General Research News
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How do you keep up to date on current research related to your specific Usher mutation? This is a hub for all Usher syndrome research updates, including progress information for each subtype, cell-based therapy approaches, current clinical trials, natural history studies and relevant publications.
When Kevin Booth started his thesis at the University of Iowa, there were 10 genes linked to Usher syndrome, including the CIB2 gene (USH1J). Interested in understanding whether mutations in the CIB2 gene cause Usher, he started his investigation in the Molecular Otolaryngology and Renal Research Laboratory with Professor Richard J. Smith. Working with clinicians and collaborators, Booth identified and examined the results of thousands of patients with the CIB2 mutation. The in-depth examinations revealed that patients had perfectly healthy retinas and no balance issues but the genetic evidence refuting CIB2’s role in Usher syndrome was not enough for Booth. Along with a team of scientists from the Institut Pasteur in Paris, Booth utilized a comprehensive approach, which included phenotyping, cutting edge genomic technologies, murine mutant models, and functional assays, that showed mutations in CIB2 do not cause Usher syndrome.
What this means for Usher Syndrome: This means that CIB2 does not cause Usher syndrome and USH1J is no longer considered a subtype of Usher syndrome. Parents of deaf children with mutations in CIB2 will no longer be told that their child will also develop retinitis pigmentosa. The counseling that these families will receive after the genetic results will change accordingly.
Cedars-Sinai, a non-profit healthcare organization based in Los Angeles, has received authorization from the FDA to launch a 16-person, Phase 1/2a clinical trial of human neural progenitor cells—stem cells that have almost developed into neural cells—for patients with retinitis pigmentosa (RP). The trial will be launched after investigators receive the final institutional review of the study protocol. The trial is being funded by a $10.5 million grant from the California Institute for Regenerative Medicine. The initial study was conducted by Dr. Shaomei Wang, MD, PhD, a professor of Biomedical Sciences and a research scientist in the Eye Program at the Board of Governors Regenerative Medicine Institute. He showed that human neural progenitor cells have the potential to treat RP. The clinical trial will be directed by Dr. Clive Svendsen, PhD, professor of Biomedical Sciences and Medicine and director the Cedars-Sinai Board of Governors Regenerative Medicine Institute. Dr. David Lao, MD, from Retina-Vitreous Associates Medical Group in Beverly Hill, will be responsible for the subretinal injection of the cells into patients. The ultimate goal of this therapy is to restore the vision by replacing the defective photoreceptors.
What this means for Usher syndrome: This means that more potential stem-cell based treatments are becoming available to treat Usher patients. Since photoreceptors are the main cell group affected in Usher syndrome, the possibility of successfully replacing them with healthy cells give hope to patients that are losing their sight. Still we need to be careful and wait for the results of this new clinical trial.
This study used the highly sensitive RNAscope in situ hybridization assay and single-cell RNA-sequencing techniques to investigate the distribution of Clrn1 and CLRN1 in mouse and human retina respectively. The pattern of Clrn1 mRNA cellular expression is similar in both mouse and adult human retina, with CLRN1 transcription being localized in Müller glia and photoreceptors. The study generated a novel knock-in mouse with a hemagglutinin (HA) epitope-tagged CLRN1 and showed that CLRN1 is expressed continuously at the protein level in the retina. Following enzymatic de-glycosylation and immunoblotting analysis, scientists detected a single CLRN1-specific protein band in homogenates of mouse and human retina, consistent in size with the main CLRN1 isoform. Taken together, their results implicate Müller glia in USH3 pathology, for future mechanistic and therapeutic studies to prevent vision loss in this disease.
What this means for Usher syndrome: As shown in previous studies of the USH1C protein in zebrafish, Müller glia, in addition to photoreceptors, may be involved in Usher syndrome.
Wake Forest Institute for Regenerative Medicine (WFIRM) scientists have fine-tuned their delivery system to send a DNA editing tool to alter DNA sequences and modify gene function. With this new method, researchers can package together the Cas9 protein and guide RNA for the CRISPR mediated gene editing. Previously, the two components—Cas9 protein and guide RNA—had to be delivered separately which was not as efficient. The new system offers the delivery efficiency of conventional lentiviral vectors that enable transient Cas9 expression. Transient Cas9 expression means a decrease chance of having unwanted effects when using this therapy.
What this means for Usher syndrome: For Usher patients, improving the efficacy of CRISPR technology means that they will be able to receive a more efficient treatment with very low side-effects.
Case Western Reserve University (CWRU) and Boston-based genetic medicine company Akouos have entered into an exclusive licensing agreement to develop a patented gene therapy that could potentially treat hearing loss associated with a type of Usher syndrome. It may be able to stop the progression of hearing loss and prevent deafness in people with USH3A. The hearing loss is “sensorineural,” meaning it is caused by abnormalities of the inner ear, while the vision is due to the degeneration of the retina at the back of the eye. The technology has allowed researchers to develop a more precise animal model of the hearing loss associated with Usher syndrome type 3A, and the potential for the technology to deliver the preservation of hearing and quality of life for children and adults diagnosed with the genetic disorder.
What this means for Usher syndrome: The development of a more precise animal model for USH3A will exponentially expedite the identification of novel and more efficient therapies to slow or complete stop the progression of this disease.
As part of the Human Cell Atlas Project, Australian scientists created the world’s most detailed gene map of the human retina. Dr. Wong says, “By creating a genetic map of the human retina, we can understand the factors that enable cells to keep functioning and contribute to healthy vision.” The map provides a detailed gene profile of individual retinal cell types that will help us study how those genes impact different kinds of cells. Scientists can have a clear benchmark to assess the quality of the cells derived from stem cells to determine whether they have the correct genetic code which will enable them to function.
