Hypothalamic AAV-BDNF gene therapy improves metabolic function and behavior in the Magel2-null mouse model of Prader-Willi syndrome

AAV-BDNF gene therapy ameliorates a hypothalamic neuroinflammatory signature in the Magel2-null model of Prader-Willi syndrome

“…Previous work by our group showed that hypothalamic BDNF gene therapy improves metabolic and behavioral health in the Magel2 -null mouse model. 21 To pursue genetic signatures underlying these outcomes, we performed a similar short-term experiment and isolated hypothalamic tissue for downstream transcriptomic analyses. Female mice were injected with either AAV-YFP or AAV-BDNF vectors ( Figure 1 A) to the arcuate/ventromedial nuclei of the hypothalamus (ARC/VMH)—known sites of BDNF and pro-opiomelanocortin (POMC)/agouti-related peptide (AGRP) action.…”

“… 17 , 18 , 19 Previous work by our lab applied an adeno-associated virus (AAV) based BDNF gene therapy to Magel2 -null mice via hypothalamic injection to determine whether the vector could rescue metabolic function via the stimulation of various BDNF-related pathways. 21 Hypothalamic BDNF gene transfer prevented weight gain, improved body composition, and increased relative energy expenditure in female Magel2 -null mice. Moreover, BDNF gene therapy improved several measures of systemic metabolic function, including glucose metabolism, insulin sensitivity, and circulating adipokine levels.…”

“…MAGE Family Member L2 ( MAGEL2 ), is located within the PWS genetic region and its loss is thought to contribute to irregularities in energy homeostasis. 17 , 18 , 19 , 20 Magel2 -null mice mirror some aspects of PWS pathophysiology, including increased adiposity, 20 , 21 impaired glycemic control, 19 , 21 and alterations in neuroendocrine responses. 17 , 18 , 19 Previous work by our lab applied an adeno-associated virus (AAV) based BDNF gene therapy to Magel2 -null mice via hypothalamic injection to determine whether the vector could rescue metabolic function via the stimulation of various BDNF-related pathways.…”

“…Male Magel2 -null mice also benefited from BDNF gene therapy, displaying improved body composition, insulin sensitivity, and glucose metabolism. 21 …”

Novel chemical tyrosine functionalization of adeno-associated virus improves gene transfer efficiency in liver and retina

“…Gene therapy with viral vectors has been used in both preclinical and clinical settings to treat cardiovascular [1] , muscular [2] , metabolic [3] , neurological [4] , hematological [5] and ophthalmological [6] diseases, as well as infectious disorders [7] and cancers [8] . Owing to their non-pathogenic nature, low immunogenicity, ease of production, and the long-term persistence of transgene expression, recombinant adeno-associated viruses (rAAV) are one of the most widely used viral vector for in vivo gene therapy.…”