General Research News
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The National Institutes of Health (NIH), the U.S. Food and Drug Administration (FDA), 10 pharmaceutical companies, and five non-profits have partnered as the Bespoke Gene Therapy Consortium (BGTC) to help speed up the development of gene therapies for rare diseases.
Professor Uwe Wolfrum of the Institute of Molecular Physiology at Johannes Gutenberg University Mainz and Professor Reinhard Lührmann at the Max Planck Institute for Biophysical Chemistry in Göttingen have identified a new pathway that leads to Usher syndrome (USH).
A recent study has estimated the annual cost of inherited retinal diseases (IRDs) in the United States and Canada from a societal perspective, including the cost to the health care system, human productivity costs, lost wellbeing and other societal economic costs.
Retinitis pigmentosa (RP) is a rare genetic disease that causes loss of photoreceptors, which are the light sensitive cells in the retina. This disease can lead to blindness and affects more than 2 million people worldwide. In a groundbreaking clinical trial led by Paris-based GenSight Biologics, a man who was blind for 40 years successfully regained some visual function with a technique called optogenetics. Optogenetics uses light to control neuron activity. In this study, a light-sensing protein called ChrimsonR was injected into the eye and delivered to the patient’s retinal cells. After a four-month period to allow his body to make ChrimsonR protein, the patient was fitted with special goggles that detect and shift incoming light into a specific color range. The patient was able to see high-contrast images and objects, and his brain activity was the same as someone with normal sight.
What this means for Usher syndrome:
More patients will need to be enrolled and evaluated, but if this study proves to be successful, RP patients who are blind may be able to regain some sight, increasing their quality of life. Because vision loss in Usher syndrome is a type of RP, this therapy may also be beneficial for Usher syndrome patients.
Researchers inject patients' retina with own platelet rich plasma as possible treatment option.
ProQR has published positive results from its Phase 1/2 Stellar trial of QR-421a, an investigational RNA therapy for the treatment of Usher syndrome and retinitis pigmentosa (RP) due to mutation(s) in exon 13 of the USH2A gene.
Photoreceptor precursor cells that were generated from stem cells were able to be successfully transplanted into the retina and demonstrate basic visual function.
A type of laser light therapy called photobiomodulation shows promising results in the ability to preserve retinal performance, structure and function.
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.
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.
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.
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.
Mice born blind have shown significant improvement in vision after undergoing new gene therapy developed by a team of Japanese scientists. This new method is an alternative strategy of gene supplementation, which involves supplementing the defective gene, such as the ones that can lead to inherited retinal degeneration with a healthy one. The healthy gene is delivered through an AAV vector, but the virus can only hold a small healthy gene. Therefore, patients with large genes cannot be treated with this method. This new gene therapy combines AAV vector delivery with CRISPR-Cas9 technology, this way researchers can target a specific defective gene, cut it out and glue in a healthy replacement. This approach rescued 10% of the photoreceptors, resulting in a visual improvement very similar to gene supplementation therapy.
What this means for Usher syndrome: This is an alternative strategy that can be developed into new therapies to treat Usher patients, but only those harboring mutations in the small genes (USH1C, USH1G, DFNB31 and USH3A).
ProQR Therapeutics N.V. (Nasdaq:PRQR), a company dedicated to changing lives through the creation of transformative RNA medicines for severe genetic rare diseases, announced today its participation in the Foundation Fighting Blindness My Retina Tracker Program, a collaborative, open access program run by Blueprint Genetics and InformedDNA providing no-cost genetic testing and genetic counseling for individuals with a clinical diagnosis of an inherited retinal disease (IRD) such as Leber’s congenital amaurosis (LCA) and Usher syndrome, amongst others.