What this means for Usher syndrome: By having this atlas of healthy cells and their interconnections, researchers will be able to predict the effect of different drugs to treat eye diseases, including Usher syndrome.
The birth control pill has been found to contain a compound which gives long-term protection against two degenerative eye diseases – glaucoma and retinitis pigmentosa (RP), according to recent research from University College Cork (UCC) scientists in Ireland. The eye protective compound was discovered during a search through all the compounds approved by the FDA for treatment of people with eye diseases. The UCC scientists have found that norgestrel in animal models can provide protection against some common degenerative diseases of the eye.
What this means for Usher syndrome: Based on this study, norgestrel therapy will be a good alternative approach for the prevention of photoreceptor cell death in Usher patients.
Researchers in Germany have recently developed a “retina-on-a-chip” which combines living human cells with an artificial tissue-like system. The scientists describe their work as “merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human Retina-on-a-Chip platform.” Ophthalmologic drugs largely rely on animal models, which often do not provide results that are translatable to human patients. In this study, researchers present the retina-on-a-chip (RoC), a novel microphysiological model of the human retina integrating more than seven different essential retinal cell-types derived from human induced pluripotent stem cells (hiPSCs).
What this means for Usher syndrome: this model can be used to test hundreds of drugs for harmful effects on the “human” retina very quickly and enables scientists to take stem cells from a specific patient and study both the disease and potential treatment in the individual’s own cells.
CRISPR (clustered regularly interspaced palindromic repeats) is a cutting-edge genetic editing technique that enables the targeting and editing of specific sequences in the human DNA. CRISPR is known to result in unwanted gene edits that can occur when working with embryos. However, if the edits are done on adult humans and children, no transference occurs, and any potential damage remains to one individual. Allergan and Editas Medicine EDIT, a pharmaceutical company in Cambridge, Massachusetts, has announced in July they are ready to enroll subjects into its first of its kind CRISPR-based therapy trials, a development that would involve gene editing inside the human body. A propriety EDIT-101 injection is administrated into the eye to deliver “gene-altering machinery” directly to the photoreceptor cells. Once injected, EDIT-101 cuts out the mutated DNA, including CEP290 gene responsible for progressive photoreceptor-cell loss, which leads to an inherited type of blindness, Leber congenital amaurosis 10. The goal is for this cut to be repair by the DNA-repairing process that will lead to the expression of the normal protein.
What this means for Usher syndrome: potential treatments for vision loss are being discovered every day. In this case, the use of CRISPR technology will help to replace and repair mutations present in the Usher proteins and thus, help to restore vision as well as hearing.
In a new study of patients with Retinitis Pigmentosa, the Keck School of Medicine of USC researchers have found that adapted augmented reality (AR) glasses can improve patients’ mobility by 50% and grasp performance by 70%. Utilizing a different approach by employing assistive technology to enhance natural senses, the team adapted AR glasses that project bright colors onto patients’ retinas, corresponding to nearby obstacles.
What this means for Usher syndrome: we can improve the quality of life for patients with low vision due to retinitis pigmentosa through the use of augmented reality technology.
Drug repurposing is a new and attractive aspect of therapy development that could offer low-cost and accelerated establishment of new treatment options. The enzyme poly-ADP-ribose-polymerase (PARP) has important roles for many forms of DNA repair and it also participates in transcription, chromatin remodeling and cell death signaling. Currently, some PARP inhibitors are approved for cancer therapy, by means of canceling DNA repair processes and cell division.
Excessive PARP activity is also involved in neurodegenerative diseases including the currently untreatable and blinding retinitis pigmentosa group of inherited retinal photoreceptor degenerations. Hence, repurposing of known PARP inhibitors for patients with non-oncological diseases might provide a facilitated route for a novel retinitis pigmentosa therapy.
What this means for Usher syndrome: PARP inhibitors are approved for their use in cancer therapy, suggesting they can be repurposed to treat retinitis pigmentosa at a very low cost and shorter waiting times compared to novel drugs.
Researchers from Sun Yat-sen University are attempting to test the efficacy and safety of oral minocycline for the treatment of retinitis pigmentosa (RP). Minocycline, a second generation, semi-synthetic tetracycline antibiotic, a highly lipophilic molecule and can easily pass through the blood-brain barrier. Several clinical trials and animal experiments have reported that minocycline exert anti-apoptotic, anti-inflammatory and antioxidant effects in treating neurodegenerative diseases. They have proposed to test the effect and safety of oral minocycline for RP.
What this means for Usher syndrome: If clinical trials are successful, Usher patients will have the possibility to be included in this non-invasive therapy to prevent photoreceptor cell death.
To develop biological approaches to restore vision, scientists developed a method of transplanting stem cell-derived retinal tissue into the retina of an animal model, a cat. Human embryonic stem cells were successfully grafted into the retina of cats. The researchers observed strong infiltration of immune cells into the graft and surrounding tissue in the cats treated with prednisolone alone. The cats treated with prednisolone plus cyclosporine A showed better survival and low immune response to the grafts. This work demonstrates the feasibility of engrafting human embryonic stem cell-derived retinal tissue into the retina of large-eye animal models. Transplanting retinal tissue in degenerating cat retina will enable rapid development of preclinical work focused on vision restoration.
What this means for Usher syndrome: This procedure may provide a platform for testing stem cell-based therapies to treat Usher syndrome patients.
