The Role of Microglia in Prader-Willi Syndrome and a Hypothalamic Gene Therapy

Funding Summary

Recently, Dr. Cao validated the safety and efficacy of a novel brain-directed gene therapy (BDNF) for metabolic and behavioral deficits observed in a preclinical mouse model of PWS, and identified BDNF as a potential therapeutic target to treat metabolic and behavioral aspects of PWS. Follow-up studies by our group investigated the genetic profile of PWS-like mice and how the introduction of BDNF alters the expression of genes in the brain. Interestingly, PWS-like mice displayed a genetic profile showing inflammation and activation of the brain’s resident immune cells, microglia. Strikingly, BDNF gene therapy resulted in a reversal of the inflammatory phenotype, leading our group to wonder whether neuroinflammation and microglia might play a role in PWS. This study will assess whether microglia structure, function, and genetic profiles are altered within a PWS mouse model. Furthermore, this study will determine whether removal of microglia can prevent PWS-related metabolic dysfunction and if microglia modulation underlies the previously observed ability of BDNF gene therapy to address PWS symptoms. If successful, this work would be among the first to identify microglia as a new cellular population of interest in PWS and could eventually lead to development of new PWS therapeutic strategies targeting microglia and neuroinflammation. 

Dr. Theresa Strong, Director of Research Programs, explains the details of this project in this video clip.

Lay Abstract

Here, we will perform a study to expand upon previous FPWR-funded work performed by our lab. Recently, we validated the safety and efficacy of a novel brain-directed gene therapy for metabolic and behavioral deficits observed in a preclinical mouse model of PWS. Brain-derived neurotrophic factor (BDNF) was chosen as a therapeutic target because it works downstream of aberrant signaling pathways in PWS and previous work has shown that the PWS-related genetic profile in the brain may result from reduced BDNF. Independent of this work, BDNF has been studied for decades and its ability to induce beneficial metabolic and behavioral outcomes—including reduced fat mass, increased energy expenditure, reduced food intake, increased physical activity, improved blood sugar control, alleviation of fatty liver, reduced anxiety-like behavior, and reduced depression-like behavior—is well known. Our proof-of-concept study was successful and indeed identified BDNF as a potential therapeutic target to treat metabolic and behavioral aspects of PWS.
    Follow-up studies by our group investigated the genetic profile of PWS-like mice and how the introduction of BDNF alters the expression of genes in the brain. Interestingly, PWS-like mice displayed a genetic profile showing inflammation and activation of the brain’s resident immune cells, microglia. These preliminary results match data that are observed in humans with PWS. Strikingly, BDNF gene therapy resulted in a reversal of the inflammatory phenotype, leading our group to wonder whether neuroinflammation and microglia might play a role in PWS. This study will assess whether microglia structure, function, and genetic profiles are altered within a PWS mouse model. Furthermore, this study will determine whether removal of microglia can prevent PWS-related metabolic dysfunction and if microglia modulation underlies the previously observed ability of BDNF gene therapy to address PWS symptoms. If successful, this work would be among the first to identify microglia as a new cellular population of interest in PWS and could eventually lead to development of new PWS therapeutic strategies targeting microglia and neuroinflammation. Furthermore, this work may help researchers understand how BDNF works to induce therapeutic benefit.