Researchers Develop New Gene Therapy Approach for Treating Congenital Blindness

Researchers Develop New Gene Therapy Approach for Treating Congenital Blindness

Researchers at Ludwig-Maximilians-Universität München in Germany have identified new potential targets for retinitis pigmentosa, one of the most common causes of congenital blindness.

Retinitis pigmentosa is one of the most common inherited retinopathies, affecting 1 in 3,500 to 1 in 4,000 people in the United States and Europe. In Germany, where the research was conducted, 40,000 people suffer from the condition.

Retinitis pigmentosa can be caused by mutations in many different genes and involves the loss of photoreceptors in the retina. The severity of the condition can vary from patient to patient depending on the cause. In mild cases, affected individuals may only have night blindness, but in more severe cases there can be progressive loss of vision, which in the most severe cases can cause total blindness. There are gene therapies available, but they are not effective at treating all causes of retinitis pigmentosa.

Gene therapy can be used to replace the defective copy of a gene with an intact version of the fully functional gene. Alternatively, it may be possible to correct a mutation that is causing the disease, without replacing the entire gene. The first option is only possible with a limited number of genes, while the second option is prohibitively expensive, as the therapy needs to be tailored for each patient.

The Ludwig-Maximilians-Universität researchers, led by Dr. Elvir Becirovic at the Department of Pharmacology of Natural Sciences, used a new approach using a form of CRISPR-Cas9 to activate genes to compensate for the hereditary genetic defect. These genes are normally suppressed but have a similar function to those carrying the mutation that causes retinitis pigmentosa.

“Our idea was to compensate for the mutant gene’s loss of function by specifically activating genes that have a similar function but are normally not expressed in retinal cells,” says Becirovic. “To do so, we delivered a system called Cas9-VPR into the affected retinal cells.”

The researchers tested their new approach in a mouse model of retinitis pigmentosa, where the mice lacked rhodopsin, the light-sensitive protein expressed in the rod cells in the retina that is necessary for vision in low light conditions. The researchers introduced Cas9-VPR and the guide RNA using a dual rAAV vector system to activate genes closely related to the gene that codes for rhodopsin. While this approach does not correct the defect that causes retinitis pigmentosa, the researchers were able to compensate for the missing rhodopsin function in the rod cells and improve retinal function.

The researchers report long term activation of the targeted genes with no detected adverse effects. This approach could potentially be used to treat retinitis pigmentosa in humans and could also potentially be used to compensate for defective genes in other genetic diseases.

You can read more about the study in the paper – A gene therapy for inherited blindness using dCas9-VPR–mediated transcriptional activation – which was recently published in the journal Science Advances. DOI: 10.1126/sciadv.aba5614

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