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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

Blocking retinoic acid receptor could prolong vision in patients with retinal degeneration

‘Noise’ produced by retinal ganglion cells as a result of photoreceptor cell death in diseases such as retinitis pigmentosa prevents processing of further light input from the surviving photoreceptors. This results in vision loss when the person still has active light-sensitive photoreceptor cells. UC Berkeley researchers have identified retinoic acid receptor as a new target; blocking it using gene therapy reduced the noise and enhanced vision in retinitis pigmentosa mice models.

Photoreceptor degeneration in retinitis pigmentosa triggers hyperactive firing of retinal ganglion cells (RGCs), blocking surviving photoreceptors from transmitting signal into the brain. The reason for this hyperactivity was largely unknown. In the present study published in Neuron, researchers have identified retinoic acid (RA) signaling through its receptor (RAR) as the mechanism behind it.

Increasing RAR signaling in healthy retinas mimics the pathophysiology of degenerating retinas. Using a drug to inhibit RAR reduced hyperactivity in degenerating retinas and regained the action of surviving photoreceptors in vision-impaired mice. Also, a gene therapy approach using an AAV vector to deliver an inactive version of RAR, successfully blocked RA signal transduction and hyperactivity in ganglion cells in vision-impaired mice.

Thus, this study discovers RAR as the trigger for hyperactivity and presents a novel therapeutic target for enhancing low vision in retinitis pigmentosa and other blinding disorders. Interventions that prevent RA signaling reverse hyperactivity, thereby improving impaired vision. Blocking RAR using drugs or gene therapy could potentially extend the period of useful vision in those with degenerative eye diseases.

Prof. Richard Kramer, principal investigator of the study at UC Berkeley said in a statement: “This isn’t a cure for these diseases, but a treatment that may help people see better. This won’t put back the photoreceptors that have died, but maybe give people an extra few years of useful vision with the ones that are left,” said “It makes the retina work as well as it possibly can, given what it has to work with. You would maybe make low vision not quite so low.”

Source: Retinoic acid induces hyperactivity, and blocking its receptor unmasks light responses and augments vision in retinal degeneration. Telias M et al., Neuron, March 2019. DOI

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