A major cause of human blindness is the death of rod photoreceptors. As rods degenerate, synaptic structures between rod and rod bipolar cells disappear and the rod bipolar cells extend their dendrites and occasionally make aberrant contacts. Such changes are broadly observed in blinding disorders caused by photoreceptor cell death and are thought to occur in response to deafferentation. How the remodeled retinal circuit affects visual processing following rod rescue is not known. To address this question, we generated male and female transgenic mice wherein a disrupted cGMP-gated channel (CNG) gene can be repaired at the endogenous locus and at different stages of degeneration by tamoxifen-inducible cre-mediated recombination. In normal rods, light-induced closure of CNG channels leads to hyperpolarization of the cell, reducing neurotransmitter release at the synapse. Similarly, rods lacking CNG channels exhibit a resting membrane potential that was ~10 mV hyperpolarized compared to WT rods, indicating diminished glutamate release. Retinas from these mice undergo stereotypic retinal remodeling as a consequence of rod malfunction and degeneration. Upon tamoxifen-induced expression of CNG channels, rods recovered their structure and exhibited normal light responses. Moreover, we show that the adult mouse retina displays a surprising degree of plasticity upon activation of rod input. Wayward bipolar cell dendrites establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings demonstrate remarkable plasticity extending beyond the developmental period and support efforts to repair or replace defective rods in patients blinded by rod degeneration.
What this means for Usher syndrome: If the same plasticity exists in the human retina, and the communications between bipolar cells and rods can be reestablished, this will suggest that future research can be directed toward the search for new therapies that will increase or accelerate these communications. Within that scenario, Usher patients will benefit in the future since they will be able preserve and restore some of their retinal activity.
Scientists from Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland and Scuola Superiore Sant’ Anna in Italy are developing a technology, OpticSELINE, for the blind that stimulates the optic nerve. The idea is to produce phosphenes, the sensation of seeing light in the form of seeing white patterns, without seeing light directly. Unfortunately, only a few hundred patients qualify for the current retinal implants on the market for clinical reasons. The intraneural electrode is a potential solution to this exclusion, since the optic nerve and the pathway to the brain are often intact. Intraneural electrodes contain an array of 12 electrodes and are more stable and less likely to move around once they are implanted. To understand the effectiveness of the electrodes, scientists delivered electric current to the optic nerve through OpticSELINE and measured the brain’s activity . The stimulation showed each electrode induces a special pattern of cortical activation, suggesting that intraneural stimulation of the optic nerve is selective and informative.
What this means for Usher syndrome: newer technologies such as the OpticSELINE are being developed as potential solutions to help the blind see. It might take some time and several clinical trials to fine-tune those stimulated cortical patterns but as they are now those visual signals generated by the OpticSELINE will be able to provide visual aid in the near future.
The identification of the causes and understandings of the functions of many inherited retinal diseases (IRDs) has led to the development of exciting new gene/disease specific treatment opportunities. There are numerous treatments available that are aimed at a level of not just targeting specific genes but also certain mutations. Therefore, gene/disease specific treatments rely on persistent target cells and sufficient visual function to work effectively. However, many patients are outside of this window of opportunity and must rely on other approaches.
What this means for Usher syndrome: there are many different treatment and therapy options that are in development for retinitis pigmentosa.
Ophthalmology researchers at the University of Louisville have discovered the loss of vision in retinitis pigmentosa is the result of a disruption in the flow of glucose to the rods and cones. Metabolic changes result in the reduced availability of glucose in the cells; thus, starving the photoreceptors of necessary nutrients. Douglas C. Dean PhD stated, “Attacking glucose utilization is a major strategy in fighting lung cancer. This unexpected connection in retinal and lung cancer metabolism has led us to link these seemingly unrelated systems to search for common drugs that target both lung cancer and retinal degeneration."
What this means for Usher syndrome: This connection between lung cancer and retinal degeneration will help us find potential drugs to treat both diseases.
Researchers at Children’s Hospital of Philadelphia (CHOP) reported a more sensitive method for capturing the footprint of AAV vectors — the range of sites where the vectors transfer new genetic material. AAV vectors are bioengineered tools that use a harmless virus to transport modified genetic material safely into tissues and cells. To use these vectors safely and effectively, researchers must have a complete picture of where in the body the virus delivers the gene. Current methods to define gene transfer rely on fluorescent reporter genes that glow under a microscope, highlighting cells that take up and express the delivered genetic material. Unfortunately, these methods reveal only cells with stable, high levels of cargo. This new technology provides a better and more sensitive method for researchers to detect where the gene is expressed, even if it is expressed at low levels or for only a short time. To address this gap, Beverly L. Davidson, PhD and her laboratory developed a new AAV screening technique that uses sensitive editing-reporter transgenic mice that are marked even with a short burst of expression.
What this means for Usher syndrome: This new method will help to improve the safety of AAV-gene editing approaches because it better defines sites where the vector expresses the modified gene. AAV-gene editing might be developed into a treatment for Usher syndrome.
Scientists from Okayama University have developed a film coupled with photoelectric dye that generates electric signals in response to light. When the device was placed on an instrument that measures electric potential, the film generated waves of electric signals after being exposed to a flashing light. Researchers have highlighted that the device may function as a “novel type of retinal prosthesis.”
What this means for Usher syndrome: This device might be developed into an implant treatment for vision loss in Usher syndrome.
When a person becomes blind their brain’s visual cortex is typically undamaged, but it is not receiving information from the eyes. Six blind people have now had their vision partially restored thanks to Orion, a new device that feeds images from a camera directly into the brain. The Orion device has two main parts: a brain implant and a pair of glasses. The implant consists of sixty electrodes that receive information from a camera mounted on the glasses. Together, they deliver visual information to the brain; thus, bypassing the eye.
What this means for Usher syndrome: This system might provide vision in Usher syndrome patients who are completely blind.
