Usher Syndrome Blog and News
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A team of researchers at Tel Aviv University are studying a virus-based gene therapy approach to treat deafness by replacing the non-functioning gene with a functional copy.
Case study and one year follow up on five patients with end-stage RP that received retinal implants.
Lentivirally modified mesenchymal stem cells from bone marrow shows promise in preserving retinal function and preventing further retinal degradation.
A type of laser light therapy called photobiomodulation shows promising results in the ability to preserve retinal performance, structure and function.
Two scientists, Emmanuelle Charpentier and Jennifer Doudna, have been awarded the 2020 Nobel Prize in Chemistry for developing the tools to edit DNA. They are the first two women to share the prize, which honors their work on the technology of genome editing. During Professor Charpentier’s studies of bacterium Streptococcus pyogenes, she discovered a previously unknown molecule called tracrRNA, which is part of the organism’s immune system. This system, now known as CRISPR/Cas9, disrupts viruses by cleaving (or cutting) their DNA – like genetic scissors. Drs. Charpentier and Doudna together recreated this system in a test tube and showed it can be reprogrammed to cut any DNA molecule at a predetermined site. Since this discovery, the CRISPR/Cas9 gene editing system has already contributed to many important discoveries in basic research; and is currently being investigated for its potential to treat sickle cell anaemia, a blood disorder that affects millions of people worldwide. In medicine, clinical trials of new cancer therapies are underway, and this technology may also have the potential to treat or even cure inherited diseases.
What this means for Usher syndrome: Researchers have already started to evaluate the use of CRISPR/Cas9 gene editing to target specific mutations in patients with USH2A. Successful in-vitro (outside the body) mutation repair was demonstrated with proven effectiveness and specificity. This indicates the CRISPR/Cas9 gene editing system shows promise and should be further explored as a potential treatment for Usher syndrome.
Delivery of therapeutic genes into retina is proving to reverse degeneration and restore vision, however, viral vector-based gene delivery is prone to immunorejection, inflammatory/immune-response and nontargeted. Here, we report nonviral gene delivery and expression of opsin encoding genes in mouse retina in-vitro and in-vivo by use of pulsed femtosecond laser microbeam. In-vitro patch-clamp recording of the opsin-sensitized retinal cells and visually evoked in-vivo electrical recording from laser-transfected eye of mouse with degenerated retina showed functional response. The ultrafast laser-based naked gene delivery showed minimal damage and reliable expression of therapeutic opsin in cell membrane of the selected cells and in targeted retinal region. Laser-based "naked DNA gene therapy" in a spatially targeted manner will pave the way for treatment of inherited retinal diseases.
What this means for Usher syndrome: Based on this study, laser-based delivery of gene therapy appears to be a viable alternative to viral-vector based gene delivery with less adverse effects. In the future, this may translate into more, and safer, treatment options for Usher patients.
Eyevensys, a biotechnology company developing non-viral gene therapies for ophthalmic diseases, today announced the U.S. Food and Drug Administration (FDA) has granted an orphan-drug designation (ODD) for EYS611 for the treatment of retinitis pigmentosa (RP). EYS611 is a DNA plasmid that encodes for the human transferrin protein which helps manage iron levels in the eye. While iron is essential for retinal metabolism and the visual cycle, too much iron is extremely toxic to the retina and has been associated with photoreceptor death in several retinal degenerative diseases. By acting as an iron chelating and neuroprotective agent (an agent that reduces level of toxic metals in the blood and tissues), EYS611 helps slow the progression of diseases like RP regardless of the specific genetic mutation causing the condition. This can potentially benefit patients diagnosed with RP, as well as other degenerative retinal diseases, including late stage, dry age-related macular degeneration and glaucoma. Eyevensys just reported data from preclinical testing in the September 2020 issue of the journal Pharmaceutics. The paper, entitled “Transferrin non-viral gene therapy for treatment of retinal degeneration” (Bigot, et al., Pharmaceutics), shows that EYS611 is safe and effective for preserving photoreceptors and retina functionality in acute toxicity and inherited rat models of retinal degeneration.
