Hyperphagia and the associated metabolic dysregulation is one of the greatest challenges that individuals with PWS and their families face on a daily basis. Dr. Cao has developed a gene therapy that targets the metabolic roots of PWS within the brain’s center for energy regulation. Their group has developed an approach using a single dose of a gene whose deficiency is associated with human obesity (Brain-derived neurotrophic factor, or BDNF). This gene therapy is highly effective in animal models of obesity but has not yet been tested in a PWS animal model. Here, Dr. Cao and team will assess this perform novel gene therapy approach for metabolic dysregulation in a PWS mouse model.
Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
Watch the full webinar describing all 9 research projects funded in this grant cycle here.
Through discussions with patient care advocates and clinicians, we understand that hyperphagia and the associated metabolic dysregulation is one of the greatest challenges that Prader-Willi Syndrome (PWS) patients and their caretakers face on a daily basis. Here, we propose a preclinical experiment to assess the viability of a novel gene therapy for metabolic dysregulation 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 this BDNF gene therapy is highly effective and well tolerated in diet-induced and genetic forms of obesity animal models. 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. Yet, this novel gene therapy has not been tested in a PWS animal model. Thus, we propose to perform the first-of-kind preclinical study in a PWS mouse model with a gene typically inactivated in PWS.
Up to date, the FDA has approved a limited number of gene therapy products in the US, among which two are based on a viral vector—AAV—for delivery of therapeutic gene to patients: Luxturna (Spark Therapeutics, Inc.) to treat a genetic retinal disorder in 2017, and Zolgensma (AveXis, Inc) to treat children with a rare genetic form of spinal muscular atrophy in 2019. Currently, hundreds of clinical trials are underway to test gene therapy as a treatment for genetic and acquired diseases, yet PWS has not been investigated. Our proposed study is important because it will allow researchers and the PWS community to understand whether this AAV-based, brain-targeting gene therapy to treat the metabolic symptoms of PWS is viable and well tolerated. This research also has the potential to reveal new insights and confirm previous findings observed in a common PWS mouse model; better characterization of the model will allow researchers to understand the degree to which the model can recapitulate human symptoms of PWS and be a valid proving ground for future preclinical work. If the first phase of this efficacy study is successful, we will seek renewal of the grant to assess dosing and long-term safety. Promising preclinical data in a mouse model will support additional safety assessment in larger animal such as dogs 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 animal model. If successful, this therapy could improve metabolic regulation and thus alleviate day-to-day pains 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.
Lei Cao, Ph.D.
The Ohio State University
Lei Cao, Ph.D.