USH2A variants are the most common cause of Usher syndrome type 2, characterised by congenital sensorineural hearing loss and retinitis pigmentosa (RP), and also contribute to autosomal recessive non-syndromic RP. Several treatment strategies are under development, however sensitive clinical trial endpoint metrics to determine therapeutic efficacy have not been identified. In the present study, scientists performed longitudinal retrospective examination of the retinal and auditory symptoms in (i) 56 biallelic molecularly-confirmed USH2A patients and (ii) ush2a mutant zebrafish to identify metrics for the evaluation of future clinical trials and rapid preclinical screening studies. The patient cohort showed a statistically significant correlation between age and both rate of constriction for the ellipsoid zone length and hyperautofluorescent outer retinal ring area. Visual acuity and pure tone audiograms are not suitable outcome measures. Retinal examination of the novel ush2au507 zebrafish mutant revealed a slowly progressive degeneration of predominantly rods, accompanied by rhodopsin and blue cone opsin mislocalisation from 6-12 months of age with lysosome-like structures observed in the photoreceptors. This was further evaluated in the ush2armc zebrafish model, which revealed similar changes in photopigment mislocalisation with elevated autophagy levels at 6 days post fertilisation indicating a more severe genotype-phenotype correlation, and providing evidence of new insights into the pathophysiology underlying USH2A-retinal disease.
What this means for Usher syndrome: If the involvement of autophagy, the body's way of cleaning out damaged cells, is confirmed in RP patients, this means that novel therapies targeting autophagy will help to alleviate the progression of the retinitis pigmentosa in Usher patients.
A team of researchers from Massachusetts Eye and Ear have identified a cellular entry factor for the adeno-associated virus vector (AAV) types—the most commonly used virus vector for in vivo gene therapy. The researchers identified that GPR108, a G protein-coupled receptor, served as a molecular lock to the cell. GPR108 is required for most AAVs, including those used in approved gene therapies, to gain access to the cell. Since gaining cellular access is a crucial step in delivering gene therapy, this discovery may provide a crucial piece of information that could one day enable scientists to better explain, predict, and direct AAV gene transfers to specific tissues.
What this means for Usher syndrome: This discovery may improve the chances for targeting gene therapy for Usher syndrome.
Scientists at the Italian Institute of Technology have created the first-ever artificial retina to be made only from organic materials: a substrate derived from a soy protein, a conductive polymer, and a semiconductor. The retina is designed to work like a solar panel, “converting light into electrical signal, which is transmitted to the retina’s neurons.” Because these artificial retinas are made from organic materials, they should be more compatible and reduce the risk of being rejected by the body after the operation.
What this means for Usher syndrome: This work may one day lead to retinal implants to treat vision loss in Usher patients.
Patients from the same family and carriers of the same genetic mutation, develop a disease differently. This disparity may be due to the existence of mutations in other secondary genes that influences the onset and progression of the disease caused by the primary mutation. Two researchers from Dr. Cerón’s group, Dmytro Kukhtar and Karina Rubio-Peña, from Bellvitge Biomedical Research Institute (IDIBELL), have worked on this topic in the last few years. Utilizing CRISPR gene-editing technology, they introduced in C. elegans worms, mutations that cause RP in humans. Next, these mutations were classified into two groups: those that caused an obvious problem to worms and those that did not. Worms that were not affected by human mutations were used to search for other genes whose inactivation caused alterations in the mutant worms, but not in the control worms. Three genes were identified as candidate disease modifiers that may interact with the primary mutation to affect disease progression. The researchers then identified drugs that were harmful to worms harboring patient mutations, but not control worms.
What this means for Usher syndrome: Although it is important to find drugs that cure, it is also important to identify those drugs that could be harmful to patients with known genetic mutations.
21 pathogenic mutations in the USH2A gene have been identified in 11 Chinese families by using the targeted next-generation sequencing (NGS) technology. We identified 21 pathogenic mutations, of which 13, including 5 associated with RP and 8 with USH II, have not be been previously reported. Visual impairment and retinopathy were consistent between the USH II and non-syndromic RP patients with USH2A mutations. These findings provide a basis for investigating genotype-phenotype relationships in Chinese USH II and RP patients and for clarifying the pathophysiology and molecular mechanisms of the diseases associated with USH2A mutations.
What this means for Usher syndrome: This study provides additional genetic information about Usher syndrome type 2.
Mojo, a startup company, has recently developed a contact lens that can be used like a smartphone. The goal is to develop lenses that show you a menu and options when you want them and hide them when you don’t. These lens would not only be functional with smart options, but could also be fitted with a patients prescription. The goal of these lenses is to provide assistance in mobility and reading for those with poor vision. The clinic trials of these lenses will take place in Palo Alta at the Vista Center for the Blind and Visually Impaired and will be focus on patients who suffer from retinitis pigmentosa and macular degeneration.
What this means for Usher syndrome: These devices may be able to assist patients with Usher syndrome.
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.
Biblical references aside, restoring vision to the blind has proven to be a major technical challenge. In recent years, considerable advances have been made towards this end, especially when retinal degeneration underlies the vision loss such as occurs with retinitis pigmentosa. Under these conditions, optogenetic therapies are a particularly promising line of inquiry where remaining retinal cells are made into "artificial photoreceptors". However, this strategy is not without its challenges and a model system using human retinal explants would aid its continued development and refinement. Here, we cultured post-mortem human retinas and show that explants remain viable for around 7 days. Within this period, the cones lose their outer segments and thus their light sensitivity but remain electrophysiologically intact, displaying all the major ionic conductances one would expect for a vertebrate cone. We optogenetically restored light responses to these quiescent cones using a lentivirus vector constructed to express enhanced halorhodopsin under the control of the human arrestin promotor. In these 'reactivated' retinas, we show a light-induced horizontal cell to cone feedback signal in cones, indicating that transduced cones were able to transmit their light response across the synapse to horizontal cells, which generated a large enough response to send a signal back to the cones. Furthermore, we show ganglion cell light responses, suggesting the cultured explant's condition is still good enough to support transmission of the transduced cone signal over the intermediate retinal layers to the final retinal output level. Together, these results show that cultured human retinas are an appropriate model system to test optogenetic vision restoration approaches and that cones which have lost their outer segment, a condition occurring during the early stages of retinitis pigmentosa, are appropriate targets for optogenetic vision restoration therapies.
What this means for Usher syndrome: For Usher patients, this means that there is a therapeutic window during which cones can be “rescued” from dying and their “normal” activity restored. Although still too premature, this type of treatment in combination with strategies to correct the mutated Usher protein will help to slow or even stop the progression of the disease.
The aim of this study is to determine if umbilical cord Wharton’s jelly derived mesenchymal stem cells implanted in sub-tenon space have beneficial effects on visual functions in RP patients by reactivating the degenerated photoreceptors in dormant phase. 32 RP patients participated in the study and were followed for 6 months after the Wharton’s jelly derived mesenchymal stem cell administration. Regardless of the type of genetic mutation, sub-tenon Wharton's jelly derived mesenchymal stem cell administration appears to be an effective and safe option. There are no serious adverse events or ophthalmic / systemic side effects for 6 months follow-up. Although the long-term adverse effects are still unknown, as an extraocular approach, subtenon implantation of the stem cells seems to be a reasonable way to avoid the devastating side effects of intravitreal/submacular injection.
What this means for Usher syndrome: If successful, this stem cell therapy will help Usher patients to recover their vision while minimizing the invasive adverse effects of the treatment.
Researchers at the University of New Hampshire have reported the first structural model for a key enzyme, PDE6, and its activating protein that play a role in some genetically inherited eye diseases, such as retinitis pigmentosa and night blindness. Creating atomic-level models is important for locating PDE6 mutations because we can learn to understand why they cause disease and develop new therapeutic interventions to manage retinal diseases. Michael Irwin, doctoral student in biochemistry stated, “Having detailed structural information about how PDE6 is activated by transduction will help us understand the molecular causes of visual disorders and blinding diseases resulting from mutations in these proteins.” Current treatments for genetically inherited retinal diseases may include gene therapy or drugs meant to inhibit the disease process. However, the drugs are not always successful in restoring the balance of PDE6 and preventing blindness.
What this means for Usher syndrome: By knowing the molecular structure of these visual signaling proteins and how they interact with each other can offer clues for the development of new drugs to restore vision and prevent blindness.
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.
