An RNA-editing gene therapy has been developed that switches off the key driver of common eye conditions affecting diabetics and the elderly. The researchers behind the innovative treatment say that it’s an alternative to the current treatment: regular injections of medication directly into the eye.
Diabetic retinopathy is a vision-threatening complication that affects 22% of diabetics worldwide. However, treatment is fairly limited. One of the most effective treatments is regular injections of medication into the eye to stabilize and improve vision. These eye injections are also used to treat age-related macular degeneration (AMD), also called ‘wet’ AMD.
Now, new research led by the Center for Eye Research Australia (CERA) and the University of Melbourne has developed a next-generation gene therapy – the editing of a person’s RNA – that could replace regular eye injections as a treatment for these eye diseases that affect millions.
“Our study shows the potential of RNA editing to develop gene therapies that offer an alternative treatment to the invasive, frequent eye injections that are currently used to treat wet macular degeneration and diabetic eye disease,” said Associate Profession Guei-Sheung (Rick) Liu, head of genetic engineering research at CERA and the study’s senior author.
In diabetic retinopathy and AMD, the body overproduces a protein called vascular endothelial growth factor (VEGF). This protein causes blood vessels in the eye to leak fluid and blood, leading to swelling in the retina, the structure at the back of the eye that turns light into signals the brain can use. Too much VEGF can also cause blood vessels to grow abnormally, which can damage the eye.
Anti-VEGF medications block the production of the protein and can improve vision. However, they currently need to be administered via an intravitreal injection, which is an injection directly into the eye’s jelly-like fluid or vitreous. Treatment requires regular injections, usually monthly for many months; sometimes, patients need the injections for the rest of their lives.
The researchers considered developing a gene therapy as an effective alternative to these regular eye injections. For the first time, they used the RNA editing tool CRISPR-Cas13 to suppress the production of VEGF in mouse models and human retinal cells derived from stem cells.
Gene therapy uses modified viruses or other tech to deliver therapeutic genes to cells or tissues, addressing genetic diseases at their source. CRISPR-Cas9 is renowned for its DNA-targeting abilities. Cas9, or CRISPR-associated protein 9, is an enzyme that uses CRISPR sequences as a guide to recognize and cut apart specific DNA strands. In contrast, the CRISPR-Cas13 system offers the ability to interfere with protein-producing RNA.
“RNA editing enables us to change the genetic instructions that influence the way cells behave without permanently altering their DNA,” said Satheesh Kumar, a PhD student at CERA and the lead author of the study. “This could allow treatments to be adjusted over time, depending on clinical need.”
Using an adeno-associated virus (AAV) as a delivery system, the researchers’ gene therapy targeted the messenger RNA (mRNA) sequence that instructs cells to produce VEGF. Administration of the therapy to human retinal cells significantly reduced VEGF production and, in the mouse models, slowed disease progression.
“Although this research is in the early discovery stages and requires further development before transitioning to clinical trials, we envision that RNA editing could become a viable alternative to invasive and costly eye injections that have become a fact of life for many people living with wet macular degeneration or diabetic eye disease.”
The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).
Source: CERA
