View the webinars that UsherKids Australia presented to our community in August, 2021 on the most up to date information on the various Australian research projects currently working on treatments for retinitis pigmentosa and Usher syndrome.
Here we share the progress of treatments and research linked to Usher syndrome around Australia. We also provide links to Global initiatives and a Glossary of Terms to help simplify the science.
Advancements in genetic and genomic testing make earlier diagnosis of rare genetic conditions such as Usher syndrome accessible to more and more children born with a hearing loss in Australia. Technological advances and increased accessibility of the Cochlear implant and hearing aid technology focus on supporting the hearing loss associated with Usher syndrome. Current focus for clinical research relates to the eye disease associated with Usher syndrome, retinitis pigmentosa (RP). The onset and progression of RP symptoms (night vision difficulties, reduced visual fields) varies, even between family members and it is referred to as a “progressive disease where no two patients record the same degree of loss at the same time in their lives”.
Genetic changes or mutations in over 13 genes have been identified to cause Usher syndrome. The sub-types are further divided into genetic sub groups that split them according to the severity of the hearing loss, presence or absence of vestibular function and on the onset of RP vision loss.
Photo credit Dr Grace Lidgerwood
Usher syndrome is clinically diagnosed by hearing, vestibular and eye examinations. With an increased understanding of the genetic basis of Usher syndrome and genetic testing becoming more affordable, it is becoming more widely available. If the genetic cause is confirmed through genetic testing, this can provide a more definite diagnosis on the type of Usher syndrome, and lead to a better understanding of whether the eye condition is more likely to remain stable or deteriorate. This is useful information as many Inherited Retinal Diseases (IRD), including Usher syndrome can be variable in age of onset, severity of vision loss and duration to legal blindness.
Once confirmed, a genetic diagnosis can also lead to informed decision making regarding family planning and eligibility for enrolment in research and clinical trials. Many studies or trials, particularly those involving gene therapy and stem cell genetic editing techniques, require this genetic information. For many inherited eye diseases, including Usher syndrome, there have been no proven treatments to stop vision loss. It is very exciting to see advances in genetics, as well as upcoming gene and stem cell-based therapies to potentially improve the quality of life for people with inherited eye diseases.
There is preliminary evidence that environmental and dietary factors may enhance the longevity of usable vision. These include protecting the retina from ultraviolet light by wearing 100% UVA/UVB sunglasses and maintaining optimal overall health. Exercise and diet, such as including seafood rich in omega-3, have also been suggested (Berson, 2000). Studies on vitamin A and docosahexaenoic acid (DHA) treatments have created some controversy (Massof & Finkelstein, 1993) and to date have only been conducted on hearing persons with nonsyndromic RP and some Usher Type II patients (Berson et al., 1993, 2004a, 2004b). Patients should be cautioned concerning vitamin A supplementation and do so only under the supervision of a medical physician.
The lack of animal models that faithfully replicate human pathology means that little is known about the pathophysiology of Usher syndrome. Little is also known about the mechanism of cellular degeneration, which is hindering the development of new therapies. Many of the research teams around Australia (and globally) are making advances in their understanding of the relationship between the genetic diagnosis and the clinical features, providing insights into disease mechanisms and potential therapeutic targets. This will in turn lead to establishing the clinical tests required to measure a true change in the condition over a fixed period of time. This means when clinical trials commence, it will be known which measures portray an accurate response to treatment.
There are a number of centres of research in Australia working in the inherited retinal disease space. This includes retinitis pigmentosa linked with Usher syndrome. They are at different stages in their research and are generally not looking at specific subtypes or genetic mutations . For information relating to a particular sub-type, you can access this up to date information on the Usher Coalition website here:
Ms Stephanie Morgan- Schlicht and Dr Damian Hernandez
Many research groups both in Australia and overseas are trying to better understand Usher syndrome.
This is where a good copy of the gene is inserted into the eye to repair or increase the function of the gene.
