This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: The ability to precisely adjust the expression of genes inside the human body—ramping up protective ones and tamping down harmful ones—holds enormous potential for treating and preventing disease. But the standard molecular tools used to tune genes, such as the CRISPR system, are too bulky to package and deliver into the body's cells.
When delivered by viral vectors, for example, which are packed with the DNA instruction manual for cells to build CRISPR themselves, the lengthy instructions for CRISPR hardly fit inside a single virus. For therapies that may require adjusting multiple genes, delivering multiple CRISPR components separately becomes complicated and inefficient. Now, Stanford Medicine scientists have developed a travel-size solution—an ultracompact gene activation tool, called TIGRa (pronounced "tiger A"), small enough that its short DNA instructions can be packed inside viral vectors with room to spare.
The study is published in the journal Cell Stem Cell. Similar to CRISPR-based gene activation tools, once inside the cell, TIGRa finds the target gene and recruits the cell's transcriptional machinery to ramp up expression of that sequence. But compared with its CRISPR counterparts, TIGRa is more versatile regarding which genes it can target and more efficient at activating multiple genes at once.
In a mouse model, the researchers used TIGRa to turn up two protective genes in retinal ganglion cells, the nerve cells in the eye that are damaged in glaucoma and other retinal degenerative conditions. When the retinal ganglion cells were injured, the mice that received the treatment retained partial vision; those that did not became nearly blind. "This is a tool that can be used to activate genes that otherwise lie dormant in our bodies," said Yang Sun, MD, professor of ophthalmology and senior author of the study.
Sun's lab studies the cellular biology of glaucoma and other eye disorders. The eye is an ideal testing ground for gene activation therapies—a relatively accessible organ with clear signals. "It's easier to measure whether the eye is able to see than whether the liver is working," he said.
"In the visual system, you can tell right away." TIGRa is based on a system of gene-targeting enzymes known as TIGR-Tas discovered only last year by researchers at the Broad Institute of the Massachusetts Institute of Technology and Harvard University. Similar to the CRISPR-Cas system (often referred to simply as CRISPR), TIGR-Tas was discovered in microbes: CRISPR evolved in bacteria as an immune system that snipped and stored pieces of DNA from infectious viruses; TIGR-Tas evolved in parasitic bacteria and viruses, perhaps as a competitive genetic weapon, though its function is not yet clear. Both are RNA-guided, DNA-targeting systems, meaning they use a snippet of guide RNA like a mug shot to find and cut a matching piece of DNA.
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