Rescue of M-cone Function in Aged Opn1mw-/- Mice, a Model for Late-Stage Blue Cone Monochromacy

Invest Ophthalmol Vis Sci. 2019 Aug 1;60(10):3644-3651. doi: 10.1167/iovs.19-27079.


Purpose: Previously we showed that AAV5-mediated expression of either human M- or L-opsin promoted regrowth of cone outer segments and rescued M-cone function in the treated M-opsin knockout (Opn1mw-/-) dorsal retina. In this study, we determined cone viability and window of treatability in aged Opn1mw-/- mice.

Methods: Cone viability was assessed with antibody against cone arrestin and peanut agglutinin (PNA) staining. The rate of cone degeneration in Opn1mw-/- mice was quantified by PNA staining. AAV5 vector expressing human L-opsin was injected subretinally into one eye of Opn1mw-/- mice at 1, 7, and 15 months old, while the contralateral eyes served as controls. M-cone-mediated retinal function was analyzed 2 and 13 months postinjection by full-field ERG. L-opsin transgene expression and cone outer segment structure were examined by immunohistochemistry.

Results: We showed that dorsal M-opsin dominant cones exhibit outer segment degeneration at an early age in Opn1mw-/- mice, whereas ventral S-opsin dominant cones were normal. The remaining M-opsin dominant cones remained viable for at least 15 months, albeit having shortened or no outer segments. We also showed that AAV5-mediated expression of human L-opsin was still able to rescue function and outer segment structure in the remaining M-opsin dominant cones when treatment was initiated at 15 months of age.

Conclusions: Our results showing that the remaining M-opsin dominant cones in aged Opn1mw-/- mice can still be rescued by gene therapy is helpful for establishing the window of treatability in future blue cone monochromacy clinical trials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Animals
  • Arrestins / genetics
  • Color Vision Defects / genetics
  • Color Vision Defects / physiopathology
  • Color Vision Defects / therapy*
  • Dependovirus
  • Disease Models, Animal
  • Electroretinography
  • Gene Expression Regulation / physiology
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Parvovirinae / genetics
  • Retina / physiopathology
  • Retinal Cone Photoreceptor Cells / physiology*
  • Rod Opsins / genetics*
  • Rod Opsins / physiology*


  • Arrestins
  • Rod Opsins
  • arrestin 4 protein, mouse
  • long-wavelength opsin
  • middle-wavelength opsin

Supplementary concepts

  • Adeno-associated virus-5
  • Blue cone monochromatism