“Researchers have developed a significantly improved delivery mechanism for the CRISPR/Cas9 gene editing method in the liver. The delivery uses biodegradable synthetic lipid nanoparticles that carry the molecular editing tools into the cell to alter the cells’ genetic code precisely with as much as 90 percent efficiency. The nanoparticles could help overcome technical hurdles to enable gene editing in a broad range of clinical therapeutic applications.”
What this means for Usher syndrome: This technique may provide a means for delivering gene therapies to the retina in Usher syndrome patients.
Researchers developed a mouse model with genetically defective rods that mimics developmental blindness disorders in humans. A team examined the structure of the defective retina, as well as its response to light with or without gene therapy. The rods that received gene therapy not only regained normal light response, but also recovered normal connections to other retinal neurons.
What this means for Usher syndrome: If future treatments for Usher syndrome can save photoreceptors from dying, the saved cells may be able to reconnect and become functional.
A new study shows that the complement system, part of the innate immune system, plays a protective role to slow the retinal degeneration in a mouse model of retinitis pigmentosa (RP). This discovery contradicts previous studies of other eye diseases suggesting that the complement system worsens retinal degeneration. Utilizing a mouse model, the researchers examined the role of C3 and CR3, the central component of complement and its receptor, by comparing mice with genetically removed C3 or CR3 to normal mice. They found that degeneration worsened in the absence of C3 or CR3. Rod photoreceptors, the light-sensing cells that die first in RP, were lost along with a surge in the expression of neurotoxic inflammatory cytokines. According to Dr. Wong, “Breakdown of this C3-CR3 interaction results in a decreased ability of microglia to phagocytose dead photoreceptors, which then accumulate in the retina, stimulating greater inflammation and degeneration.” These results demonstrate that complement activation is helpful for clearing away dead cells and “maintaining a state of homeostasis, a physiological balance, in the retina.”
What this means for Usher syndrome: this study demonstrates the fundamental role the complement system, part of the immune system, plays in countering retina degeneration.
This study discovered that a classic anti-malarial drug can help sensory cells of the inner ear recognize and transport the Clarin-1 protein to its normal location in the cell. Usher syndrome 3A is due to mutations in Clarin-1. The researchers found that the mutant Clarin-1 protein is not transported properly and then tested drugs that target the transport system. They found that the drug, artemisinin, restores inner ear sensory cell function, and thus hearing and balance, in zebrafish genetically engineered to have mutant human versions of the Clarin-1 protein.
What this means for Usher syndrome: This study identifies a drug that might be useful for treating hearing loss in Usher syndrome 3A patients.
This study aims to analyze the effect of nutraceutical molecules with antioxidant properties, on progression of the disease in an established animal model with retinitis pigmentosa (RP). We saw that long-term treatment with a flavanone (naringenin) or flavanol (quercetin) present in citrus fruits, grapes, and apples, preserves retinal functionality. These two molecules possess antioxidant properties, limiting neurodegeneration, and thus preventing cone damage.
What this means for Usher syndrome: If this treatment preserves cone functionality, it could slow vision loss in Usher syndrome patients.
OliX Pharmaceuticals Inc., a leading developer of RNAi therapeutics announced today an expansion of its ocular disease pipeline. OLX304A has been developed as an RNAi therapeutic with an undisclosed target for the treatment of Retinitis Pigmentosa. OLX304A is a program to develop a treatment that targets a single gene for patients with Retinitis Pigmentosa regardless of their disease-causing mutation. This treatment is different from conventional strategies that focus on targeting individual disease-causing genes.
What this means for Usher syndrome: This strategy could result in a single type of treatment that could help all Usher syndrome patients.
GenSight Biologics, a biopharma company focused on discovering and developing gene therapies for retinal neurodegenerative diseases and central nervous system disorders, announced that the independent Data Safety Monitoring Board (DSMB) has completed its first safety review of the ongoing PIONEER Phase I/II clinical trial of GS030 combining gene therapy and optogenetics for the treatment of Retinitis Pigmentosa (RP). No safety issues have been found for the first cohort of subjects who received a single intravitreal injection of 5e10 vg combined with a wearable optronic visual stimulation device. Therefore, the DSMB has recommended moving forward with the plan without any modification to the protocol and recruiting the second cohort of subjects to receive an escalated dose of 1.5e11 vg.
What this means for Usher syndrome: This clinical trial could lead to a treatment for RP and may be applicable to Usher syndrome.
Researchers at Baylor College of Medicine, the Cardiovascular Research Institute and the Texas Heart Institute have discovered that although the mammalian retina—a layer of specialized nerve cells that mediates vision and is located on the back of the eye—does not spontaneously regenerate, it has a regenerative capacity that is kept dormant by a cellular mechanism called the Hippo pathway. The retina does not regenerate in humans, but other animals such as zebrafish can reverse blindness due to specialized cells in their retina, Müller glial cells. When the retina is damaged, the Müller glial cells multiply and become the lost retinal neurons—replacing injured cells with functional ones. Although Müller glial cells do not restore vision in humans, research has shown that when the retina is injured, “a small subset of Müller glial cells takes the first steps needed to enter the proliferation cycle, such as acquiring molecular markers scientists expect to see in a proliferating cell.”
What this means for Usher syndrome: Discovery of the Hippo pathway suggests that it may be possible to activate the retina’s ability to restore vision loss by manipulating this pathway.
ReNeuron Group plc has announced the latest updated positive preliminary results in the company’s ongoing phase 1 and 2a clinical trial of its human retinal progenitor cell (hRPC) therapy candidate in retinitis pigmentosa. All three subjects in the first group of phase 2a have demonstrated a sustained and further improvement in vision compared to their pre-treatment baseline.
