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The Genes Have It

Posted by Ilena Di Toro | Posted on March 1, 2022

Genetic research has revealed many things about eye diseases. Two studies in particular have revealed how gene variants in inherited retinal dystrophies (IRDs), such as retinitis pigmentosa, lead to these diseases and how gene therapy can help preserve vision.

Whole-Genome Sequences
Researchers at the University of California San Diego School of Medicine and at Shiley Eye Institute at UC San Diego Health did whole-genome sequences (WGS) of 409 people from 108 unrelated family lineages, each with a diagnosed IRD. The participants came from three geographic regions: Mexico, Pakistan and European Americans living in the U.S. The WGS provides a wide-ranging view of the person’s entire genome, which includes mutations and variants.

This study identified a large portion of new IRD causative mutation specific to the populations studied and it showed the typed of mutations that contributed to inherited retinal dystrophies. About 13 percent of the families in the study had atypical changes in the genome. Five of the lineages had mutation in more than one gene and one family had mutations in different genes in different affected members. In addition, a new mutation was found in one person that was not found in both parents. It was also found that eight percent of the families had large changes in the structure of their genome that caused IRD and the initial clinical diagnosis was changed based on their genotype.

The study’s authors said that these findings increase the understanding of the distribution of the IRD mutations in these populations and that also increases the understanding of disease variation and presentation. That will help in designing more efficient genetic testing strategies and genetic therapies.

Gene Therapy to Combat Vision Loss
Scientist are doing more than just mapping out genes. Scientists at University of California, Berkeley are looking to see if either a drug or gene therapy can help those with IRD’s hold on to functional vision for as long as possible. Researchers in the lab of neuroscientist Richard Kramer, a professor of molecular and cell biology at UC Berkeley, are working to reduce the “noise” generated by nerve cells in the eye. This noise interferes with vision in the same way tinnitus interferes with hearing. This approach has been shown to improve vision in mice with retinitis pigmentosa.

Researchers have known for many years that retinal ganglion cells, which are the cells that connect to the vision center in the brain, generate static as the photoreceptors start to die. Since the sharp edges of an image are overcome by such static, the brain isn’t able to interpret the image.

Kramer’s lab is focused on the role of retinoic acid, since it is linked to eye changes resulting from retinal degeneration. The photoreceptors are filled with proteins called opsins. Each opsin combines with a molecule of retinaldehyde to form a light-sensitive protein called rhodopsin. Once the photoreceptors start dying, the retinaldehyde is free to turn into other things, like retinoic acid. This acid floods the retina and stimulates the retinal ganglion cells to make more retinoic acid receptors. These receptors make the retinal ganglion cells hyperactive, which creates activity that stifles the image in question. This prevents the brain from picking out the visual signal from the noise.

The idea is to hamper the receptor for retinoic acid, reverse the process and shut off the hyperactivity. Researchers used both drugs known to block the receptor and gene therapy in mice with retinitis pigmentosa, in both cases, the mice behaved like normal sighted mice.

“This isn’t a cure for these diseases, but a treatment that may help people see better.” said Kramer. “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.”

Research for both projects show that there is more than one way to develop treatments for IRDs. Either by looking at the person’s genome to develop therapies or by studying if gene therapy or drugs can preserve vision, these projects aim to increase treatment options and improve outcomes for people with IRDs.


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