Year Identified: 1998
Each research project listed below will include a graphic of the research continuum. The gold box indicates where this project falls on the continuum, illustrating its progress towards reaching people living with Usher syndrome, from "Bench to Bedside."
RUSH2A Natural History Study
According to Dr. Jacque Duncan, RUSH2A Study Chair, "Natural history studies are important to prepare investigators to design clinical trials. It's essential to know how vision is affected in patients with USH2A mutations in order to determine what to measure and how much change we expect to see over time, in order to know whether a potential treatment improves the vision or decreases the rate of vision loss in the long run."
ProQR's Stellar Clinical Trial
March 2021 Update: 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. Stellar study, Phase 1/2 clinical trial showed investigational RNA therapy QR-421a is effective and safe. ProQR plans to start final phase trials for people with USH2A mediated retinitis pigmentosa. With only one injection of QR-421a, the Stellar study showed benefit in the treated eye in comparison to the untreated eye across multiple eye tests. This benefit was seen across all participants in the Stellar study, which included clinical trial participants with both advanced vision loss as well as early to moderate vision loss. Based on these positive results, ProQR plans to conduct two final stage clinical trials or Phase 2/3 trials. ProQR will work with regulators to submit clinical trial protocols for two final stage registration trials called Sirius and Celeste. For more information on the safety & efficacy of the Stellar trial, please read ProQR’s Community Statement, QR-421a program update March 2021.
STELLAR or PQ-421a-001, is a first-in-human study that will initially include approximately 18 adults with vision loss due to mutations in exon 13 of the USH2A gene and will be conducted at about seven expert sites in North America and Europe. QR-421a is designed to exclude exon 13 from the USH2A mRNA, thereby removing the mutation in exon 13. This approach is also known as exon skipping. RNA is the "blueprint" for protein synthesis, and the skipping of exon 13 in the "blueprint" is expected to lead to a shortened but functional Usherin protein.
- Link to study details on ClinicalTrials.gov
- View presentation on this study from the USH2019 Connections Conference
Pre-clinical USH2A c.2299delG mutation gene editing using the CRISPR system
Carla Fuster Garcia, Ph.D. and her team at Instituto de Investigación Sanitaria La Fe in Valencia, Spain have successfully investigated CRISPR/Cas9 gene editing in USH2A c.2299delG mutation on fibroblasts. In vitro mutation repair was demonstrated to be successful. The proven effectiveness and specificity of these correction tools indicate that the CRISPR system should be considered to further explore a potential treatment of Usher syndrome.
AON-based splice correction for the USH2A deep intronic c.7595-2144A>G mutation
Erwin van Wijk, Ph.D. and his team at Radboud University Medical Center Nijmegen in the Netherlands are utilizing an AON-based splice correction as an approach for the development of a future treatment for USH2A-associated Retinitis Pigmentosa caused by the deep-intronic c.7595-2144A>G mutation.
Prime Editing for Usher Syndrome Type 2A
Bence György, MD, PhD:
Institute of Molecular and Clinical Ophthalmology Basel (IOB)
Dr. György is developing a gene correction strategy known as prime editing, a novel technology that is in some ways similar to gene editing with CRISPR/Cas9, but potentially more precise and efficient. Instead of cutting the double strands of DNA, it nicks the DNA, which may be a preferred approach to correcting single-letter mutations. Dr. György is developing a prime editing treatment to insert the missing G nucleotide into retinal cells with the relatively common USH2A mutation del2299G. In order to facilitate translation of this concept to the clinic, he will evaluate the therapy in human retinal explants, human engineered retinal organoids and humanized mouse models. If the approach is successful, it may be applied to other mutations and IRDs.
USH2A-Related Science News
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.
Usherin, a protein associated with the USH2A gene that causes Usher Syndrome Type 2A, helps us see and hear. A new study has discovered that this protein may also be involved in a third sense – the sense of touch. Researchers found Usherin protein in the “Meissner corpuscle”, which is a nerve ending in the skin of our fingers. When the production of Usherin is affected due to a mutation in the USH2A gene, this results in Usher syndrome, with known impairments in vision and hearing. It is now thought also to be involved with touch. Experiments were performed with two groups of mice, with and without the USH2A gene. Both groups of mice were able to detect temperature changes and pain, but the mice with USH2A were better at detecting low levels of vibrations than the mice without this gene.
What this means for Usher syndrome:
This discovery increases our understanding of the USH2A gene, the Usherin protein, and how they are connected to our senses. These insights may lead to additional research and discoveries that may one day, turn into a cure for Usher syndrome.
Researchers in China have identified a new USH2A gene mutation in an individual with Usher syndrome type 2. Mutations are genetic changes that affect the proper function of the gene and/or the protein it encodes. Identifying and understanding a genetic mutation is important because it opens up the possibility of gene therapy in the future. Here, the researchers used a technique called targeted exome sequencing (TES), where they analyzed thousands of genes at one time to look for changes or new information. In this case, they found that this new mutation blocks important proteins from being made. This new discovery not only provides more insights into the causes of Usher Syndrome Type 2A, but also demonstrates advantages that TES can bring to Usher syndrome researchers.