What this means for Usher syndrome: This potential therapy could provide a means to restore lost vision in Usher syndrome patients.
Ganglion cells in the eye generate noise as the light-sensitive photoreceptors die in diseases such as retinitis pigmentosa (RP). Now, neurobiologists have found a drug and gene therapy that can tamp down the noise, improving sight in mice with RP. These therapies could potentially extend the period of useful vision in those with degenerative eye diseases, including, perhaps, age-related macular degeneration.
What this means for Usher syndrome: This type of therapy may also extend the period of useful vision in Usher syndrome.
ProQR Therapeutics N.V., a company dedicated to changing lives through the creation of transformative RNA medicines for the treatment of severe genetic rare diseases, today announced the first patient treated in the Phase 1/2 STELLAR clinical trial for QR-421a in patients with Usher syndrome type 2 or non-syndromic retinitis pigmentosa (RP). Interim data from the trial are expected to be announced by mid-2019. According to David G. Birch, Ph.D., Principal Investigator of STELLAR and Scientific Director of the Retina Foundation of the Southwest in Dallas, Texas, “The STELLAR study is one of the first studies of its kind exploring the impact of ProQR’s RNA therapies on patients with Usher syndrome type 2 due to an Exon 13 mutation. The STELLAR trial will explore whether QR-421a (ProQR’s RNA therapy) can slow disease progression or even reverse it.”
What this means for Usher syndrome: There may be a potential drug available to reverse blindness caused by Usher syndrome.
Researchers at the University of Science and Technology of China injected tiny nanoparticles into mouse eyes that bind the retina into the eyeballs, hence giving them what the team calls ‘super vision.’ The injected nanoparticles bind to photoreceptors and shift the wavelength of light. After the injection, the mice could see normally invisible near-infrared light effectively extending ‘mammalian vision’. Scientists predict that these kinds of nanoparticles could help repair vision in humans who experience loss of retinal function or red color blindness. Additionally, this method is less invasive than other conventional vision repair methods.
What this means for Usher syndrome: This method might be used to increase light sensitivity as vision is lost.
ReNeuron Group, a UK-based global leader in the development of cell-based therapeutics, announced positive preliminary results in the company’s ongoing Phase 1/2 clinical trial of its human retinal progenitor cells candidate therapy for the blindness-causing disease, retinitis pigmentosa (RP). All three subjects in the first group of the Phase 2 part of the trial demonstrated a significant improvement in vision at the follow-up compared to their pre-treatment baseline and compared with their untreated control eye.
What this means for Usher syndrome: A similar cell-based therapy tailored to Usher syndrome may help restore vision.
The Sanford Health Lorraine Cross Award worth $1 million was established to award game-changers in medicine. The award is not to have people to live forever, but to “live life without suffering.” The winners of the award are Dr. Jean Bennett and Dr. Katherine High of the University of Pennsylvania, pioneers of gene therapy research. The award is in recognition of the improvements in gene therapy that led to an FDA-approved treatment for Leber’s congenital amaurosis.
What this means for Usher syndrome: This award not only reflects the importance of gene therapy for the treatment of genetic disorders but could accelerate research in Usher syndrome through gene therapy.
A team of scientists from Sechenov First Moscow State Medical University (MSMU), together with colleagues from leading scientific centers in India and Moscow, described several genetic mutations causing Usher syndrome.
What this means for Usher syndrome: These previously unstudied genetic mutations will allow us to identify new targets for specific therapies.
The United States Patent & Trademark Office (USPTO) has approved the usage of mesencephalic-astrocyte-derived neurotrophic factor (MANF) or cerebral dopamine neurotropic factor (CDNF) as a treatment for various retinal disorders including retinitis pigmentosa, macular degeneration, or glaucoma. Both factors can be administered as an eye drop or by intravitreal injection. MANF is believed to have potential because it is a naturally-occurring protein produced by the body to reduce or prevent cell death in response to injury or disease through unfolded protein response.
What this means for Usher syndrome: Since MANF reduces or prevents cell death, in the case of Usher syndrome, it could prevent photoreceptor cells from dying, and thus preserve vision.
A new purple protein, bacteriorhodopsin, has made its way from a tiny laboratory in Farmington, Connecticut, all the way up to the International Space Station. Since bacteriorhodopsin is light-sensitive, researchers hope to implant it into human eyes. The thought is that the protein could be used to replace cells that die due to diseases like retinitis pigmentosa and age-related macular degeneration. To simulate the cells, the laboratory in Farmington needs to build what it is called “organic implants” by layering the bacteriorhodopsin onto a film and dipping it over and over into a series of solutions. These solutions need to have a uniform distribution that can be adversely affected by gravity. To test this, LambdaVision has secured a spot for their experiment aboard the International Space Station, using funding from the ISS National Lab and Boeing.
What this means for Usher syndrome: These “organic implants”, composed of bacteriorhodopsin, could be capable of replacing dying photoreceptors in the retina.
Researchers revealed that culturing human induced pluripotent stem cells with different isoforms of the extracellular component laminin led to the creation of cells specific to different parts of the eye, including retinal, corneal, and neural crest cells. They showed that the different laminin variants affected the cells' motility, density, and interactions, resulting in their differentiation into specific ocular cell lineages. Cells cultured in this way could be used to treat various ocular diseases.
What this means for Usher syndrome: There is the possibility of replacing the photoreceptor cells that are dying in the retina with pluripotent cells that have been grown and induced into healthy photoreceptor cells.
