Gene therapy in patient-specific stem cell lines and a preclinical model of retinitis pigmentosa with membrane frizzled-related protein defects

Yao Li, Wen Hsuan Wu, Chun Wei Hsu, Huy V. Nguyen, Yi Ting Tsai, Lawrence Chan, Takayuki Nagasaki, Irene H. Maumenee, Lawrence A. Yannuzzi, Quan V. Hoang, Haiqing Hua, Dieter Egli, Stephen H. Tsang

Research output: Contribution to journalArticlepeer-review

Abstract

Defects in Membrane Frizzled-related Protein (MFRP) cause autosomal recessive retinitis pigmentosa (RP). MFRP codes for a retinal pigment epithelium (RPE)-specific membrane receptor of unknown function. In patientspecific induced pluripotent stem (iPS)-derived RPE cells, precise levels of MFRP, and its dicistronic partner CTRP5, are critical to the regulation of actin organization. Overexpression of CTRP5 in naive human RPE cells phenocopied behavior of MFRP-deficient patient RPE (iPS-RPE) cells. AAV8 (Y733F) vector expressing human MFRP rescued the actin disorganization phenotype and restored apical microvilli in patient-specific iPS-RPE cell lines. As a result, AAV-treated MFRP mutant iPS-RPE recovered pigmentation and transepithelial resistance. The efficacy of AAV-mediated gene therapy was also evaluated in Mfrprd6/ Mfrprd6 mice-an established preclinical model of RP-and long-term improvement in visual function was observed in AAV-Mfrp-treated mice. This report is the first to indicate the successful use of human iPS-RPE cells as a recipient for gene therapy. The observed favorable response to gene therapy in both patient-specific cell lines, and the Mfrprd6/Mfrprd6 preclinical model suggests that this form of degeneration caused by MFRP mutations is a potential target for interventional trials.

Original languageEnglish (US)
Pages (from-to)1688-1697
Number of pages10
JournalMolecular Therapy
Volume22
Issue number9
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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