What this means for Usher syndrome: The orphan-drug designation by the FDA means that Eyevensys has been granted a seven year window to exclusively develop EYS611. This gene therapy is intended for all RP patients regardless of the underlying mutation, is less invasive than viral-vector gene therapies, and can be used at earlier stages of the disease. Since this is not mutation specific, this non-viral gene therapy will be a viable option for Usher patients.
Intravitreal injection of human retinal progenitor cells (hRPCs;jCells) is a novel stem cell treatment currently in development for retinitis pigmentosa (RP. In a recently completed phase 2b study, this treatment was injected into the jelly-like center or vitreous of the eye and has demonstrated promising biologic activity and an excellent safety profile. In this study, 84 patients diagnosed with RP and with best-corrected visual acuity (BCVA) between 20/80 to 20/800 were randomly assigned to 2 different doses (low or high) of jCells or a placebo. The primary end point (or target outcome) was the mean change in the BCVA at 12 months; the secondary end points were identification of the lowest light level at which patients could navigate through a structured mobility maze, along with the mapping of each patient’s kinetic visual field, the evaluation of their performance on contrast sensitivity testing, and completion of a low vision–specific quality-of-life questionnaire. In a post hoc analysis of this target population, an early and significant improvement in vision was seen in the higher-dose group, with average gain of 16 letters at month 12 compared with 2 letters in the control group. Improvement in the higher-dose group compared to the control group was also true for the secondary outcomes. While there were some mild cases of eye inflammation and one severe case of hypertension associated with treatment, these adverse effects were addressed. These study results showed that intravitreal injection of allogeneic jCells that were not derived directly from the patient shows promising results. The study is expected to continue with expected redosing of patients and further monitoring as this treatment is not expected to be permanent.
What this means for Usher syndrome: These results from a Phase 2b study demonstrate that intravitreal injection of retinal progenitor stem cells shows measurable improvement in vision and may be a viable treatment option in the future for both Usher and RP patients.
LambdaVision, a biotech company that is developing a treatment to help patients regain sight, will launch their artificial retina technology with engineering partner Space Tango on Northrop Grumman’s 14th Commercial Resupply Services Mission for NASA (NG-14) to the International Space Station (ISS) U.S. National Laboratory. Scheduled to launch on September 30th at 10:26 p.m. ET, NG-14 is the first of a series of NASA flights to the ISS in low-Earth orbit (LEO) focused on developing the on-orbit production of LambdaVision’s artificial retina. LambdaVision’s research on the ISS focuses on exploring the benefits of microgravity for producing its artificial retina, and expands on research being conducted on Earth and previous efforts on the ISS. Initial studies will evaluate the effects of microgravity on protein function and stability, which is critical for the quality and performance of the artificial retina. Outcomes of this experiment will provide a foundation for future ISS-based trials. Over the next three years, the LambdaVision-Space Tango partnership will serve to evaluate and improve on-orbit production processes, and to produce artificial retinas that will then be evaluated on Earth.
What this means for Usher syndrome: Artificial retinas are intended for individuals who have lost their vision due to degenerated photoreceptor cells, but still possess functional or intact retinal nerve cells and optic nerves. If LambdaVision's unique approach to on-orbit production successfully delivers high quality and high performing artificial retinas, Usher patients may one day be able to regain some of their sight.
Scientists from Australia's Monash University, who spent more than a decade developing a bionic vision system where signals from a wireless brain implant are transmitted to a camera mounted on a special pair of glasses, are gearing up for human clinical trials. The Gennaris bionic vision system is a unique solution that completely bypasses the eye, and do not require wires to protrude through the scalp. A small microchip is implanted on the surface of the brain and can generate 172 different bright spots called phospenes, in order to provide visual cues to the user about what is in front of them. This innovative technology within the Gennaris system has been previously tested on sheep, yielding very positive results and no noticeable side effects after more than 2700 hours of visual stimulation. While the Gennaris system is designed specifically to restore vision, the technology has potential for other applications, such as overcoming paralysis by bypassing injured nerves and connecting affected limbs directly to the brain.