Scientists at the Francis Crick Institute have discovered a set of simple rules that can determine the precision of CRISPR/Cas9 genome editing in human cells. These rules could help to improve the efficiency and safety of genome editing in both the lab and the clinic. By examining the effect of CRISPR genome editing at 1491 target sites across 450 genes in human cells, the team have discovered that the outcomes can be predicted based on simple rules. In this study, researchers have found that the outcome of a particular gene edit depends on the fourth letter from the end of the RNA guide, synthetic molecules made up of about 20 genetic letters (A, T, C, G). “The team discovered that if this letter is an A or a T, there will be a very precise genetic insertion; a C will lead to a relatively precise deletion and a G will lead to many imprecise deletions. Thus, simply avoiding sites containing a G makes genome editing much more predictable.”
What this means for Usher syndrome: Scientists will theoretically be able to repair the mutation present in an Usher gene by selecting the correct genetic letter from the end of the RNA guide.
The light scalpel has the potential of preventing the “ripple effect” that occurs following a trigger that leads to glaucoma or macular degeneration. By utilizing the femtosecond laser, small holes appear in the cells of the eye’s retina, making it possible to effectively inject drugs or genes in specific areas of the eye. The key feature of this technology is extreme precision because through the usage of gold nanoparticles, the light scalpel makes it possible to precisely locate the family of cells where the doctor will have to intervene.
What this means for Usher syndrome: In CRISPR/Cas9 editing or drug delivery, the utilization of the femtosecond laser will improve the delivery of the specific compound to the affected area with minimum side effects.
The Bertarelli Foundation has awarded collaborative research grants to four teams of scientists from Harvard Medical School (HMS) and the Institute of Molecular and Clinical Ophthalmology in Basel, Switzerland, all focused on understanding and treating some of the most devastating sensory disorders such as Usher syndrome. Two HMS neurobiologists, studying the origins of deafness—David Corey and Arthur Indzhykulian—are joining forces with Botond Roska, an expert on retinal biology and eye disease at the Institute of Molecular and Clinical Ophthalmology in Basel, Switzerland to develop treatments for Usher syndrome type 1F. The researchers will focus on developing gene therapy aimed at overcoming a hurdle that has hindered therapeutic efforts so far: the unusually large Usher 1F protein.
What this means for Usher syndrome: This research could open the door for development of therapies to treat Usher 1F.
In August, it will be a year since the first commercial IRIS®II retinal chip implantation in Europe took place; it has allowed a blind patient to perceive light stimuli and use it to locate objects, meaning that she can be more independent. This work has made it possible to integrate artificial vision technology, which includes an electrical retinal stimulator with over 150 electrodes, glasses with a bio-inspired mini-camera and a pocket processor into this patient’s day-to-day life. For the patient, blind from a result of retinitis pigmentosa, the retinal chip is another way of supporting her in her daily life, together with her guide dog and the use of a cane.
What this means for Usher syndrome: There are possible technologies available to help the blind live and navigate independently.
Research suggests that the herb, cannabis, impacts every organ in the body including the eyes. Cannabis compounds work their magic in the eyes by interacting with one of the largest cellular communication networks—endocannabinoid system (ECS)—in vertebrates. Cannabis compounds interact with the ECS by engaging the cannabinoid receptor. By manipulating the cannabinoid receptors, we can change the way electroretinographic waves pass through the retina. In 2014, research published in Experimental Eye Research suggested that cannabis medicines may be able to slow down degenerative blindness by preventing the death of photoreceptors in those with retinitis pigmentosa.
What this means for Usher Syndrome: Patients with Usher syndrome may benefit from cannabis therapies by slowing down the progression of retinitis pigmentosa.
Since 1995, University of California, Irvine stem cell researcher Magdalene J. Seiler, PhD has pursued promising research into the development and usage of retinal sheet transplantation. The treatment is based on transplanting sheets of stem cell-derived retina, called retina organoids to the back of the eye with hopes of re-establishing the neural circuity within the eye. Recently, Seiler has received a $4.8 million grant from the California Institute of Regenerative Medicine (CIRM) to continue to develop a stem cell-based therapy for retinal diseases such as retinitis pigmentosa.
A group of research physicians have discovered that using stem cells from a person’s own bone marrow has reported success in improving vision for patients with Retinitis Pigmentosa. The bone marrow stem cells come from the same person; therefore, there can be no rejection. Of the 33 eyes studied, 45.5% of individual eyes improved and 45.5% remained stable over the follow-up period when they typically have been worsening. Vision improvement is 98.4% likely to be a consequence of this treatment.
A US clinician has received a five-year £6.1 million grant to investigate the potential of advancing a gene therapy currently used in dogs to help retinitis pigmentosa (RP) patients. The treatment restored the night vision and stopped the progression of the daytime vision-loss in dogs with progressive retinal atrophy (PRA). PRA is an inherited condition in dogs and is caused by the same genes that are responsible for RP. This new grant will allow clinicians to build on primary studies in preparation for a possible clinical trial in human patients with RP.
Sparing Vision, a French biotech, plans to use a naturally occurring protein called rod-derived cone-viability factor, which binds to a peptide on cone photoreceptor cells in the retina and allows more glucose to enter the cell. By allowing more glucose in, it will slow down or prevent cell death; thus stopping vision loss. This could be beneficial for patients with retinitis pigmentosa.
The nonprofit biomedical institute is seeking to acquire samples of every drug ever developed to see if they can be used to treat diseases besides those for which they were intended. That means collecting roughly 10,000 to 11,000 compounds discovered since the end of the 19th century. Most never made it to market, often because they weren’t effective or had unexpected side effects.