Stem cells have the potential to be turned into many different cell types i.e. heart, nerve, eye tissue.
There are two kinds of stem cells from humans:
The use of stem cells obtained from “skin” samples do not have the same associated ethical issues as the use of embryonic stem cells.
Skin samples from individuals with specific eye problems are grown in the laboratory, turned into stem cells and reprogrammed to become retinal tissue i.e. rods and cones which are damaged in RP.
This allows researchers to study the cells at the back of your eye without actually needing to take a sample from your eye.
This will help researchers better understand how Usher syndrome occurs, possibly develop new treatments and test new drugs that might minimise vision and/or hearing loss.
Dr Grace Lidgerwood
A team of researcher and clinicians in Tasmania are working through Menzies Institute for Medical Research.
Professor Alex Hewitt is collaborating with University of Melbourne’s researcher Alice Pebay to lead a team that is using patient skin samples, cutting-edge stem cell technology and gene-editing techniques in the hope of developing new treatment options for inherited eye diseases.
While the team has worked together for many years on gene discovery and stem cell technology, their new work has focused on gene-editing, specifically for the eye problem associated with Usher syndrome – retinitis pigmentosa (RP). If the DNA (deoxyribonucleic acid) change causing the RP is known, scientists can now use genetic editing technology to edit and fix the DNA change.
Before this work can be used in humans, there is still an enormous amount of work to be done. The Hewitt-Pébay team are focusing on studying and developing techniques to safely and effectively deliver this technology into the eye. Their goal is to complete all the required background research, and work with the Australian regulatory authorities to move the gene-editing approach from the laboratory to approved human clinical trials.
The path to finding a treatment for Usher syndrome is expensive and funding is essential. In 2019 Professors Hewitt and Pébay were awarded funding from Stem Cells Australia as part of the Australian Government’s Medical Research Future Fund (MRFF) Accelerated Research program. They are also grateful for the support provided by the Foundation for Children, Sydney NSW.
Professor Hewitt said “the funding was an opportunity to build on our work and is another step closer to finding a treatment for Usher syndrome. The “gene editing approach also has real potential for treating other blinding inherited eye disease”.
Professor Alex Hewitt (Menzies Institute for Medical Research Tasmania, and Centre for Eye Research Australia)
Professor Alice Pébay (University of Melbourne)
Ms Lisa Kearns (Centre For Eye Research Australia)
In Western Australia there are teams at the Australian Inherited Retinal Disease Registry and DNA Bank in the Department of Medical Technology & Physics at the Sir Charles Gardiner Hospital , and Lions Eye Institute, University Of Western Australia
Identifying the genetic cause for an inherited retinal condition is an important stage in preparation for therapeutic interventions, as in order to evaluate possible solutions, a genetic cause must be known.
To this end, the Australian Inherited Retinal Disease Registry (AIRDR) recently launched the Australian Usher Project. This research involves genetic testing of affected individuals and family members from around 160 Usher-affected families within the Registry, representing 15-20% of all those in Australia.
The Australian Usher Project represents by far the most significant genetic study of Usher syndrome ever carried out in Australia.
Upon completion, DNA from these Usher-affected individuals will have been analysed by interrogation of 577 ocular genes in collaboration with Molecular Vision Lab (Oregon, US), revealing a genetically defined group of Usher-affected Australians. This is central to the development of personalised medicine applicable to Australian Usher families (e.g. through collaborators at Lions Eye Institute and partner, Phylogica Ltd), and important for the identification of potential candidates for clinical trials, including those currently underway for the Usher genes MYO7A and USH2A.
The Australian Usher Project is just one of the many research projects being undertaken by these Western Australia researchers. Through this team’s national and international collaborative research efforts, similar work on other forms of inherited retinal disease (IRD) is underway and at various stages of completion.
As a result, this ever expanding National IRD database is a valuable resource for the identification of candidates for upcoming clinical trials and relevant IRD research.
The team at the AIRDR greatly appreciate the time and effort invested by their participants, and encourage enquiries and updates from existing participants as well as queries from those considering becoming involved.
