Year Identified: 2001
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."
Gene Therapy USH3A
Astra Dinculescu, Ph.D.:
University of Florida
Dinculescu and her team at the University of Florida have been working on developing therapeutic approaches for USH3A, which is caused by mutations in a small gene: Clarin-1 (CLRN1). Perinatal transfection of hair cells in mice with a single injection of AAV-Clrn1-UTR vector showed preservation of the hair bundle structure and hearing throughout adult life. Additionally, they are investigating on optimized AAV-vector designs to develop a gene therapy treatment for the vision loss in USH3A with the potential to provide a basis for future clinical trials in humans.
Dr. Astra Dinculescu's Lab Page
Link to Relevant Publication
Developing an Animal Model with USH3A
Kumar Alagramam, Ph.D.:
Case Western Reserve University
Alagramam is working with Case Western Reserve University and University Hospitals in Cleveland, OH on a technology that allows to develop a more precise animal model of hearing loss associated with USH3A and that has the potential to preserve the hearing through gene therapy and to serve as a basis for development of gene therapies for other types of Usher syndrome.
Link to Relevant Grant
Link to Relevant Publication
Developing Drugs for USH3A (N48K Mutation)
Yoshikazu Imanishi, Ph.D.:
Case Western Reserve University School of Medicine
Imanishi and his team are working on to develop therapies for USH3A with a focus on the N48K mutation. N48K is one of the most frequent mutations in USH3A. Imanishi studies the clarin-1 (CLRN1) protein in USH3A with the N48K mutation in cultivated cells. A study demonstrated that the N48K mutation makes the CLRN1 protein unstable. As a result of the instability, the rods and cones of patients with the mutation show a lack of functional CLRN1 proteins. Imanishi has been experimenting with different drugs such as BF844 that can stabilize the CLRN1 protein.
Dr. Yoshikazu Imanishi's Lab Page
Link to Relevant Publication
USH3A-Related Science News
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.
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.
Geng R, Omar A., Gopal SR, Chen DH, Stepanyan R, Basch ML, Dinculescu A, Furness DN, Saperstein D, Hauswirth W, Lustig LR, Alagramam KN
Researchers developed a new USH3 mouse model that displays delayed-onset progressive hearing loss, then tested a viral therapy to preserve hearing in the mouse models. Their results show that gene therapy is a promising approach to preserve hearing in USH3 patients.
Kumar N Alagramam, Suhasini R Gopal, Ruishuang Geng, Daniel H-C Chen, Ina Nemet, Richard Lee, Guilian Tian, Masaru Miyagi, Karine F Malagu, Christopher J Lock, William R K Esmieu, Andrew P Owens, Nicola A Lindsay, Krista Ouwehand, Faywell Albertus, David F Fischer, Roland W Bürli, Angus M MacLeod, William E Harte, Krzysztof Palczewski & Yoshikazu Imanishi.
A new study published in Nature Chemical Biology reports the first small molecule targeted therapy for progressive hearing loss in a mouse model of USH3, an USH classified by progressive loss of hearing and vision starting in the first few decades of life along with variable balance disorder.
Astra Dinculescu, Rachel M. Stupay , Wen-Tao Deng, Frank M. Dyka, Seok-Hong Min, Sanford L. Boye, Vince A. Chiodo, Carolina E. Abrahan, Ping Zhu, Qiuhong Li, Enrica Strettoi, Elena Novelli, Kerstin Nagel-Wolfrum, Uwe Wolfrum, W. Clay Smith, William W. Hauswirth.
The ongoing challenge to develop an animal model mimicking the effects of Usher III (in particular, the loss of vision) makes it impossible for researchers to test therapies in development using conventional means. This study has important implications for designing gene therapy studies in a rational manner, to produce Clarin-1 in the correct cell type and at levels that mimic its natural production.
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.