Researchers at the National Eye Institute are launching a clinical trial to test the safety of a novel patient-specific stem cell-based therapy to treat geographic atrophy, the advanced “dry” form of age-related macular degeneration (AMD), a leading cause of vision loss among people age 65 and older. This is the first clinical trial in the USA to utilize replacement tissues from patient-derived induced pluripotent stem cells (iPSC). Under the phase I/IIa clinical trial protocol, 12 patients with advanced-stage geographic atrophy will receive the iPSC-derived RPE implant in one of their eyes. The patients will be closely monitored for at least one year to confirm safety.
What this means for Usher syndrome: This trial could pave the way to stem cell treatments of other eye diseases, including Usher syndrome.
Neuroscientists at Lund University in Sweden have developed a new technology that engineers the shell of a virus to deliver gene therapy to the precise cell type that needs to be treated. According to neuroscientist Tomas Björklund, “Thanks to this technology, we can study millions of new virus variants in cell culture and animal models simultaneously. From this, we can subsequently create a computer simulation that constructs the most suitable virus shell for the chosen application.” With this new method, researchers have been able to reduce the need for laboratory animals significantly because millions of the variants of the same drug are studied in the same individual. Additionally, they have been able to move important parts of the study from animals to cultured human stem cells.
What this means for Usher syndrome: This study provides potential methods to deliver genes effectively to the appropriate cells required for vision.
The identification of genetic defects that underlie inherited retinal diseases (IRDs) paves the way for the development of therapeutic strategies. Nonsense mutations result in a premature termination codon (PTC) and cause approximately 12% of all IRD cases. An approach that targets nonsense mutations could be a promising pharmacogenetic strategy for the treatment of IRDs. We provide novel data on the read-through efficacy of Ataluren, a translational read-through inducing drug (TRID), on a nonsense mutation in the Usher syndrome gene USH2A that causes deafblindness in humans. We validated Ataluren's efficacy to induce read-through on a nonsense mutation in USH2A-related IRD. Our findings support the use of patient-derived fibroblasts as a platform for the validation of preclinical therapies.
What this means for Usher syndrome:This study tests a potential therapy that could be used to treat Usher syndrome patients who have nonsense mutations.
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.
Retinitis Pigmentosa targets the rod and cone photoreceptor cells, but the disease does minimal damage to the retina’s many other neurons, which “process signals from the rods and cones and convey the results to the optic nerve.” One way to restore vision is to replace the damaged photoreceptors with a device that generates electrical pulses in response to light. Through the various points on the device, pulses can communicate with the retina’s surviving neurons in a natural way. Lanzani and colleagues at IIT are investigating a new kind of retinal prosthesis made from semi-conductive polymers, a class of carbon-based plastics that can conduct electricity in the same way that silicon microchips do.
What this means for Usher syndrome: Researchers are developing new types of prosthetics that will replace damaged photoreceptors and potentially restore vision for those with RP.
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.
A major challenge in the treatment of retinal degenerative diseases, with the transplantation of replacement photoreceptors, is the difficulty in inducing the grafted cells to grow and maintain light sensitive outer segments in the host retina, which depends on proper interaction with the underlying retinal pigment epithelium (RPE). Here, for an RPE-independent treatment approach, we introduce a hyperpolarizing microbial opsin into photoreceptor precursors from newborn mice, and transplant them into blind mice lacking the photoreceptor layer. These optogenetically-transformed photoreceptors are light responsive and their transplantation leads to the recovery of visual function, as shown by ganglion cell recordings and behavioral tests. Subsequently, we generate cone photoreceptors from human induced pluripotent stem cells, expressing the chloride pump Jaws. After transplantation into blind mice, we observe light-driven responses at the photoreceptor and ganglion cell levels. These results demonstrate that structural and functional retinal repair is possible by combining stem cell therapy and optogenetics.
What this means for Usher syndrome: Although it is still too early, we can hope that, in the future, a therapy like this will be available to people suffering from retinitis pigmentosa. If that is the case, people with Usher syndrome will be able to undergo photoreceptor transplantation to recover visual function.