Participant Contact: 08 6457 2449 (Ling)
This process is highly collaborative and the database is available to researchers all over the Globe under confidentiality agreements. Continued appointments with Clinicians is essential as up to date data on your individual case makes you a more attractive candidate for a clinical trial
Also taking place in WA is research focusing on the gene therapy strategy to eventually deliver a good copy of the photo receptors back into the retina.
A crucial step in any gene replacement therapy approach is the latter stage when the correct gene is required to be inserted back into the sub-retinal space so it can reach the photoreceptor cells. There needs to be a delivery method to do this. In the last few decades, a lot of research has gone into modifying certain viruses so that they can be used as the delivery agent. These modifications include eliminating the bad aspects of the virus so they cannot cause disease while keeping its ability to infect cells and therefore deliver the corrected gene. Research labs from the US and the University of Western Australia are working together on an exciting gene therapy strategy to deliver a good copy of the Usher genes to photoreceptor cells in the retina. As some genes can be too large to fit into one virus particle, their strategy consists of splitting the larger genes in two halves. The two halves will be delivered to the photoreceptors in the retina in separate virus particles but will come together inside the cell to make the full length gene. Dr Carvalho at the University of Western Australia/Lions Eye Institute, has been working on creating the two gene halves, which Dr Vandenberghe (Harvard University, USA) will package into the virus particles. The virus will then be tested on a mouse model by Prof Zubair Ahmed (University of Maryland, USA) to hopefully restore vision.
Furthermore, an Australian cross country researcher-clinician collaboration between Dr Carvalho, Dr Mellough and Dr Chen (Lions Eye Institute), Prof Alex Hewitt (University of Tasmania) and Dr Alice Pebay (Melbourne University) have also been testing this dual approach directly on skin samples donated by Usher patients.
Fred K Chen Consultant Ophthalmic and Vitreoretinal Surgeon
Royal Perth Hospital, Perth Children’s Hospital
Lions Eye Institute Research Australia)
John De Roach Principle Medical Physicist & Principle Investigator, Australian Inherited retinal Disease Registry & DNA Bank, Dept Of MedicalTechnology and Physics Sir Charles Gairdner Hospital
Tina Lamey Senior Research Scientist ,Australian Inherited retinal Disease Registry & DNA Bank, Dept Of MedicalTechnology and Physics Sir Charles Gairdner Hospital
Livia Cavalho– Assistant Professor University Of Western Australia
NEW SOUTH WALES
In NSW there are teams at the Children’s Medical Research Institute, University Of Sydney, Save the Sight Institute
At the Children’s Medical Research Institute in Sydney, a team of researchers led by Dr Anai Gonzalez Cordero at the Stem Cell Medicine Group is focused on two complementary fields of research: stem cells and regenerative medicine. Using the potential of induced pluripotent stem (iPS) cells to create laboratory models of eye and ear diseases they are trying to understand disease mechanisms and develop new therapeutic approaches. The iPS cells are stem cells which are generated from tissues of children or adults, including blood and skin cells. They can direct the iPS cells to turn into cells that can form tissue and mini-organ structures (“organoids”) in the laboratory dish, a process biologists called “differentiation”, so they can be used in studies. Within this they have been able to generate retinal and inner ear organoids from iPS cells.
The research team at CMRI Sydney is working on a specific project to investigate the pathophysiology of Usher syndrome using iPS cells and thus improve their understanding of Usher syndrome.
The main objectives of their research is to characterise both retinal and inner ear USH iPS-derived organoids to investigate disease physiology and most importantly to develop new therapeutic approaches, such as gene therapies.
