Miniature Gene Tool ‘TIGRa’ Prevents Vision Loss in Mice

A miniature gene-activation tool has been developed, and in experiments in mice it partially prevented vision loss caused by retinal diseases such as glaucoma.

Researchers at Stanford Medicine said on the 31st (local time) that they had developed TIGRa, pronounced “tiger A,” which is much smaller than existing gene-regulation tools. The findings were published in the international journal Cell Stem Cell.

TIGRa is a tool that finds target genes inside cells and increases their expression. It performs the same function as existing CRISPR-based gene-activation tools, but is less than half their size, making it easier to package in a viral vector and deliver to cells in the body.

The researchers used TIGRa to activate two protective genes in retinal ganglion cells in mice. Retinal ganglion cells are optic nerve cells damaged in glaucoma and retinal degenerative diseases.

Two weeks later, after the mice were subjected to retinal damage that causes blindness, mice treated with TIGRa retained about one-third of their vision. By contrast, untreated mice were nearly blind.

“TIGRa injection doubled the survival rate of retinal ganglion cells,” the researchers said, adding that “the effects on preserving retinal structure and protecting vision were pronounced.” The therapeutic effects persisted even after four months.

TIGRa is based on the TIGR-Tas enzyme system discovered last year by the Broad Institute in the United States. Like CRISPR, it is derived from microbes and uses a guide RNA to find a specific region of DNA.

The researchers confirmed in laboratory cells that TIGRa can activate up to 12 different genes simultaneously. It also switched on all seven genes needed to reprogram adult fibroblasts into induced pluripotent stem cells in an embryonic state.

When they tested nine target genes, the researchers found that TIGRa was more efficient than existing CRISPR activation tools for six of them. They also confirmed its effects on genes involved in retinal degeneration, congenital muscular dystrophy and obesity.

The researchers have filed a patent application for the tool. Yang Sun, a professor of ophthalmology at Stanford Medicine, said, “Because it is small and versatile, it could be used for a range of diseases, including heart, liver and skin diseases, cancer, neurodegeneration and stroke.” He added, “If the right gene is targeted for the appropriate disease, it could be applied more quickly than other gene therapies.”

However, the researchers estimated that it could be several more years before the approach is used to treat retinal degeneration in humans. Dr. Liu Zhiquan explained, “Neurodegenerative diseases are very complex, and better results will require regulating more genes in different combinations.”