Noninvasive gene delivery to foveal cones for vision restoration

JCI Insight. 2018 Jan 25;3(2):e96029. doi: 10.1172/jci.insight.96029.


Intraocular injection of adeno-associated viral (AAV) vectors has been an evident route for delivering gene drugs into the retina. However, gaps in our understanding of AAV transduction patterns within the anatomically unique environments of the subretinal and intravitreal space of the primate eye impeded the establishment of noninvasive and efficient gene delivery to foveal cones in the clinic. Here, we establish new vector-promoter combinations to overcome the limitations associated with AAV-mediated cone transduction in the fovea with supporting studies in mouse models, human induced pluripotent stem cell-derived organoids, postmortem human retinal explants, and living macaques. We show that an AAV9 variant provides efficient foveal cone transduction when injected into the subretinal space several millimeters away from the fovea, without detaching this delicate region. An engineered AAV2 variant provides gene delivery to foveal cones with a well-tolerated dose administered intravitreally. Both delivery modalities rely on a cone-specific promoter and result in high-level transgene expression compatible with optogenetic vision restoration. The model systems described here provide insight into the behavior of AAV vectors across species to obtain safety and efficacy needed for gene therapy in neurodegenerative disorders.

Keywords: Gene therapy; Genetic diseases; Ophthalmology; Surgery; Therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • Cell Line
  • Dependovirus / genetics
  • Female
  • Fovea Centralis / diagnostic imaging
  • Fovea Centralis / pathology*
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage*
  • Genetic Vectors / genetics
  • Humans
  • Induced Pluripotent Stem Cells
  • Injections, Intraocular
  • Intravital Microscopy
  • Macaca fascicularis
  • Male
  • Mice
  • Models, Animal
  • Optogenetics / methods
  • Patch-Clamp Techniques
  • Promoter Regions, Genetic / genetics
  • Transduction, Genetic / methods*
  • Transgenes / genetics
  • Vision Disorders / genetics
  • Vision Disorders / pathology
  • Vision Disorders / therapy*