Gene Therapy of Obesity in Prader-Willi Syndrome by an Autoregulatory BDNF Vector (Year 2)

Funding Summary

Dr. Cao has been developing a gene therapy approach that addresses the major symptoms of PWS, through the delivery of a gene that modulates metabolism and behavior (Brain-derived neurotrophic factor, or BDNF). In her 2nd year of funding, her team will assess whether this single-dose viral gene therapy into brain improves metabolism and behavior in a PWS mouse model. This study will determine if this gene therapy approach is feasible and well tolerated, and if it can positively impact PWS metabolism, activity and behavior.

Lay Abstract

Here, we propose a preclinical study to assess the viability and safety of a novel viral gene therapy for metabolic dysregulation and aberrant behaviors in a PWS mouse model. This therapy targets the metabolic roots of PWS within the brain’s center for energy regulation by introducing a gene whose deficiency is associated with human obesity (Brain-derived neurotrophic factor, or BDNF). A single dose of BDNF gene therapy is highly effective and well tolerated in several PWS-adjacent animal models of obesity. The metabolic benefits of BDNF manifest in reduced fat mass, increased energy expenditure—despite no change in food intake or a reduction in food intake, increased physical activity, improved blood sugar control, alleviation of fatty liver and other obesity-related metabolic syndromes. Despite previous successes in adjacent models, this novel gene therapy has not been tested in a PWS-relevant animal model. Here, we propose to perform a first-of-kind preclinical gene therapy study in a PWS mouse model using a gene typically inactivated in PWS. This study will assess whether this gene therapy improves PWS-aberrant metabolism and behavior. To date, the FDA has approved a limited number of gene therapy products—two of which utilize the same class of viral vectors used in this study—for delivery of therapeutic genes to patients: Luxturna (Spark Therapeutics, Inc., 2017) to treat a genetic retinal disorder and Zolgensma (AveXis, Inc., 2019) to treat spinal muscular atrophy. Currently, hundreds of clinical trials are underway to test gene therapy as a treatment for genetic and acquired diseases. This study is important because it will allow the PWS community to determine whether this brain-targeting gene therapy is viable and well tolerated. Promising preclinical mouse data will support additional safety assessments in larger animals—like rats or nonhuman primates—prior to human clinical trials. In sum, this project attempts to evaluate the therapeutic efficacy of a gene therapy in a PWS-relevant animal model. If successful, this therapy could improve metabolic regulation and thus alleviate day-to-day challenges relating to PWS patient eating habits, physical activity, obesity, etc. Previous work suggests that this method may provide therapeutic gains over other treatment methods due to the observed long-term, sustained expression of our vector following a single therapeutic administration.

Research Outcomes: Public Summary

Our study was designed to determine whether a brain-directed gene therapy could resolve metabolic dysfunction in the Magel2-null mouse model of PWS. BDNF (brain-derived neurotrophic factor) was chosen as a molecular target due to its known roles in neuronal development, energy homeostasis, and behavior. Moreover, previous work suggested individuals with PWS exhibit reduced gene expression of hypothalamic BDNF and its receptor, NTRK2 (encoding TrkB), and lower circulating levels of BDNF in plasma.
Female Magel2-null mice exhibited a positive response, as BDNF gene transfer prevented weight gain, improved body composition, and enhanced other metrics of metabolic performance. Interestingly, we also observed an improvement in several behavioral outcomes relating to exploratory behavior, cognition, and depression. Male Magel2-null mice largely mirrored female observations. Together, our data suggest that regulating hypothalamic BDNF could be effective in the treatment of PWS-related metabolic and behavioral abnormalities. Overall, the gene therapy was well tolerated and effective. To our knowledge, this work represents the first published gene therapy attempt in a PWS-relevant model.
Subsequent work by our group has identified that Magel2-null mice exhibit a baseline level of hypothalamic inflammation that mirrors human observations. Interestingly, BDNF gene therapy reverses this neuroinflammatory signature. Additional work by our group will continue this line of thinking to determine whether microglia, a brain-residing immune cell, contribute to PWS phenotypes.

Research Outcomes: Publications

AAV-BDNF gene therapy ameliorates a hypothalamic neuroinflammatory signature in the Magel2-null mouse model of Prader-Willi syndrome. Queen NJ, Huang W, Zou X, Mo X, Cao L. Molecular Therapy: Methods & Clinical Development (2023), doi: j.omtm.2023.09.004.

Hypothalamic AAV-BDNF gene therapy improves metabolic function and behavior in the Magel2-null mouse model of Prader-Willi syndrome. Queen NJ, Zou X, JM, Huang W, Appana B, Komatineni S, Wevrick R, Cao L.  Molecular Therapy Methods & Clinical Development (2022):

Funded Year:


Awarded to:

Lei Cao, Ph.D.




The Ohio State University


Lei Cao, Ph.D.

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