John Grigg Professor and Head, Discipline of Ophthalmology
Professor of Clinical and Experimental Ophthalmology
University of Sydney | SAVE SIGHT INSTITUTE Faculty of Medicine and Health
Professor Robyn Jamieson Clinical Geneticist (HGSA), Eye Genetics Research Unit Head, Professor of Genomic Medicine, University of Sydney — leads the Eye Genetics Research Unit at CMRI, and heads Eye Genetics Clinics at The Children’s Hospital at Westmead and Westmead Adult Hospital. She is also Director of the Western Sydney Genetics Program, The Children’s Hospital at Westmead, and Head, Discipline of Genetic Medicine, University of Sydney.
Dr Anai Gonzalez Cordero is a Group Leader of the Stem Cell Medicine team and also the manager for the Stem Cell & Organoid Facility at Children’s Medical Research Institute.
Approximately 30% of genetic mutations in Usher syndrome are due to an abnormal stop signal being introduced in the gene (this is called a nonsense mutation). When your cells try to read your gene, if it encounters this premature stop signal it will stop making the required protein, and this loss of function leads to Usher syndrome. There are now a group of drugs that can bind to your protein-making machinery in your cells and override the abnormal stop signals leading to the formation of normal full length functioning protein. This can restore between 20-25% levels of normal protein and this may be enough to halt or slow the retinal degeneration seen in Usher syndrome. This work has been published in the scientific literature and we are now trying to translate this therapy to patients.
To learn more, please visit: https://vimeo.com/199657263.
Small molecule drugs only work on a subset of patients with a particular mutation. The gene USH2A is the commonest cause of Usher syndrome type 2 and contributes to the majority of Usher syndrome cases overall. Mutations in this gene can also cause retinitis pigmentosa without any hearing problems. The gene is very large and extends over 19,000 kilobases (or letters of the genetic code). Unfortunately, conventional viral gene therapy vectors can only accommodate genes that are smaller than 9000 kilobases. Therefore, it is necessary to find an alternative form of gene delivery for USH2A. Overseas research teams are developing a non-viral gene delivery system which can hold large genes, including USH2A, and testing its safety and effectiveness in Usher disease models. This includes (i) a zebrafish model with an ush2a genetic change generated through gene editing, and (ii) human retinal models from patients own skin samples, which are reprogrammed to stem cells and then differentiated into early eye cups growing in a dish.
To learn more about this stem cell technology watch this animation:
This project is still in the preclinical phase and will last 3 years. For more information on its progress stay linked to https://www.facebook.com/DrMariyaMoosajeeLab/
The Usher Coalition website now has a dedicated page to listing all the global research and clinical trials that are ongoing. It is easy to use and is broken down according to the Usher sub-types. For those specifically looking to see what is taking place for a particular gene this is a great resource. It can be found at this link here:
What is next for people with Usher syndrome?
Stay up-to-date with their eye checks and be in contact with local eye research organisations (including the registries held by the Usher Coalition USA and AIRDR) so when new technologies or potential trials become available they know how to make contact with people.
Usher Coalition Registry https://www.usher-registry.org
Australia Inherited Retinal Disease DNA Bank https://www.scgh.health.wa.gov.au/Research/DNA-Bank
Understanding Genetics and Genome Sequencing:
This NSW Health Department of Genetic Education fact sheet is a resource dedicated to understanding DNA, the role of genetic testing and what is used to test for a gene variation.
Although many clinical trials are now underway, stem cell treatments remain experimental. Initial promising studies need to be further explored in clinical trials over the long term and in larger numbers of patients to establish safety and effectiveness . For more information on what questions you should be asking regarding stem cell therapies use this resource provided by RANZCO (Royal Australian & New Zealand College of Ophthalmologists )
For information on how stem cells can be used to model disease and as a resource for testing new medical treatments
Efforts to advance the field of stem cell treatments need to be distinguished from services offered by unregulated stem cell clinics that claim they can already use stem cells to treat a range of conditions associated with vision loss. These expensive and non-evidence based practices can be very risky for patients. Please use the resource from ASSR to guide you regarding non-evidence based practices. Our recommendation is to sign up to the IRDR in Western Australia or the International Usher Coalition Registry (USH Registry click here for the link) which will both be used by researchers looking for a cohort of Usher syndrome patients when they are starting clinical trials. For more information read section on Clinical Trials below ( link here to section below on clinical trials )
The ASSCR (Australian Society for Stem Cell Research) web page is for anyone looking to understand stem cell research and cell therapies.
