Yao, X., Liu, X., Zhang, Y., Li, Y., Zhao, C., Yao, S., Wei, Y.Q. (2017) Gene Therapy of Adult Neuronal Ceroid Lipofuscinoses with CRISPR/Cas9 in Zebrafish. Human gene therapy. 28(7):588-597.
Adult-Onset Neuronal Ceroid Lipofuscinosis (ANCL), one of the neuronal ceroid lipofuscinosis (NCLs), is an inherited neurodegenerative disorder with progressive neuronal dysfunction. Recently, mutations in DNAJC5 gene that encodes Cysteine-String protein Alpha (CSPα) have been reported to be associated with familial Autosomal-Dominant ANCL (AD-ANCL). Here, we constructed an ANCL transgenic zebrafish model expressing human mutant DNAJC5 (mDNAJC5) gene under the control of a zebrafish neuron-specific promoter. To investigate whether gene therapy based on genome-editing technology could treat ANCL, we designed a panel of TALEN and Cas9 nucleases to disrupt the mDNAJC5 gene in this transgenic animal model. By screening these nucleases, we found one nuclease that targeted 5' coding region efficiently alleviated mDNAJC5 protein aggregates in the affected neurons. Therefore, our study provides a gene therapy strategy via the use of the CRISPR/Cas9 system to treat neural genetic diseases.