What this means for Usher syndrome:
With the discovery of this new mutation, researchers are continuing to learn more about Usher syndrome and the causes behind it. Over time, this may lead to new gene therapies, treatments, or possibly a cure one day.
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.
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.
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.
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.
How do you cope with living with Usher syndrome? What strategies do you use to overcome challenges? In this USH Talk, Dr. Moa Wahlqvist summarizes the findings from the first qualitative scientific study of its kind, exploring the strategies described by 14 people with Usher syndrome type 2 seeking to remain active agents in their own lives.
Inherited retinal dystrophies (IRDs) are characterized by progressive photoreceptor degeneration and vision loss. Usher syndrome (USH) is a syndromic IRD characterized by retinitis pigmentosa (RP) and hearing loss. USH is clinically and genetically heterogeneous, and the most prevalent causative gene is USH2A. USH2A mutations also account for a large number of isolated autosomal recessive RP (arRP) cases. This high prevalence is due to two recurrent USH2A mutations, c.2276G>T and c.2299delG. Due to the large size of the USH2A cDNA, gene augmentation therapy is inaccessible. However, CRISPR/Cas9-mediated genome editing is a viable alternative. We used enhanced specificity Cas9 of Streptococcus pyogenes (eSpCas9) to successfully achieve seamless correction of the two most prevalent USH2A mutations in induced pluripotent stem cells (iPSCs) of patients with USH or arRP. Our results highlight features that promote high target efficacy and specificity of eSpCas9. Consistently, we did not identify any off-target mutagenesis in the corrected iPSCs, which also retained pluripotency and genetic stability. Furthermore, analysis of USH2A expression unexpectedly identified aberrant mRNA levels associated with the c.2276G>T and c.2299delG mutations that were reverted following correction. Taken together, our efficient CRISPR/Cas9-mediated strategy for USH2A mutation correction brings hope for a potential treatment for USH and arRP patients.
What this means for Usher syndrome: Although still in its initial steps, the implementation of this type of strategy will people with Usher the possibility of replacing the defective photoreceptors with their own corrected ones. This will be especially relevant for those patients carrying mutations in some of the largest genes.
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.
ProQR Therapeutics announced that the FDA has cleared the Investigational New Drug (IND) application for QR-421a. QR-421a is a first-in-class investigational RNA-based oligonucleotide designed to address the underlying cause of the vision loss associated with Usher syndrome type 2 and non-syndromic retinitis pigmentosa due to mutations in exon 13 of the USH2A gene. ProQR plans to start enrolling patients in a Phase 1/2 trial named STELLAR in the coming months with preliminary data expected in mid-2019.
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.
In this USH Talk, Dr. Hannie Kremer explains genetic testing of the USH2A gene, as conducted at the Radboud University Medical Center in Nijmegen, Netherlands.
Jennifer Phillips, Ph.D. recaps ARVO 2017 Day 2 with highlights on Usher syndrome type 2A research from Erwin van Wijk and colleagues at Radboud University Medical Center in the Netherlands and RP research by Neena Haider and her team at Massachusetts Eye and Ear.
In this USH Talk, Dr. Erwin van Wijk shows that AON-based splice correction could be a promising approach for the development of a future treatment for USH2A-associated retinitis pigmentosa caused by the deep-intronic c.7595-2144A>G mutation.
Our latest USH Talk features researcher Dr. Jacque Duncan from the University of California, San Francisco. Dr. Duncan shares an overview of an upcoming clinical trial that aims to study the rate of progression of USH2A related retinal degeneration: The RUSH2A Study.
Researchers study genotype–phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP.
Researchers investigated the proportion of exon deletions and duplications in PCDH15 and USH2A in 20 USH1 and 30 USH2 patients from Denmark.
Since I've spent the past few days talking in generalities, I’ll spend today’s blog giving a brief overview on the research specifically dealing with Usher syndrome.
Foundation Fighting Blindness' deputy chief research officer, Dr. Brian Mansfield, explains how retinal researchers are working with induced pluripotent stem cells (iPSC), a patient's own skin cells, to gain a better understanding of the RP caused by defects in the gene USH2A. This basic research provides critical information for developing future treatments.
Steele-Stallard, Le Quesne Stabej P, Lenassi E, Luxon LM, Claustres M, Roux AF, Webster AR, Bitner-Glindzicz M..
Screening for duplications, deletions and a common intronic mutation detects 35% of second mutations in patients with USH2A monoallelic mutations on Sanger sequencing. An overview of a study to improve the molecular diagnosis in families with USH2A by screening USH2A for duplications.
Whew! Day 4 is in the books, and what a day it was. I saw more excellent science presentations than I can count (and a few disappointing ones, too, but that’s a story for another day). I engaged in stimulating discussions about research directions throughout the day and managed to catch sight of a few Seattle landmarks while walking and talking with a colleague before hunkering down in my quaint little hotel room to write this up.
Since my return to blogging with an analysis of recent peer-reviewed literature on Usher research, another paper that will probably have relevance to a lot of our blog readers has come to my attention. In contrast to those first two papers on new Usher genes, however, this one isn’t exactly a cause for celebration.
Today was an 11-hour maelstrom* of really good science. Of all the great research stories I heard, there are several that will likely be of interest to our readers: