When it comes to our health, an ounce of prevention is worth is a pound of cure. Yet, despite a person’s best efforts, he or she could develop age related macular degeneration or retinitis pigmentosa. Is there a way to fix the internal mechanisms that lead to vision loss or even repair what is damaged to the point of vision restoration? Research at Louisiana State University (LSU) Health New Orleans, and the Board Institute of the Massachusetts Institute of Technology and Harvard University demonstrate that these two things are possible.
Protein Mechanisms
Scientists at LSU Health New Orleans’ Neuroscience Center of Excellence identified a new mechanism that regulates a protein vital for cell survival. This is known as Elovanoid-34, and it controls the activity of the TXNRD1 protein. This protein starts the process of oxidative stress, which occurs when there is an imbalance between free radicals and antioxidants that work to neutralize them. This imbalance can lead to tissue damage and start of diseases. Elovanoid-34 protects against excessive oxidative stress, which precedes the development of neurodegenerative diseases of the brain and eye.
Researchers screened 130,000 protein sequences that correspond to over 4700 proteins and found that only one changed its structure when it came into contact with Elovanoid-34. They discovered that TXNRD1 is a fundamental component of the antioxidant system Glutathione and that it targets a regulator of ferroptosis, a kind of cell death. This cell death occurs in age-related macular degeneration, where the retinal pigment epithelial cells succumb to oxidative stress conditions. Elovanoid-34 can prevent the retinal pigment epithelial cells from dying, stopping retinal degeneration that leads to blindness. This protein discovery may lead to targeted therapies for age-related macular degeneration, as well as age-related diseases, stroke, ALS, while promoting healthy aging.
Fixing Genetic Mutations
What if the problem lies the genes? Specifically, is it possible to correct mutation at the genetic level? Scientists at the Broad Institute of the Massachusetts Institute of Technology and Harvard University were able to correct disease-causing mutations in mice.
Scientists used engineered virus-like particles to deliver prime editors—a form of gene editing that can correct most disease-causing genetic mutations—into the eyes of mice that had genetic blindness. They were able to partially restore the mice’s vision. The scientists adapted the virus-like particles to carry base editors capable of making precise changes to the DNA.
This is the first time such therapeutic editing of DNA in animals has been accomplished, and while the results are promising, they came with challenges. The prime editing system has three parts, a Cas9 protein that makes a small cut in the DNA, an engineered prime editing guide RNA, known as pegRNA, that identifies the location of the edit and contains the new edited sequence to install at that location and a reverse transcriptase that uses the pegRNA as a template to make specific DNA changes.
Traditionally, virus-like particles used to deliver genetic material yielded modest outcomes. In this study, the scientists re-engineered both virus-like particles and the prime editing machinery, improving the delivery and editing systems’ efficiency. While the improvements led to small increases in the prime editors’ efficiency, the sum of the changes lead to a 100-fold improvement of the virus-like particles, compared to their initial versions. The next step is to testing this on other animals.
The system was tested in mice to correct two different genetic mutations in the eyes. One mutation, in the gene Mfrp, causes retinitis pigmentosa, which leads to retinal degeneration. The other mutation, in the gene Rpe6, is associated with Leber congenital amaurosis, which causes blindness. The engineered virus-like particles corrected both types of mutations in approximately 20 percent of the animals’ retina cells and partially restoring their vision.
Researchers also demonstrated that the virus-like particles containing the editing machinery can edit genes in the brains of living mice. In fact, almost half of the cell in the cortex of the brains of mice that received the editing machinery showed a gene edit. Of course, more research is necessary in order to minimize side effects and adapt the technology for use in other parts of the body.
Learning more about the proteins that lead to oxidative stress can lead to therapies that effectively treat age related macular degeneration. Developing ways to edit genes in living organisms can provide treatments for retinitis pigmentosa and Leber congenital amaurosis. Both advancements could significantly improve the quality of life for people with these diseases.