ZFIN ID: ZDB-PUB-170510-15
Gene Therapy of Adult Neuronal Ceroid Lipofuscinoses with CRISPR/Cas9 in Zebrafish
Yao, X., Liu, X., Zhang, Y., Li, Y., Zhao, C., Yao, S., Wei, Y.Q.
Date: 2017
Source: Human gene therapy   28(7): 588-597 (Journal)
Registered Authors: Li, Yuhao, Yao, Shaohua, Zhang, Yaguang
Keywords: none
MeSH Terms:
  • Aging/pathology*
  • Animals
  • Animals, Genetically Modified
  • Base Sequence
  • CRISPR-Cas Systems/genetics*
  • Disease Models, Animal
  • Female
  • Genetic Therapy*
  • HSP40 Heat-Shock Proteins/genetics
  • Humans
  • Male
  • Membrane Proteins/genetics
  • Neuronal Ceroid-Lipofuscinoses/genetics*
  • Neuronal Ceroid-Lipofuscinoses/therapy*
  • Neurons/metabolism
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Transcription Activator-Like Effector Nucleases
  • Zebrafish/genetics*
  • Zebrafish Proteins/genetics
PubMed: 28478735 Full text @ Hum. Gene Ther.
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 (CSPĪ±) 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.