How Gene Therapy Can Cure Blindness
It begins with difficulty seeing in dim-lit environments. Your night vision is significantly impaired. Then it evolves to having tunnel vision, unable to see in one’s peripheral views. Sooner or later, facial recognition and your ability to read is affected, and by age 40 you can no longer see and are legally blind. This is the progression of vision loss for people who have Retinitis Pigmentosa. Retinitis Pigmentosa (RP) is a group of rare inherited vision loss diseases that affects 1 in 3500 people in the world. It usually begins in childhood, but when it starts and the rate of how quickly it progresses varies by the individual.
What is Retinitis Pigmentosa Caused by?
The culprit for development of Retinitis Pigmentosa is a mutation in a gene. Researchers have found that mutations in over 60 genes can cause RP. RP can be inherited in an autosomal dominant, autosomal recessive, or an X-linked recessive pattern.
Quick Definitions:
Autosomal Dominant: only one parent needs to be a carrier for the mutated gene, for their child to develop the disease.
Autosomal Recessive: both parents need to be carriers for the mutated gene for their child to develop the disease.
X-linked Recessive: the female parent has an abnormal part of a gene on their X chromosome, and can pass it down to their children.
In our retinas, there are two kinds of photoreceptors, which are rods and cones. Rods and cones are cells that absorb and convert light into electrical signals our brains can interpret. 95% of photoreceptors in our eyes are rods, while cones make up 5% of them. Rods allow us to see in low light conditions, and cones allow us to see in high light conditions and are capable of color vision. Any mutation that causes retinitis pigmentosa results in a progressive loss of rods and cones, which causes progressive vision loss. The rods typically deteriorate before the cones, which is why the first indication of the disorder is the loss of night vision. When both rods and cones are lost, this is when daytime vision is lost.
How is RP Diagnosed?
RP is diagnosed through the exams electroretinogram (ERG), visual field testing and genetic testing. An ERG detects the amount of electrical activity present in the photoreceptors, and people with RP have decreased electrical activity, which demonstrates the loss of photoreceptors. A clinician may use a visual field test to map the central vision of a patient. The patient would push a button if they can see a light as it moves in a 180 degree circle. To confirm that a patient’s condition is RP, a clinician will take a DNA sample. This way, the patient can learn about the specific form of their disorder and how they can treat it in the future.
What Treatments Are There?
There’s no definite cure for retinitis pigmentosa, but researchers are hard at work trying to pave a way to it. A few treatments that can slow the progression of vision loss is Vitamin A Palmitate, a retinal implant or acetazolamide. Vitamin A palmitate may slow RP every year. However, there is some concern that taking high doses of it may be harmful. There’s a retinal implant called Argus II for late-stage RP patients, which is implanted into the eye and paired with glasses that have a camera. The glasses take in the images in front of the patient and convert them into electrical signals that can be sent to the retina and relayed to the brain. Acetazolamide has been shown to alleviate swelling and improve vision.
What New Research Is There for RP?
There are many gene therapies currently on the horizon, from companies AGTC, Janssen/MeiraGTx, Biogen and more, which strive to cure Retinitis Pigmentosa once and for all with a single administration of their medication. They do this by using a virus as a vehicle to transport a gene into the affected cells of the patient. The gene doesn’t integrate with the patient’s genome, but instead functions as a therapeutic device that produces the proteins the patient’s body is currently not producing, but still however needs in order to function normally. In the eyes of these researchers, RP is a curable disease.
The gene therapy being pioneered by Applied Genetic Technologies Corporation, or AGTC, is called AGTC-501, which uses a genetically engineered AAV vector that delivers a normal copy of the Retinitis Pigmentosa GTSse Regulator (RPGR) gene into a patient’s photoreceptors. This therapy specifically treats X-linked Retinitis Pigmentosa, which is an inherited disorder that affects boys. It is made up of the gene and a strategic promoter that has been selected to drive high gene expression in the rods and cones. It has been shown to maintain normal photoreceptor function and slow the progress of RP. The product was granted US FDA orphan drug designation in 2017.
Results from the Phase 1/2 trial of AGTC-501 demonstrated that at one year post-treatment, half of the patients who received a high dose of the therapy responded to the treatment favorably in terms of visual sensitivity and extent of visual acuity. And most importantly, the therapy was generally safe and tolerated well at all doses. Currently, machine learning algorithms and understanding of a patient’s characteristics at the baseline are being applied to ongoing clinical trials to identify patients who are most likely to respond to the therapy. AGTC is currently conducting a Phase 2/3 trial to further analyze clinical benefit and safety of the treatment.
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