ProQR Therapeutics N.V. announced the results for their clinical trial of QR-110 LCA 10 is on track, and eight out of twelve patients have been enrolled in a Phase 1/2 trial. The results for safety and efficacy for the trial are expected to be announced in the second half of 2018. Currently, they planing to announce data from a QR-421 study for Usher Syndrome. The organization has received $7.5 million in funding from the Foundation Fighting Blindness (FFB) and hopes to use QR-421a for Usher Syndrome Type 2A to target mutations in exon 13.
For the last couple years, Ophthalmologist Dr. Kang Zhang and UC San Diego researchers have been working with CRISPR by injecting it into the eyes of mice with Retinitis Pigmentosa. According to Dr. Zhang, they have been able to bring back 30 percent of vision and sometimes 50 percent of vision. Zhang’s lab has recently received the green light to start clinical trials this fall and if the trial goes well then CRISPR can be applied to all human genetic diseases or conditions.
Researchers at Duke University believe they have developed an approach to treat retinal conditions such as Retinitis Pigmentosa, which include misfolded proteins in the cell that the eye cannot process. Scientists have shown by boosting the cells’ ability to process misfolded proteins could keep them from clustering inside the cell. They created and tested the strategy in mice, significantly delaying the onset of blindness. This technique would not be used to prevent cell death retinal diseases but also neurodegenerative diseases such as Huntington’s, Parkinson’s, and Alzheimer’s.
David Rand, Marie Jakešová, Gur Lubin, Ieva Vėbraitė, Moshe David-Pur, Vedran Đerek, Tobias Cramer, Niyazi Serdar Sariciftci, Yael Hanein, Eric Daniel Głowacki
A simple retinal prosthesis is being developed in collaboration between Tel Aviv University in Israel and Linköping University in Sweden. Fabricated using cheap and widely-available organic pigments used in printing inks and cosmetics, it consists of tiny pixels like a digital camera sensor on a nanometric scale. Researchers hope that it can restore sight to blind people.
Ekaterina S. Lobanova, Stella Finkelstein, Jing Li, Amanda M. Travis, Ying Hao, Mikael Klingeborn, Nikolai P. Skiba, Raymond J. Deshaies, Vadim Y. Arshavsky
New research outlines a strategy that in mouse models significantly delayed the onset of blindness from inherited retinal degeneration such as retinitis pigmentosa.
Bill Whitaker of CBS’s 60 minutes interviewed Feng Zeng to learn more about Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). Whitaker’s interview with Zhang provides basic facts that are accessible to anyone on CRISPR and its possibility of not only curing genetic diseases but preventing them altogether.
An Ottawa-based company, iBionics, is working to improve the effectiveness of vision-restoring technology by developing a bionic retina, the Diamond Eye implant. iBionics is targeting for full approval and commercial availability by 2024.
One of these recent discoveries doesn't replace an entire eye, but supplants a major component of vision. It holds some promise for millions of people who could otherwise go blind. In a first, scientists in China have created artificial photoreceptors to help blind mice see.
ReNeuron, a developer of cell-based therapeutics, received a $1.5 million grant award from the UK Innovations agency. The project will allow further development of cell banks of ReNeuron’s hRPC candidate and as well as the development of product release assays for late-stage clinical development. The hRPC therapy is currently being tested in a Phase III clinical trial in the US for patients suffering retinitis pigmentosa.
A retinal implant allowed a 69 year old woman with macular degeneration to see more than double the usual number of letters on the vision chart. Luxturna, the gene therapy was approved by the FDA in 2017, corrects a mutation found in Leber congential amaurosis (LCA).
Caroline C. W. Klaver, MD, PhD; Alberta A. H. J. Thiadens, MD, PhD
Children with retinitis pigmentosa who received vitamin A supplementation were associated with slower rate of cone electroretinogram amplitude compared to children who did not, a small study found.
This story is designed to help you find an answer to the question: will a stem cell therapy work for me? To get an answer, Dr. Mary Sunderland of the Foundation Fighting Blindness Canada, suggests that you pay attention to three key points when you read new stories about stem cell discoveries or clinical trials...
Rajiv Gandhi Govindaraj, Misagh Naderi, Manali Singha, Jeffrey Lemoine, Michal Brylinski
Researchers at the LSU Computational Systems Biology group have developed a sophisticated and systematic way to identify existing drugs that can be repositioned to treat a rare disease or condition. They have fine-tuned a computer-assisted drug repositioning process that can save time and money in helping these patients receive effective treatment.
Odylia Therapeutics aims to advance gene therapies that are getting left behind. Odylia’s focus is gene therapies with scientific promise but limited commercial opportunity that maybe gathering dust on the selves of labs or companies.
Three blind mice could be a thing of the past. Scientists have restored the sight of blind mice by implanting tiny gold prosthetic photoreceptors into their eyes. So far, this incredible technique has only been carried out on mice. However, the work holds some hope for people with degenerative eye diseases such as retinitis pigmentosa or macular degeneration.
Pixium Vision, a company developing innovative bionic vision systems to enable patients who have lost their sight to lead more independent lives, announces today the world’s first successful human implantation and activation of PRIMA, its new generation miniaturized wireless photovoltaic sub-retinal implant, in a patient with severe vision loss from atrophic dry Age-related Macular Degeneration (AMD).
A French biopharma company has announced their plans to carry out human trials of a new treatment that would insert genes from light-seeking algae into the eyes of patients with inherited blindness in order to help them regain sight. The treatment involves optogenetics, a technique that converts nerve cells into light sensitive cells.
GenSight will start a clinical trial in the UK testing a combination of gene therapy and a wearable device to restore sight in patients with retinitis pigmentosa. The Phase I and II trial, PIONEER, will study the safety and tolerability of GenSight’s therapy called GS030, in patients with end-stage retinitis pigmentosa with vision not better than “counting fingers.” The first patient will be tested in the first quarter of 2018 and outcomes will be measured after a year.