What this means for Usher Syndrome: The Gennaris system is intended to restore limited vision to the blind, regardless of the cause. Therefore, if proven successful, this bionic vision system will be an option for Usher patients in addition to those with retinitis pigmentosa and other visual impairments.
This year’s Körber Prize for European Science was given to a Hungarian scientist whose revolutionary gene-editing treatment could cure a type of blindness that affects around one in 4,000 children. Cell biologist Botond Roska’s pioneering work on the human retina has placed him among the world leaders in the study of ophthalmology—work that included the presumably painstaking effort of identifying over 100 different retina cell types and their complex interrelations. His work on novel gene therapies has led to discovery of a possible cure for retinitis pigmentosa. Roska’s work which involves the reprogramming of retina cells into photoreceptors, thereby taking over from the damaged ones and restoring light and color in blind retina, is currently going through clinical trials. As a result of this ground-breaking discovery, he was granted the prestigious award of €1 million.
What this means for Usher syndrome: If proven successful, this novel gene therapy may restore partial vision to affected Usher patients by enabling previously blind retinas to detect light and color.
Mark Dunning, founder of the Usher Syndrome Coalition steps down from the Board of Directors and warmly welcomes long-time supporter Lanya McKittrick, Ph.D., as the new chair of the Usher Syndrome Coalition.
Researchers have discovered a technique for directly reprogramming skin cells into light-sensing rod photoreceptors used for vision. The laboratory-made rods enabled blind mice to detect light after the cells were transplanted into the animals’ eyes. According to Anand Swaroop Ph.D., senior investigator, “This is the first study to show that direct, chemical reprogramming can produce retinal-like cells, which gives us a new and faster strategy for developing therapies for age-related macular degeneration and other retinal disorders caused by the loss of photoreceptors.” The immediate benefit of this technique will be the ability to develop models to allow us to study the mechanisms of the disease and design better cell replacement approaches. Induced pluripotent stem (IPS) cells take about six months to create, however direct reprogramming takes only about ten days to convert skin cells into functional photoreceptors. A clinical trial to test the therapy in humans for degenerative rental diseases such as retinitis pigmentosa is in the works.
What this means for Usher syndrome: This new technique holds promise for treatment of many retinal degenerative diseases, including Usher syndrome.
The Scientific and Medical Advisory Board of Retina International recommends that those affected by an underlying retinal dystrophy do not self-medicate with chloroquine and strongly advises patients to follow the advice of their healthcare provider prior to any use of chloroquine. It is still unclear how chloroquine or any antimalarial drug would work against COVID-19.
Chloroquine is an antimalarial drug that was FDA approved in 1934. Since then it has been found to be beneficial for the treatment of autoimmune diseases such as lupus or rheumatoid arthritis. The standard doses of chloroquine used for the treatment of malaria and other diseases have few side effects. However, toxicity is encountered when high doses are injected very rapidly into the bloodstream (parenterally) or taken as tablets (orally) in regular doses over many years. Patients with underlying retinal disease may be at higher risk for chloroquine toxicity. The most serious complications of chloroquine are retinopathy, cardiomyopathy, neuromyopathy and myopathy. The retinopathy is encountered with the prolonged use of chloroquine that can lead to irreversible damage to the retina and the loss of vision. Chloroquine toxicity is of serious concern for the retina because it is not treatable. Additionally, there have been cases of progressive vision loss in patients even years after the treatment by chloroquine or hydroxychloroquine.
