September 18 is Usher Syndrome Awareness Day. To bring attention to the debilitating condition that renders patients blind and deaf, Mass Eye and Ear researchers Zheng-Yi Chen, DPhil, and Qin Liu, MD, PhD, lent their expertise on the condition and explained a novel gene editing technique potentially capable of producing a long-sought-after cure.
Usher syndrome is a hereditary condition responsible for nearly half of all deaf-blindness cases. According to the National Institute on Deafness and Other Communication Disorders, anywhere between four to 17 of every 100,000 people have Usher syndrome.
The rare condition has a disastrous effect on the quality of life of thousands of individuals worldwide. There is no cure for the blindness and hearing loss caused by the condition, which varies in severity depending on the type of Usher syndrome. Most patients depend on occupational therapy, and few are fortunate enough to have hearing levels restored by a hearing device.
Focus caught up with Dr. Zheng-Yi Chen, an associate scientist in the Eaton-Peabody Laboratories, and Dr. Qin Liu, a member of the Harvard Medical School and Mass Eye and Ear Ocular Genomics Institute, to discuss what causes the disease, why it’s so hard to treat, and why there’s reason to believe a treatment could one day become available.
“Some goals for researchers have been to develop a one-sized-fits-all approach or to use precision medicine to treat patients with Usher syndrome,” Dr. Liu said. “Mass Eye and Ear is in a unique position to develop and test new therapies thanks to its cross functional research between our ophthalmology and otolaryngology departments.”
What causes Usher syndrome?
Photoreceptors in the eye and hair cells in the ear are responsible for seeing and hearing, respectively. These photoreceptors and hair cells rely on an array of proteins, including a protein called usherin, to transmit sights and sounds to the brain.
A person is born with Usher syndrome when a mutation in the genome results in defective Usher proteins that adversely affect these photoreceptors and hair cells. The ensuing vision loss, deafness and, in rarer cases, imbalance, are the symptoms of Usher syndrome.
Dr. Liu says the severity and progression of each of these symptoms varies. As a result, there are three different types of Usher syndrome; but everyone with Usher syndrome develops retinitis pigmentosa (RP), an incurable genetic disease that damages the retina located in the back of the eye. Some patients begin to lose their vision as children or teenagers, while others experience more moderate loss of sight in middle age and may maintain good reading vision until their 60s.
Currently there are at least 11 genes that have been identified to be responsible for Usher syndrome.
“Knowing which genes cause Usher syndrome by genetic testing plays a vital role in predicting the disease progression as well as developing treatments for Usher syndrome patients,” added Dr. Liu.
Why is Usher syndrome so hard to treat?
The vast majority of Usher syndrome patients have either Usher syndrome type 1 or type 2. Dr. Liu estimates that more than a half of people with Usher syndrome have a mutation in the USH2A gene, one of the largest genes in the human body. While gene therapy has emerged as a potential pathway for treatment, the massive size of the USH2A gene makes it almost impossible for conventional gene therapies to work.
Dr. Chen says that traditional gene therapies rely on vectors, such as adeno-associated viruses (AAV), to transport corrected versions of a gene into a cell in hopes of repairing the faulty version. A typical vector can transport up to 5 kilobase (kb) of a gene. The size of the USH2A gene, however, is 15 kb; more than three times the capacity of a typical vector.
“It’s nearly impossible for us to use vectors because of the sheer size the mutated gene responsible for Usher 2A,” Dr. Chen said. “It’s not as easy as fixing a single mutation, either. It’s fixing and repairing countless mutations that exist on the genome.”
Is there a treatment for Usher syndrome on the horizon?
Drs. Liu and Chen are developing a new type of gene editing strategy called exon skipping, that could lead to a breakthrough in Usher syndrome 2A treatment. The technique uses CRISPR/Cas9 editing tools to bypass small chunks of a gene, known as exons, so that the body can produce a slightly shortened, albeit effective, version of the usherin protein needed to restore the function of photoreceptors and hair cells in Usher 2A patients.
Think of exon skipping in of the context of baking a chocolate cake, except the recipe contains hundreds of steps with dozens of faulty instructions scattered throughout. In one instance, the recipe step might call for hamburger meat and, later, a bag of jellybeans. By this analogy, traditional AAV gene therapies would attempt to fix the recipe by adding missing ingredients to correct the mistakes, whereas exon skipping would edit the faulty instructions in the recipe so that it skips over faulty steps, resulting in a tasty cake.
“The translational possibilities of exon skipping are endless,” Dr. Chen said. “This technique could trailblaze treatments that extend well beyond Usher syndrome and impact other debilitating conditions that stem from mutations on massive genomes. It has already been applied to diseases such as Huntington’s disease and genetic muscular dystrophy, both of which result from mutations on large sequences of genes.”
How close is this technique to entering the clinic?
Drs. Liu and Chen are currently working to implement exon skipping in animal studies. They have successfully skipped over an exon in the USH2A gene, which produced a protein that corrected cell- or tissue-specific defects caused by a loss of usherin protein in a mouse model of Usher 2A. They successfully demonstrated that their strategy could be used to rescue vision and hearing in the animal model. Through a partnership with a biotech company, Dr. Liu hopes one day this treatment can be moved to a clinical trial.
For exon skipping to work in humans, researchers would need to test its efficacy in human hair cells and photoreceptors. Organoids, or artificial cells and tissues grown from stem cells, has given Dr. Chen reason to believe exon skipping could move from the bench to the bedside more quickly. By developing human organoids that mimic the hair and retinal cells of an Usher syndrome patient, researchers could perform controlled experiments on exon skipping without testing the technique on a live patient.
“I truly believe that given how fast research and technology are progressing, we can achieve efficient and efficacious exon skipping,” Dr. Chen said. “With these resources at our disposal, we can continue to refine and test the technique until it’s been nearly perfected. Because of this, there’s no telling what we can accomplish in the next decade.”