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.
Currently, there are no studies on life strategies in people with Usher syndrome and people with deafblindness are often described in terms of poor health and low quality of life. From a clinical standpoint, it is important to balance this picture with an increased knowledge of life strategies. Fourteen people between the ages of 20 to 64 years with USH2A in Sweden participated in focus group interviews, which were transcribed and analyzed by qualitative content analysis. The findings show that people with USH2A have a variety of life strategies that can be interpreted as highlighting different aspects of psychological flexibility in a life adjustment process. The study demonstrates that people with USH2A manage in many ways, and metaphorically, by “taking the helm,” they strive to actively navigate towards their own chosen values.
What this means for Usher syndrome: More studies like the one described here will help Usher patients to look for strategies to cope with this disease and improve their quality of life.
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 aim of this study is to report the prevalence of treatable complications—cystoid macular edema (CME), epiretinal membrane (ERM), and cataract—in patients with retinitis pigmentosa. Spectral domain-optical coherence tomography was used to determine the presence of CME and ERM. Clinic records were reviewed to identify cataract and pseudophakia. The prevalence of treatable RP complications is high and suggests it may be clinically beneficial to screen patients with RP to identify those who may benefit from current or future interventions.
What this means for Usher syndrome: Clinicians will be able to screen Usher patients for CME, ERM or cataract and treat them accordingly.
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.
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.
This study was aimed at understanding the anatomical choroidal features with the presence of cystoid macular edema (CME) in eyes with Retinitis Pigmentosa (RP). A total of 159 RP patients were enrolled in this cross-sectional case-control study and divided into two groups based on the presence or absence of CME. The retinal and choroidal features were evaluated on spectral domain optical coherence tomography including central macular thickness (CMT) and subfoveal choroidal thickness (CT). In patients with CME associated with RP, the choroid exhibited significant greater subfoveal thickening and decreased choroidal vascular index. The choroid may be an important factor to consider in the etiology of CME in patients with RP.
What this means for Usher syndrome: Since CME is a treatable complication, this study supports the choroid as an important therapeutic target in Usher patients. Moreover, further studies into the mechanism of disease progression will facilitate the search for more efficacious treatments for these patients.
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.
In this study, we proposed a new method for evaluating the results based on the sizes of the phosphenes that the patient drew. Additionally, we described the methodology of psychological testing and support for a deaf-blind patient. The patient with the retinal prosthesis, Argus II, felt more independent, confident, and healthier.
What this means for Usher syndrome: The results of this study provide a better understanding of retinal implants for patients with vision loss.
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.
To describe the genetic and phenotypic spectrum of Usher syndrome after 6 years of studies by next-generation sequencing, researchers propose an up-to-date classification of Usher genes in patients. The systematic review and meta-analysis protocol were based on the Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Researchers performed (1) a meta-analysis of data from 11 next-generation sequencing studies in patients with Usher syndrome and (2) a meta-analysis of data from 21 next-generation studies in 2,476 patients to assess the involvement of Usher genes in nonsyndromic hearing loss, and then 3) a statistical analysis of the differences between parts 1 and 2. The new findings provide evidence that Usher protein dysfunction is the second cause of genetic sensorineural hearing loss after connexin dysfunction.
What this means for Usher syndrome: These results will promote the inclusion of early genetic screening for all the Usher genes in deaf children and also it will help to establish the proportion of patients that will be at high-risk of developing retinitis pigmentosa.
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.
Scientists have developed a retinal implant that can restore lost vision in rats and are planning to trial the procedure in humans later this year. The implant made from a thin layer of conductive polymer, placed on a silk-based substrate and covered with semiconducting polymer, is being developed into a prosthetic that serves as a working replacement for a damaged retina. Based on results from initial studies, the team has concluded that the implant directly activates “residual neuronal circuitries in the degenerate retina.” Although there are no guarantees that results obtained in rats will translate to humans, the team is hopeful that they will.
What this means for Usher syndrome: This is another example of a prosthetic that could potentially replace damaged photoreceptors and potentially restore vision for those with RP.
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.