The Usher Syndrome Coalition has been closely monitoring the rapidly evolving coronavirus (COVID-19) situation, while listening to speaker and attendee concerns. The Coalition’s Board of Directors and staff have made the difficult decision to postpone the in-person USH Connections Conference and to hold a virtual event in its place this July 2020.
Originally planned for July 10-11, 2020 at the Omni Austin Hotel at Southpark, the venue has been incredibly accommodating, offering us the opportunity to postpone the event to the same time next year, July 9-10, 2021.
Please join our Hearts on Hand outreach campaign to inform, reach out and provide virtual support to our USH Family during this difficult time.
Stem cell technology has enabled new possibilities for understanding and treating rare diseases such as Usher syndrome. The technology for stem cell treatment is still relatively new and complex. Unfortunately, several private clinics are attempting to financially capitalize on patients’ desperation and confusion for a cure. David Gamm, MD, PhD, a researcher at the University of Wisconsin-Madison, wrote an article for Foundation Fighting Blindness explaining the ten things we should know before falling victim to a retinal stem cell scam. Even if the treatment does not cause physical harm, it can result in significant financial damage; therefore, it is important to be aware of these scams.
ProQR Therapeutics announces positive findings from a planned three-month interim analysis of its Phase I/II Stellar trial of QR-421a to treat retinitis pigmentosa (RP) in adults who have Usher syndrome type 2 or non-syndromic RP due to mutations in a specific part of the USH2A gene, called exon 13. QR-421a, ProQR’s experimental RNA therapy is designed to skip exon 13 in the RNA with the aim to stop or reverse vision loss. QR-421a given as a single intravitreal injection was safe and well-tolerated. It also showed early and encouraging evidence of activity, with 25% of patients showing a benefit across multiple outcome measures.
What this means for Usher syndrome: While this particular experimental drug is only applicable to those with Usher syndrome due to mutation(s) in exon 13 of the USH2A gene, early positive findings mean that the trial will continue as designed and could lead to other RNA/drug therapies that will benefit people with Usher syndrome caused by other mutations.
For the first time, scientists have used the gene-editing technique CRISPR to try to edit a gene while the DNA is still inside a person’s body. The procedure involved injecting the microscopic gene-editing tool into the eye of a patient blinded by a rare genetic disorder, in hopes of enable the participant to see. Researchers hope to know within weeks with the approach is working and, if so, to know within two or three months how much vision will be restored.
What this means for Usher syndrome: If successful, this will be a huge step forward towards the development of therapies to restore vision in Usher patients.
Ocugen Inc., a clinical-stage company focused on discovering, developing, and commercializing transformative therapies to treat rare ophthalmic diseases, announced today in the publication in 'Nature Gene Therapy' preclinical data of nuclear hormone receptor gene NR2E3 as a genetic modifier and therapeutic agent to treat multiple retinal degenerative diseases. The publication details efficacy results in five different mouse models of RP that underwent administration of NR2E3-AAV by subretinal injection. The study demonstrates the potency of a novel modifier gene therapy to elicit broad-spectrum therapeutic benefits in early and intermediate stages of RP.
What this means for Usher syndrome: This gene modifier has been successfully tested in five genetic mouse models for RP. Although nothing is known regarding the involvement of this modifier in Usher syndrome, it will be interesting to know whether this modifier can rescue photoreceptor activity in animal models for Usher syndrome. If it does, it will mean it can be used in gene therapy or as a drug target.
Allergan, a global pharmaceutical company, and Editas Medicine, a genome editing company, have announced treatment of the first patient in the BRILLIANCE clinical trial for AGN-151587 (EDIT-101) at Oregon Health & Science University (OHSU) Casey Eye Institute. AGN-151587 is a CRISPR-based experimental medicine under development for the treatment of Leber congenital amaurosis 10 (LCA10), an inherited form of blindness cau sed by mutations in the centrosomal protein 290. This potential treatment targets photoreceptor cells and is delivered via sub-retinal injection. The BRILLIANCE clinical trial is the world’s first human study of an in vivo (inside the body) CRISPR genome editing medicine, and is currently in Phase I/2 to assess the safety, tolerability, and efficacy of AGN-151587 in approximately 18 patients with LCA10.
What this means for Usher syndrome: If the clinical trial is successful, this CRISPR-based treatment which targets photoreceptor cells may be an option for other forms of blindness, including Usher syndrome.
There are hundreds of millions of rare disease patients, half of them children, whose conditions are not getting enough funding for research and treatment. However, by banding together, the patients are changing how the medical community responds to their diseases. A highly organized group of patients can play a pivotal role in accelerating medical research. The need is immense. Similar to cystic fibrosis, many rare diseases are deeply debilitating, if not deadly. Individually they are rare but are remarkably common. Roughly about 25-30 million Americans are living with a rare disease and roughly 400 million worldwide.
What this means for Usher syndrome: It is important that those of us who are living with Usher syndrome continue to spread awareness and advocate for research on Usher syndrome.
In this USH Talk, Marcia Brooks shares an overview of iCanConnect, the National Deaf-Blind Equipment Distribution Program. iCanConnect provides free equipment and training to people with both significant hearing and vision loss who meet federal disability and income eligibility guidelines. iCanConnect is a national program with local contacts.
The ReNeuron Group has announced positive long-term data from its ongoing phase 1/2a clinical trial of its hRPC (human retinal progenitor cells) stem cell therapy candidate in Retinitis Pigmentosa. In October 2019 at the American Academy of Ophthalmology Meeting in San Francisco, data presented by Pravin Dugel, MD showed “a group of subjects who had a successful surgical procedure with sustained clinically relevant improvements in visual acuity compared with baseline, as measured by the number of letters read on the ETDRS chart.” The company has submitted a protocol amendment to the FDA to expand their 1/2a study to treat up to a further nine patients in the phase 2a segment of the study with a dose of two million hRPC cells compared to the dose of one million cells used so far. The amended trial protocol allows for a greater range of pre-treatment baseline visual acuity in patients and includes changes that enhance the ability to use microperimetry testing to measure and detect changes in retinal sensitivity in patients treated. If the amendment is approved the company expects to have sufficient data to commence a pivotal clinical study with its hRPC cell therapy candidate in RP by 2021. Furthermore, this clinical program has been granted Orphan Drug Designation in Europe and the US, as well as Fast Track designation from the FDA.
What this means for Usher syndrome:That Usher patients may benefit from this stem cell therapy in the near future if the amendment is approved and the company obtain sufficient data for the initiation of the pivotal clinical trial .
Gene-infused nanoparticles used for combating disease work better when they include plant-based relatives of cholesterol because their shape and structure help the genes get where they need to be inside cells. The type of nanoparticle used to deliver genes in this study has already been clinically approved; it's being used in a drug given to patients with a progressive genetic condition called amyloidosis.
What this means for Usher syndrome: This new nanoparticle composition could be a more efficient alternative strategy to deliver the wild type gene into the photoreceptors of Usher patients.
Usher syndrome, a genetic condition that results in hearing and vision loss in childhood, affects about 4 out of every 100,000 Canadians. Fighting Blindness Canada (FCB) has provided new funding that will allow Vincent Tropepe, the professor and departmental chair of cell and systems biology in the Faculty of Arts & Science, to try to identify the causes of retinal degeneration due to Usher. Tropepe’s lab will focus on a particular protein associated with the mutated gene that is also thought to be crucial to the photoreceptors’ larger support system. If researchers can find defects in this protein and the structure it is part of, they may be able to reveal new mechanisms that maintain the stability and functionality of the photoreceptors.
What this means for Usher syndrome: If they can find an association between photoreceptor survival and this protein, this will lead to novel gene therapy strategies and, maybe to the discovery of therapeutic drugs that will help to stabilize the larger photoreceptor structure when that particular protein is dysfunctional.