rAAV-CRISPRa therapy corrects Rai1 haploinsufficiency and rescues selective disease features in Smith-Magenis syndrome mice |
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Authors: | Hao-Cheng Chang Yu-Ju Lee Sehrish Javed Minza Haque Ya-Ting Chang Yu Cheng Lin Cameron Oram Wei-Hsiang Huang |
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Affiliation: | 1.Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, McGill University, Québec, Canada;2.Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montréal, Québec, Canada |
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Abstract: | Haploinsufficiency in retinoic acid induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), a severe neurodevelopmental disorder characterized by neurocognitive deficits and obesity. Currently, curative treatments for SMS do not exist. Here, we take a recombinant adeno-associated virus (rAAV)-clustered regularly interspaced short palindromic repeats activation (CRISPRa) approach to increase expression of the remaining intact Rai1 allele. Building upon our previous work that found the paraventricular nucleus of hypothalamus plays a central role in SMS pathogenesis, we performed paraventricular nucleus of hypothalamus–specific rAAV-CRISPRa therapy by increasing endogenous Rai1 expression in SMS (Rai1±) mice. We found that rAAV-CRISPRa therapy rescues excessive repetitive behavior, delays the onset of obesity, and partially reduces hyperphagia in SMS mice. Our work provides evidence that rAAV-CRISPRa therapy during early adolescence can boost the expression of healthy Rai1 allele and modify disease progression in a mouse model of Smith-Magenis syndrome. |
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Keywords: | CRISPR activation gene therapy mouse models neurodevelopmental disorders retinoic acid induced 1 Smith-Magenis syndrome |
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