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New MiniPromoter Ple345 (NEFL) Drives Strong and Specific Expression in Retinal Ganglion Cells of Mouse and Primate Retina.

  • Simpson, Elizabeth M1, 2, 3, 4
  • Korecki, Andrea J1
  • Fornes, Oriol1, 2
  • McGill, Trevor J5, 6
  • Cueva-Vargas, Jorge Luis7
  • Agostinone, Jessica7
  • Farkas, Rachelle A1
  • Hickmott, Jack W1, 2
  • Lam, Siu Ling1
  • Mathelier, Anthony1, 2
  • Renner, Lauren M5
  • Stoddard, Jonathan5
  • Zhou, Michelle1
  • Di Polo, Adriana7
  • Neuringer, Martha5, 6
  • Wasserman, Wyeth W1, 2
  • 1 1 Centre for Molecular Medicine and Therapeutics at BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada. , (Canada)
  • 2 2 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. , (Canada)
  • 3 3 Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada. , (Canada)
  • 4 4 Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada. , (Canada)
  • 5 5 Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon.
  • 6 6 Department of Ophthalmology, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon.
  • 7 7 Department of Neuroscience and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, Québec, Canada. , (Canada)
Published Article
Human Gene Therapy
Mary Ann Liebert
Publication Date
Mar 01, 2019
DOI: 10.1089/hum.2018.118
PMID: 30062914


Retinal gene therapy is leading the neurological gene therapy field, with 32 ongoing clinical trials of recombinant adeno-associated virus (rAAV)-based therapies. Importantly, over 50% of those trials are using restricted promoters from human genes. Promoters that restrict expression have demonstrated increased efficacy and can limit the therapeutic to the target cells thereby reducing unwanted off-target effects. Retinal ganglion cells are a critical target in ocular gene therapy; they are involved in common diseases such as glaucoma, rare diseases such as Leber's hereditary optic neuropathy, and in revolutionary optogenetic treatments. Here, we used computational biology and mined the human genome for the best genes from which to develop a novel minimal promoter element(s) designed for expression in restricted cell types (MiniPromoter) to improve the safety and efficacy of retinal ganglion cell gene therapy. Gene selection included the use of the first available droplet-based single-cell RNA sequencing (Drop-seq) dataset, and promoter design was bioinformatically driven and informed by a wide range of genomics datasets. We tested seven promoter designs from four genes in rAAV for specificity and quantified expression strength in retinal ganglion cells in mouse, and then the single best in nonhuman primate retina. Thus, we developed a new human-DNA MiniPromoter, Ple345 (NEFL), which in combination with intravitreal delivery in rAAV9 showed specific and robust expression in the retinal ganglion cells of the nonhuman-primate rhesus macaque retina. In mouse, we also developed MiniPromoters expressing in retinal ganglion cells, the hippocampus of the brain, a pan neuronal pattern in the brain, and peripheral nerves. As single-cell transcriptomics such as Drop-seq become available for other cell types, many new opportunities for additional novel restricted MiniPromoters will present.

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