PUBLICATION

Gene Therapy of Adult Neuronal Ceroid Lipofuscinoses with CRISPR/Cas9 in Zebrafish

Authors
Yao, X., Liu, X., Zhang, Y., Li, Y., Zhao, C., Yao, S., Wei, Y.Q.
ID
ZDB-PUB-170510-15
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.
Abstract
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping