduction: Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by the lack of expression of paternally inherited genes in the 15q11.2-q13 region. PWS patients display developmental delays, cognitive impairment, excessive eating, central obesity, hypothalamic hypogonadism, obsessive compulsive behavior, and temper tantrums. Additionally, affected individuals often experience significant skeletal complications, including early-onset osteoporosis, increased fracture risk, and scoliosis. Up to date, effective and sustained treatments are limited to address metabolic and skeletal dysregulations, highlighting the urgent need for new therapeutic strategies. Our previous research has demonstrated that a hypothalamic adeno-associated virus (AAV) serotype 1-based brain-derived neurotrophic factor (BDNF) gene therapy normalized metabolic disturbance in the Magel2-null mouse model of PWS with high levels of efficacy and safety.

Methods: To facilitate clinical translation, we used a newly developed engineered AAV serotype vector (V1) as a vehicle for BDNF gene therapy to reduce the dose 10-fold lower than that used in previous preclinical studies in Magel2-null mice. Female Magel2-null mice and wildtype littermates, 6-8 months of age, were randomized to receive either V1-GFP or V1-autoregulatory BDNF via stereotaxic injection to the hypothalamus (1x10^9 viral genome/side, bilateral injection). Efficacy and safety assessments mirrored previous studies. Weekly body weight, endpoint tissue mass, body composition, glucose tolerance, and serum leptin level were measured for metabolic phenotyping. Bone and bone marrow adipose tissue (BMAT) were assessed with uCT and osmium staining.

Results: V1-BDNF gene therapy normalized genotype-driven metabolic abnormalities, including excessive body weight, increased adiposity, impaired glucose tolerance, and hyperleptinemia. V1-BDNF with a dose of 2x10^9 vg/mouse achieved therapeutic effects equivalent to AAV1-BDNF dosed at 2x10^10 vg/mouse. Additionally, V1-BDNF gene therapy also normalized genotype-driven trabecular bone gain and bone marrow adipose tissue expansion. Interestingly, V1-BDNF gene therapy decreased the cortical thickness and bone area independently of genotype, suggesting a potential negative effect of V1-BDNF gene therapy on bone strength associated with weight.

Conclusion: The newly developed V1 vector enhances the efficiency of BDNF gene therapy by 10-fold with a similar improvement of metabolic phenotypes, suggesting the V1 serotype might be a promising vector system for BDNF gene therapy to treat PWS. However, the overall effect of hypothalamic AAV-BDNF gene therapy on skeletal health requires further investigation.

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