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The eye, it turns out, is an excellent laboratory in which to explore the possibilities and potential of various genetic therapies. It’s an extremely contained area with relatively small patches of affected tissue. It can also be accessed and monitored more easily than, say, a section of brain or heart tissue. Consequently, certain eye conditions may be among the earliest to be routinely treated and even cured using various gene and RNA therapies. In this installment of Vision Tech, we’ll discuss two companies that are currently or about to initiate clinical trials to treat a trio of such diseases: Usher syndrome type 2 (USH2), autosomal dominant retinitis pigmentosa (adRP), and Leber’s congenital amaurosis 10 (LCA10.).
Overview of Diseases
All three of the eye diseases mentioned above are caused by genetic defects or mutations, most often inherited. All three also affect the eyes rods and cones, the photoreceptor cells that turn light into chemical signals, which are then transformed into neural signals and passed up the optic nerve to the brain. The specific mechanisms of each of these eye conditions are different, however.
Usher Syndrome Type 2
Usher syndrome is the leading cause of deafblindness. Patients with USH2, the most common type of Usher syndrome, have a moderate to severe hearing impairment from birth and commonly experience the first symptoms of night blindness in their second decade of life, which progresses to complete blindness by the third or fourth decade. USH2 is most commonly caused by mutations in the USH2A gene. This gene is responsible for the formation of the usherin protein. The mutation results in a lack of functional usherin protein, and disrupts the ability of rods and cones to convert light into the electrical signals necessary for the brain to see.
Autosomal Dominant Retinitis Pigmentosa
adRP is a rare genetic eye disease caused when an individual inherits one normal copy and one mutated copy of the rhodopsin gene. The defective gene spurs the production of a form of rhodopsin that is actually toxic to photoreceptor cells, leading to their progressive degeneration, and ultimately, blindness. Symptoms usually begin with night blindness during childhood and progress to a loss of peripheral vision, leading to tunnel vision. Loss of central vision appears during adulthood and blindness is frequent by mid-adulthood.
Leber’s Congenital Amaurosis 10
LCA is a group of eye diseases that result from various mutations in at least 14 genes, all of which are necessary for normal vision. At least 13 different types of Leber’s congenital amaurosis have been described. The types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities. LCA is the most common cause of inherited childhood blindness, with an incidence of two to three per 100,000 live births worldwide. The most severe form of the disease, LCA10, is most often caused by the p.Cys998X mutation in the CEP290 gene.
ProQR Therapeutics is a Netherlands-based company currently researching RNA therapies to inhibit or counteract the harmful effects of the defective genes associated with the above retinal diseases. How does that work? As you may recall from biology class, genes are the building blocks for the proteins that build and maintain our bodies. They are located on chromosomes of which humans have 23 pairs, half from the mother and the other half from the father. In its simplest form, RNA acts as the blueprint for protein synthesis. The RNA “translates” the genetic information, then turns that information into various proteins, including the defective and toxic proteins associated with various retinal diseases.
“We’ve found a way to use tiny strands of artificial RNA, designed molecule by molecule to either block or modify these disease processes,” says ProQR Therapeutics CEO, Daniel de Boer. The company is currently engaging in clinical trials for an investigational medication called QR-421a, which is designed to treat RP in patients that have USH2 due to mutations in a specific part of the USH2A gene, called exon 13. “QR-421a is designed to exclude exon 13 from the USH2A mRNA, thereby removing the mutation,” says de Boer. This approach is also known as ment. Exon skipping. Skipping of exon 13 in the "blueprint" is expected to lead to a shortened but functional usherin protein. “By restoring functional usherin protein expression, we hope to treat the underlying cause of RP associated with USH2,” says de Boer.
A second new medication showing great potential for the treatment of inherited retinal disease is the company’s QR-1123. The compound is aimed at people who suffer from adRP due to the P23H mutation in the rhodopsin gene. “Our goal is to block the formation of the mutated toxic version of the rhodopsin protein by specifically binding to the mutated RHO mRNA,” says de Boer. “Binding of QR-1123 causes the degeneration of the mRNA by a mechanism called RNase H mediated cleavage. This should prevent the loss of the light detecting cells and potentially stop or reverse the vision loss associated with P23H adRP."
A third ProQR drug currently being tested is sepofarsen. This medication shows early potential to restore sight, or slow down the process of vision loss, in patients with Leber‘s congenital amaurosis 10 by correcting the most common p.Cys998X gene mutation associated with the retinal disease. The company recently released some impressive Phase 1 results. de Boer relates the story of one North American patient, “This man had been totally blind for over 15 years, but six weeks after a single injection of sepofarsen in one eye he called his physician to tell him he was walking through an airport, and he could read every sign.”
de Boer foresees an ultimate treatment that requires a single, maybe two injections per year. Currently the company is enrolling patients for a Phase 1/2 study for Usher syndrome type 2 and an ongoing Phase 2/3 “Efficacy and Safety Study” for Leber’s congenital amaurosis 10. The company also anticipates gearing up for a Phase 1/2 clinical trial for adRP in the coming months.
Cambridge, Massachusetts-based Editas Medicine is taking a different approach to treating LCA10. Instead of replacing the defective gene that produces the CEP290 protein that is essential for photoreceptor function, company scientists plan to “edit” the defective portion out of the chromosome using CRISPR technology.
CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, but basically, it’s cut and paste for chromosomes. Again, back to that biology class. You will recall that chromosomes are made of strands of DNA, which, in turn, are composed of various sequences of four bases: adenine guanine, cytosine, and thymine. The order of these bases define our genes which encode our proteins.
Building upon many years of research mapping out the human genome, researchers at Editas have created special enzymes that include strands of RNA that together with a bacterial protein, known as CAS9, seek out and specifically cut DNA. By using two of these cutting enzymes, EDIT-101 can remove a piece of DNA the contains the mutation which causes LCA10. Think of it as the “highlight and then cut” portion of cut and replace. New genetic information can now be inserted, or “pasted in,” if desired, though in the case of LCA10 removing the mutated piece of DNA is the end goal.
“Following cutting, the cell has a natural mechanism for repairing DNA breaks,” says Editas Medicine’s Chief Scientific Officer, Charles Albright. “In this case [the repair will occur] without the gene mutation that causes LCA10.”
Until now most gene editing therapies have accomplished this cut-and-paste outside the body, and then delivered the edited cell back into the body. Editas is actually editing cells inside the body. “Our goal is to inject the CRISPR machinery into the eye itself, using a tiny bit of an inactive virus as a delivery tool, and enable the cut and splice to occur within the defective retinal tissue, says Albright.
After successful animal studies the FDA has cleared Editas Medicine in partnership with Allergan to commence a Phase 1/2 interventional study of their experimental, CRISPR genome editing medicine called EDIT-101. Notes Albright, “EDIT-101 will be the very first CRISPR editing treatment to take place in vivo, which is to say inside the body.”
This article is made possible in part by generous funding from the James H. and Alice Teubert Charitable Trust, Huntington, West Virginia.
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