Gene therapy restores vision to blind mice

In 2007, Bo Chang, M.D., a Jackson Laboratory research staff scientist, together with collaborators at the University of Florida and State University of New York Upstate Medical University, reported that gene therapy can restore sight in mice (Alexander et al. 2007). This was the first time that cone cell-targeted gene therapy was used to correct cone cell-mediated electroretinogram (ERG) function and restore visual acuity.

Bo Chang, M.D.

Dr. Chang is director of the Eye Mutant Resource site at The Jackson Laboratory. The site describes mouse models for ocular research available from the Laboratory, updates the results from the Laboratory's screening program to identify genes and new mutations that affect vision, lists known mouse mutations that affect vision and presents current information on the cloning of vision-related genes.

The mouse and the mutant gene

For their landmark paper, the researchers used the ALS/LtJ strain (003072), which is homozygous for the spontaneous cone photoreceptor function loss 3 (Cpfl3) mutation in the guanine nucleotide binding protein (G protein), alpha transducing activity polypeptide 2 (Gnat2) gene. Dr. Chang and his staff discovered and identified the Gnat2cpfl3 mutation in 2004, while screening many strains of JAX® Mice for vision problems (Chang et al. 2006). Since then, the mutation has been identified in 13 other JAX® Mice strains (Table 1).

In humans, mutations in the orthologous GNAT2 gene give rise to complete achromatopsia, a cone cell disease resulting in permanent central vision loss, deficient cone cell-mediated ERG signals, color blindness, and a visual acuity of 20/200 or less. Because people with this disease have virtually no functioning cone cells, their rods become light-saturated, and they are extremely light-sensitive and blind during the day. The disease affects about 1 in 30,000 Americans. ALS/LtJ mice develop a similar phenotype.

Table 1. JAX® Mice strains with the Gnat2cpf3 mutation (confirmed by genotyping or complementation tests; Bo Chang M.D., pers. comm.).

Strain Name Stock Number

STOCK Tg(Fos-lacZ)34Efu/J


STOCK Tg(Trp53A135V)L3Ber/J


















STOCK Tg(tetO-Ipf1,EGFP)956.6Macd/J


STOCK Tg(Neurog3-cre)C1Able/J


STOCK fzica/McirJ


Vision restored

To restore vision in ALS/LtJ mice, the researchers inserted a vector containing the wild-type Gnat2 gene into the subretinal space of young ALS/LtJ mice. When the mice were 1-2 months old, their vision was tested. Of 21 treated eyes, 19 responded to the therapy, 17 of them exhibiting normal light-adapted ERG amplitudes. The vision of these mice was tested again when they were 6-7 months old. Of 21 treated eyes, 18 had recordable cone-mediated ERG signals;17 of those had normal ERG signals. In effect, normal light-adapted ERG responses were restored in 80% of the treated eyes. Similar results were obtained in a second group of mice tested on another ERG-measuring device, and in a third group of older (10-month old) mice injected with the wild-type gene when 9 months old.

Behavioral tests overseen by Dr. Robert B. Barlow, Professor of Ophthalmology at State University of New York Upstate Medical University, revealed that the visual acuity of treated mice was restored to normal. In the test, the mice were surrounded by four computer monitors that simulated the appearance of being inside a moving drum with vertical stripes on the walls. The researchers knew the mice could see the stripes because sighted animals naturally move their heads in the same direction as moving stripes. By making the stripes ever-narrower (similar to how letters are smaller at the bottom of an eye chart), the researchers were able to assess the mice's visual abilities. All the treated mice displayed normal visual acuity. Lead researcher Dr. John J. Alexander, postdoctoral fellow in the department of ophthalmology at the University of Florida, remarked: "People can talk and tell us what they see. Animals are much more difficult. What makes this test so fantastic is that it involves an animal's natural response, and the results tell us that the animal's brains are involved in the process - that they are actually seeing something (The Jackson Laboratory 2007)."

Implications for human sight

The results of this research demonstrate the feasibility of targeting cone cells to treat many common human vision disorders, including cone cell and cone-rod dystrophies, late-stage retinitis pigmentosa (in which cone cells are lost after most rods have degenerated), and the exudative forms of age-related macular degeneration and diabetic retinopathy (in which macular cone cell loss accompanies both macular edema and retinal neovascularization). William W. Hauswirth, Ph.D., Rybaczki-Bullard Professor of Ophthalmic Molecular Genetics and member of the University of Florida Genetics Institute, was also enthusiastic about the results: "Cone vision defines whether someone is blind or not. If you can usefully deliver a gene specifically to cone cells, there are implications for all blinding diseases, not just inherited ones. Even in two very common types of blindness, age-related macular degeneration and diabetic retinopathy, if you can target cones, you might be able to rescue that vision (The Jackson Laboratory 2007)."


Alexander JJ, Umino Y, Everhart D, Chang B, Min SH, Li Q, Timmers AM, Hawes NL, Pang JJ, Barlow RB, Hauswirth WW. 2007. Restoration of cone vision in a mouse model of achromatopsia. Nat Med 13:685-7.

Chang B, Dacey MS, Hawes NL, Hitchcock PF, Milam AH, Atmaca-Sonmez P, Nusinowitz S, Heckenlively JR. 2006. Cone photoreceptor function loss-3, a novel mouse model of achromatopsia due to a mutation in Gnat2. Invest Ophthalmol Vis Sci 47:5017-21.

The Jackson Laboratory. 2007. Vision cells light up in blind mice. Jackson Laboratory press release, May 22 (