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Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2021)

Haploinsufficiency, having only one functional gene copy, is associated with close to 100 autism spectrum disorder (ASD) risk genes. Here, using SCN2A haploinsufficiency, a major ASD risk condition, we show that CRISPR activation (CRISPRa) of the existing functional copy at adolescent stages provides a viable therapeutic approach. First, we demonstrate the potential for a therapeutic to rescue electrophysiological deficits in mice by utilizing heterozygous Scn2a conditional knockin mice. Next, using an AAV-based CRISPRa approach, we rescue these electrophysiological deficits in Scn2a heterozygous mice and human SCN2A heterozygous excitatory neurons. Our results provide a novel therapeutic approach for numerous ASD-associated genes and also suggest that rescue Scn2a function, even in relatively mature developmental stages, could ameliorate neurodevelopmental phenotypes.

    Cover page: Development of a CRISPR activation-based approach for the treatment of SCN2A haploinsufficiency in Autism Spectrum Disorder
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2019)
    A wide range of human diseases result from haploinsufficiency, where the function of one of the two gene copies is lost. Here, we targeted the remaining functional copy of a haploinsufficient gene using CRISPR-mediated activation (CRISPRa) in Sim1 and Mc4r heterozygous mouse models to rescue their obesity phenotype. Transgenic-based CRISPRa targeting of the Sim1 promoter or its distant hypothalamic enhancer up-regulated its expression from the endogenous functional allele in a tissue-specific manner, rescuing the obesity phenotype in Sim1 heterozygous mice. To evaluate the therapeutic potential of CRISPRa, we injected CRISPRa-recombinant adeno-associated virus into the hypothalamus, which led to reversal of the obesity phenotype in Sim1 and Mc4r haploinsufficient mice. Our results suggest that endogenous gene up-regulation could be a potential strategy to treat altered gene dosage diseases.
      Cover page: CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2020)
        Cover page: Rapid deployment of SARS-CoV-2 testing: The CLIAHUB
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