What this means for Usher syndrome: If GenSight’s therapy succeeds, it will very likely be tested in other diseases such as Usher syndrome.
GenSight Biologics, a biopharma company focused on discovering and developing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, announced UK Medicines and Healthcare Regulatory Agency (MHRA) acceptance of the Company’s Clinical Trial Application (CTA) to initiate the PIONEER Phase I/II study of GS030 in patients with Retinitis Pigmentosa (RP).
Raghavi Sudharsan, Daniel P. Beiting, Gustavo D. Aguirre, William A. Beltran
In studying the late stages of disease in two different canine models of retinitis pigmentosa, a group of progressive and inherited blinding diseases, researchers found commonalities, specifically involving the innate immune system. The findings point to potential new treatment options for the conditions.
jCyte, one of the leaders in developing cell-based therapies for RP, announces positive 12-month results from its Phase 1/2a clinical trial to treat retinitis pigmentosa with stem cells.
Usher syndrome is the most common cause of deafness associated with visual loss of a genetic origin. The purpose of this paper is to report very severe phenotypic features of type 1B Usher syndrome in a Saudi family affected by a positive homozygous splice site mutation in MYO7A gene. This mutation manifested with advanced retinal degeneration at a young age.
What this means for Usher syndrome: Individuals with this particular mutation may experience more severe symptoms than other Usher 1B patients.
The prestigious Institute of Ocular Microsurgery in Barcelona implanted the first patient in Spain with IRIS® II, a bionic vision system equipped with a bio-inspired camera and a 150-electrode epi-retinal implant that is designed to be explantable.
The FDA has granted GenSight’s developing drug, GS030, Orphan Drug Disease Designation for the treatment of retinitis pigmentosa.
The Foundation Fighting Blindness Clinical Research Institute (FFB-CRI) has announced an investment of up to $7.5 million to advance the potential therapy into and through a Phase II clinical trial for the usage of N-acetylcysteine-amide (NACA). NACA has recently emerged as a promising drug for Retinitis Pigmentosa because in several FFB-funded lab studies at Johns Hopkins University, it has slowed down retinal degeneration.
Tongchao Li, Nikolaos Giagtzoglou, Dan Eberl, Sonal Nagarkar-Jaiswal, Tiantian Cai, Dorothea Godt, Andrew K Groves, Hugo J Bellen.
Myosins play essential roles in the development and function of auditory organs and multiple myosin genes are associated with hereditary forms of deafness. Our work reveals a novel mechanism that regulates protein complexes affected in two forms of syndromic deafness and suggests a molecular function for Myosin IIa in auditory organs.
João Carlos Ribeiro, Bárbara Oliveiros, Paulo Pereira, Natália António, Thomas Hummel, António Paiva & Eduardo D. Silva
Study aimed at identifying and characterizing putative differences in olfactory capacity between patients with USH and controls, as well as among the subtypes of USH.
Guilian Tian, Richard Lee, Philip Ropelewski, and Yoshikazu Imanishi
The purpose of this study was to obtain an Usher syndrome type III mouse model with retinal phenotype.
Debra A. Thompson, Robin R. Ali, Eyal Banin, Kari E. Branham, John G. Flannery, David M. Gamm, William W. Hauswirth, John R. Heckenlively, Alessandro Iannaccone, K. Thiran Jayasundera, Naheed W. Khan, Robert S. Molday, Mark E. Pennesi, Thomas A. Reh,Richard G. Weleber, David N. Zacks, and for the Monaciano Consortium.
The present position paper outlines recent progress in gene therapy and cell therapy for this group of disorders [retinal dystrophies], and presents a set of recommendations for addressing the challenges remaining for the coming decade.
Ben Shaberman provides an overview of emerging therapies for Usher syndrome in the article "Saving Vision for People with Usher Syndrome" in the July/August 2014 edition of Hearing Loss Magazine.
"A highly potent synthetic form of THC, the substance in marijuana that produces a high for users, has shown strong vision-preserving effects in rats with a form of autosomal dominant retinitis pigmentosa (adRP). ”
Previous cell culture studies have suggested that CLRN1, the causative gene for USH3A, is localized to the plasma membrane and interacts with the cytoskeleton. However, less is known about CLRN1’s role with vision because the mouse model does not exhibit a retinal phenotype and expression studies in murine retinas have provided conflicting results. This study described the cloning and expression analysis of the zebrafish CLRN1 gene, and report protein localization of CLRN1 in auditory and visual cells from embryonic through adult stages. The data provide a foundation for exploring the role of CLRN1 in retinal cell function and survival in a diurnal, cone-dominant species.
What this means for Usher syndrome: Zebrafish may provide a good model for studies of USH3A.
The Coxsackievirus and Adenovirus Receptor (CAR) is an essential regulator of cell growth and adhesion during development. The gene for CAR, CXADR, is located within the genetic locus for USH1E. Based on this and a physical interaction with harmonin, the protein responsible for USH1C, researchers hypothesized that CAR may be involved in cochlear development and that mutations in CXADR may be responsible for USH1E.
What this means for Usher syndrome: We have potentially identified CXADR as the gene responsible for USH1E.
Stephen E. Zrada, Kevin Braat, Richard L. Doty, Alan M. Laties
Olfactory testing should be included as a part of test batteries used for comprehensive evaluation of patients with USH1 and USH2, this may aid in the classification of specific genotypic and phenotypic forms, and in the identification of the subset of patients with significant smell deficits, thereby providing the clinician with an opportunity to counsel individuals with USH-related olfactory dysfunction.