Gene therapy injected into eye may fix FA vision problems: Study
Experimental treatment preserved structure, function of retina in mouse models
An experimental gene therapy injected directly into the eye preserved the structure and function of the retina — the light-sensitive tissue at the back of the eye — in mouse models of Friedreich’s Ataxia (FA), according to a proof-of-concept study.
These data support “continued efforts toward the development of a gene therapy to target FA-associated vision loss,” researchers wrote in the study, “Development of an AAV-Based Gene Therapy for the Ocular Phenotype of Friedreich’s Ataxia,” which was published in Molecular Therapy.
New gene therapy targets FA-related eye symptoms
Beyond the neuromuscular symptoms of FA, many patients experience vision problems or even blindness caused by damage to the optic nerve, which transmits visual information from the nerve cells in the retina to the brain.
Several gene therapies are currently under development to deliver a working version of the FXN gene, whose mutations cause FA. However, their routes of administration are designed to address the heart and nervous system manifestations of FA and may not reach the eyes to correct vision problems.
Instead, researchers in the U.S. and the Czech Republic have now developed and tested a more direct gene therapy approach to treat FA-related eye symptoms.
First, the team generated new mouse models to mimic FA-related vision problems and assess the effectiveness of their gene therapies. Models were created by deleting FXN in all retinal cells or only in retinal ganglion cells (RGCs), the nerve cells in the retina that connect to form the optic nerve.
Packaged in a modified adeno-associated virus (AAV), the gene therapy delivered a healthy version of the FXN gene via intravitreal injection into the gel-like substance that fills the eye.
One month after injection, the researchers observed significant preservation of all retinal layers in mice with retinal-wide FXN deletion compared with untreated controls, which developed early-onset retinal degeneration. At two months post-injection, the retina was significantly thicker overall.
Our study establishes proof-of-concept for an intravitreally injected, AAV-based approach for addressing the retinal phenotype of FA and supports continued efforts [toward] the development of a gene therapy to target FA-associated vision loss.
Despite improvements in retinal structure following gene therapy, the function of rods or cones, the photoreceptor cells in the retina, as well as the electrical nerve response of the retina to light, were similar between treated and untreated eyes.
“This lack of functional rescue is likely attributed to the early, retina-wide depletion of FXN in these mice,” the team noted.
The team then focused on the mouse model in which FXN is selectively absent in RGCs, which more closely resembles the nerve cells affected in FA patients. In these mice, degeneration was observed in multiple retinal layers, primarily in the inner retina, and was accompanied by a significant decline in retinal function and response to visual stimuli.
One to three months post-injection, gene therapy appeared to preserve multiple retinal layers and improve RGC function compared with control mice. Still, no differences were noted in the function of rods and cones or visually guided behavior.
“Our study establishes proof-of-concept for an intravitreally injected, AAV-based approach for addressing the retinal phenotype of FA and supports continued efforts [toward] the development of a gene therapy to target FA-associated vision loss,” the researchers wrote.
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