ISSCR’s A Closer Look at Stem Cells includes a Patient Handbook on Stem Cell Therapies and other trustworthy patient resources.
Stem Cells Australia brings together top Australian scientists to harness the potential of stem cells for diagnostic, therapeutic and biotechnological purposes through an Australian Research Council’s Special Research Initiative scheme.
They have an easy to understand resource explaining the steps of a clinical trial so you can understand the process the researchers and scientists undertake before a therapy is widely available to patients.
Clinical trials are undertaken to test whether a proposed new therapy is safe, as well as for its effectiveness. It is a very important part of clinical research. Results from clinical trials are shared so that the broader medical, scientific and patient communities can benefit from this knowledge. We recommend you only take part in clinical trials that have ethics approval and meet the standards of Australia’s regulatory body, the Therapeutic Goods Administration. Approved clinical trials will be registered on the Australian and New Zealand Clinical Trials Registry and will monitor patients over time to assess the long-term safety and outcomes of treatment. You are not usually expected to pay to participate in an approved clinical trial.
Click here to review Stem Cell Australia’s guidelines on clinical trials:
The Foundation Fighting Blindness (USA) is also a great resource and has directed significant funds to move research for inherited retinal dystrophies from the clinic to the patient.
They recently announced a collaboration with the NIH to fund genetic testing and a genetic counselor for all US patients with a clinical diagnosis of an inherited retinal disease (IRD). “With the increasing number of therapies being developed, an accurate genetic diagnosis is critical for any person affected with an inherited retinal disease. We are also encouraged by the large number of patients enrolling in the registry who are continuing to drive progress in the field, including access to clinical trials.”
Usher 1F Collaborative -USA
Usher 1F Collaborative is a 501c3 nonprofit foundation whose mission is to fund medical research to find an effective treatment to save or restore the vision of those with Usher syndrome type 1F. For more information on the research they are funding go to this link
One of the researchers linked to this organisation has created this short video to explain his work on stem cell therapies & is a good visual reference to explain how researchers are moving from the lab to the patient
David Corey, PhD, Bertarelli Professor of Translational Medical Science, Harvard University Medical School Department of Neurobiology, discusses his work to find a cure for the progressive vision loss of Usher syndrome type 1F
These are some of the terms you may come across when reading articles about research on Usher syndrome. For a more detailed glossary of scientific terms please download this PDF from NSW Government Centre for Genetic Education:
Adeno-associated virus (AAV)
A type of virus that is able to get inside many different types of cells throughout the body, but not known to cause sickness in people. Because of this, it is a promising vector, or delivery vehicle, for gene replacement therapy.
Cas9 (CRISPR Associated Protein 9)
A specialized enzyme known as a nuclease that has the ability to cut DNA sequences. Cas9 makes up part of the “toolkit” for the CRISPR/Cas9 method of genome editing.
Deoxyribonucleic acid (DNA)
The carrier of the body’s genetic information, DNA is the template used by the body to make every substance in our body, such as proteins. It is made up of 2 strands of molecules that wind around each other in a double helix, a structure like a twisted ladder.
The basic units of heredity, and made up of DNA, genes carry the instructions cells need to make proteins used throughout the body.
Also called genome editing, this treatment inserts, removes, changes, or replaces specific pieces of a person’s existing DNA.
Gene replacement therapy
This type of gene therapy uses a new, working gene to replace the function of a nonworking or missing gene. This gene then provides the instructions for your body to make the missing or insufficient protein.
Gene therapy is a treatment to cure disorders by adding genes to cells. The extra genes contain the information for producing Usher proteins, which are not produced with patients as a result of mutations in Usher genes. This may possibly slow down or completely stop the deterioration of the functioning of the retina or the cochlea.