Prader-Willi Syndrome (PWS) is a rare (Prevalence: 1-9/100000; ORPHA:739) neurodevelopmental disorder caused by genetic defects on chromosome 15 (15q11-q13). In PWS, the loss of expression of paternally inherited genes causes severe symptoms such as neurodevelopmental delays, cognitive and social behavior deficits, hyperphagia/obesity, as well as various disturbances in the rhythms of sleep and wakefulness. This parent-of-origin genetic mechanism, namely genomic imprinting, emerged during evolution of placental mammals and accumulated pivotal functions in organismal homeostasis, brain functions and sleep-wake behaviors. To date, a number of imprinted diseases present with neurodevelopment consequences such as social and cognitive deficits, and sleep-wake disorders. For many of them there is only little understanding of the biological mechanisms, which negatively impact on the development of proper interventions. For individuals with PWS, there is no current pharmacological treatment that is able to ameliorate social, cognitive and sleep deficits. However, we have recently identified an appealing mechanism, related to the neurotransmitter GABA in the brain, which acts through chloride (Cl)-permeable neuronal receptors. In particular, we found upregulation of the Cl importer NKCC1 in a mouse model of another neurodevelopmental disorder characterized by cognitive and sleep deficits (i.e., Down syndrome). This mechanism, common also to autism -a neurodevelopmental disorder which presents social and sleep disturbances- and other brain disorders, promises to reveal a novel understanding of how some of the core symptoms of many neurodevelopmental disorders are generated. The results of our investigation in identifying a pharmacological treatment for this brain defect (i.e., NKCC1 upregulation), lead to a clinical trial for the repurposing of an FDA-approved (NKCC1 inhibitor and diuretic) drug, bumetanide in individuals with Down syndrome. A constantly increasing body of preclinical and clinical literature is showing that bumetanide is a promising drug treatment for a number of other neurodevelopmental disorders, but also neurological and neurodegenerative disorders. Recently, we have gained preliminary evidence (unpublished) in the Cancedda and Tucci labs that a similar NKCC1 upregulation is present also in a mouse model of PWS (i.e., Snord116 mouse). Moreover, we report preliminary results showing that bumetanide is able to rescue general cognitive deficits in the Snord116 mutants. The goal of this new proposal is to test the ability of bumetanide treatment to rescue social, cognitive and sleep symptoms in Snord116 mice, which are relevant to the human PWS pathology. As bumetanide has been extensively used in patients as a diuretic in the past, it is orally active and it is very economical, we will test here its effects in preclinical mouse models, so to explore a novel therapeutic approach that has the potential to be translated in a clinical trial for individuals with PWS. As a complementary investigation, we will explore the side effects and potential biomarkers of bumetanide treatment in PWS mice. Finally, we will search for the presence of NKCC1 upregulation in post-mortem samples of individuals with PWS, as a proof of concept of the validity of our therapeutic approach also in humans. Bumetanide treatment represents a safe pharmacological approach for inhibiting NKCC1, and we believe that this could rescue specific behavioral abnormalities in PWS. This approach is based on a clinically tested drug, which represents an innovative therapeutic strategy in the field of neurodevelopment, with a high potential to be rapidly translated into clinical practice for programs aimed at ameliorating social, cognitive and sleep defects in individuals with PWS.
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Treatment of social, cognitive, and sleep impairment in a mouse model of Prader- Willi syndrome by repurposing of the FDA-approved diuretic Bumetanide.
Total budget: 100.000,00€
Total contribution: 100.000,00€