The Ingenious Gene

Glaucoma is a devastating disease of the eye that is typically associated with aging. It’s the leading cause of blindness, along with cataracts, affecting 70 million people worldwide. Specifically, glaucoma comes from the deterioration of retinal nerve ganglion cells. There is currently no cure. For the first time, scientists at the Vision Institute (Sorbonne University) and the National Institute of Health and Medicine have prevented and reversed glaucoma in over 70 mice by injecting them with a single gene.

The ingenious gene that the scientific team injected into the glaucomatous mice is called Ngb, which codes for neuroglobin, a protein that is abundant throughout the brain and eye. Neuroglobin scavenges toxic reactive oxygen species (ROS) such as hydrogen peroxide, nitric oxide, and other radicals that corrode the body. It also protects the mitochondria — the cell’s smoky, ROS-ridden energy producer — in a host of ways. The Paris team showed how in glaucomatous retinal nerve cells, there is significant mitochondrial dysfunction as well as a 50 percent loss of neuroglobin. Unlike most other cells, they are highly dependent on mitochondria for energy supply, since they don’t have the fatty myelin sheath to insulate energy and boost synaptic signaling.

To deliver the Nbg gene into the mice, the scientists used an adeno-associated viral vector (AAV), a virus whose DNA has been removed and replaced with a gene of the scientist’s choice. The Ngb-filled AAV was then proliferated in the lab, and injected into the retina of 55 young mice (aged 2 months with a predisposition for glaucoma) and into 18 old mice (aged 8 months with developed glaucoma). The injected Ngb-AAV virus penetrated surrounding cells, and released its’ Ngb gene into the nuclei where unsuspecting RNA printed it into the eventual neuroglobin protein.

When the mice reached 12 months (their typical lifespan), the results were unprecedented: in all mice, Ngb neuroglobin doubled in their retinas. In mice treated at a young age, glaucoma never developed and their retinal ganglion cell numbers, visual cortex activity, and other vision markers were the same as that of young, healthy mice.

In mice that received the Ngb-AAV injection at the old age of 8 months, glaucoma was reversed: mitochondrial respiratory function, visual cortex activity, retinal cell function, and other vision markers were completely restored. Their retinal ganglion cell numbers, however, were the same as old healthy mice (only 34 percent of young healthy mice), indicating that the AAV didn’t replace cells that had died off with age.

Promising Research

Dr. Corral-Debrinkski, who heads the research team and is now based at the National Institute of Health and Medicine noted, “The data reached in this study is very promising not only for glaucoma but for many conditions in which mitochondrial function is impaired, including a wide range of optic nerve diseases and devastating neurological diseases such as cerebellar ataxias or leuokodystrophies.” Based on these results, her team plans to conduct human cell and primate studies before moving into human trials.

Over the last several years, adeno-associated viral vectors have been preferred over other vectors because of their lower immune response. AAV’s also tend to stabilize near chromosome 19, versus disrupting the DNA strand. They also cannot replicate with cell division. However, significant challenges remain: creating vectors that can avoid an immune response altogether, or can invade a large number of host cells, has not been easy. AAV’s are also tiny and can therefore only accommodate tiny genes. More research is also needed to determine long term toxicity. Even still, as scientists fine tune these masterful genetic envoys, unprecedented results have been achieved in such diseases as hemophilia B, sickle cell disease, muscle degeneration, and now vision.