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: Publications

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.

Search Projects

Donate for PWS Research