Usher Syndrome knows six different genes (USH 1B, 1C, 1D, 1F, 1G and 1J) and many different mutations. Additional information about these genes, the Usher proteins involved and the various mutations in these USH1 genes are to be found in ‘Usher Syndrome and DNA diagnostics’.
Which developments, innovations and studies are currently being conducted for patients suffering from Usher Syndrome type 1? In this chapter we will discuss the developments in the area of gene therapy.
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.
Insert genes by means of virus
In gene therapy a gene is inserted at a specific place of the body. This is usually done with the help of a virus. This virus is used as a means of transport and makes sure that the cells in the body can absorb the therapeutic gene and convert this into protein. Not any virus can be used as a means of transport. A suitable virus is first deactivated, so that it cannot multiply itself and cause any other disease. This is called a vector, a kind of ‘packaging’. Then the required Usher gene is inserted into the DNA of the virus in the vector. Finally, the vector with its new content is applied by means of an injection or a surgical procedure. For treatment of the eye, injections in the vitreous or a surgical injection below the retina are applied. The most commonly used vector is the adeno-associated viral vector (AAV), but in some cases lentiviral vectors are used.
The major challenge in research into gene therapy for people suffering from Usher Syndrome lies in the fact that most Usher genes are too large to be packed in the AAV vector. Therefore, the researchers have to think of alternatives to make the Usher gene fit into the vector.
Gene therapy for USH1B.
- Clinical trial @UshStat
Myosin 7A (MYO7A) is the gene involved in USH1B, the most common form of USH type 1.
In Paris (Hopital Nationale des Quinze-Vingt, France) and Portland (Casey Eye Institute, Portland, Oregon, USA), researchers have in cooperation with the pharmaceutical company Sanofi been busy for some time conducting a study with patients (clinical trial) into the safety and effectiveness of gene therapy for USH1B. The trial study is called @UshStat and focuses on delivering the normal MYO7A gene with one single surgical injection below the retina. In this study no use is made of the AAV vector but of a Lentiviral vector, called EIAV. Contrary to an AAV vector, a lentiviral vector has sufficient capacity to deliver the entire MYO7A gene.
In phases 1 and 2 of clinical trials the safety and the effectiveness are tested with a small number of persons. The main objective of the study is to find out whether the therapy does not have any side effects and is safe for use on patients. The phase 1/2 clinical studies for @UshStat have already been started. The test persons treated in this study suffer from really serious retinal degeneration caused by mutations in the MYO7A gene, USH1B. Only 1 eye is treated during the trial in order to be able to compare the effect of the treatment with the untreated eye of the patient. The first test with a low dose appeared to be safe. When applying a higher dose, 1 of the 9 test persons developed pan-uveitis, an infection in the vitreous of the injected eye. This patient was treated for the developed infection and fully recovered. All treated test persons were followed for 150 days after the treatment. An improved sharpness of vision in the treated eyes was recorded. Some test persons also showed some differences in the size of their fields of vision.
The serious infection as a possible side effect of the treatment made the Independent Safety Committee in France decide to pause the 1/2 trial.
The trial was stopped for a year and this year was used to increase the safety of the treatment. The researchers received approval to resume the trial @UshStat (MYO7A gene replacement therapy) late 2018/early 2019.
However, the pharmaceutical company Sanofi has decided not to continue this study and wants to sell the licenses. The @UshStat trial study (SAR 421869) is now pending a new pharmaceutical company that wants to buy the licenses and restart the trial. (July 2019 update).
- Start trial ‘double AAV vector’ USHTher
Dr Alberto Auricchio from Naples (Italy) also does research into a treatment for USH1B. As the MYO7A gene is too large to be packed in one AAV vector, he studies the possibility to deliver a healthy MYO7A gene with a double AAV vector in the retina. The MYO7A gene is split in two and each part is packed in an AAV vector. After application of the 2 AAV vectors to the eye, the cells in the retina should reconnect the information from both vectors and so create the good Myosin 7A protein. Auricchio demonstrated that this method worked in the eyes of the animal models ‘pigs’ and ‘mice’. It was also shown that when this therapy is applied during the embryonic development to the cochlea in animal models, the morphology (structures) of the cilia can be recovered. This study demonstrated that the method also worked in the eyes of mice and pig models. Recently, Auricchio was given approval for a phase 1/2 clinical trial, in which this therapy will be tested for the first time with Usher Syndrome type 1B patients for safety and effectiveness.
Mouse model for USH type 1
Both the @UshStat and the double AAV therapy for Usher Syndrome type 1B have been tested in animal models before approval was given for treating the first people. For both therapy types use was made, among other things, of the ‘shaker’ mouse. The ‘shaker’ mouse suffers from loss of hearing and progressive blindness and it has mutations in the MYO7A gene, just like people suffering from USH1B. The name ‘shaker’ was derived from the typical way of walking of this mouse as a result of the reduced functioning of the organ of balance. Read more about this mouse in the scientific publication ‘Shaker mouse’.
Gene therapy for USH1C
Gwenaëlle Géléoc is assistant professor in the Boston Children’s Hospital and the Harvard Medical School. She did research into gene therapy for USH1C. The USH1C gene does the coding for the ‘harmonin’ protein. Géléoc and her colleagues applied the USH1C gene with the help of an AAV vector to mice with mutations in the USH1C gene. Their experiments showed that this type of gene therapy can recover the production of the harmonin protein in the cochlea. The hearing and the balance of these mice almost fully recovered after this treatment. This type of therapy is different from the therapy for USH1C developed by Jennifer Lentz and colleagues (see ‘Development of a therapy for USH type 1’). The therapy of Lentz is only applicable to a specific mutation in the USH1C gene (c.216G>A ), whereas the therapy of Géléoc and colleagues can theoretically be applied to all USH1C patients. Just like Lentz, Géléoc tested her USH1C therapy on mouse models with the c.216G>A mutation in the USH1C gene.
For additional reading, see
USH-talks: gene therapy for usher syndrome type 1c’.
Gene therapy restores hearing in deaf mice… down to a whisper
Gene therapy for USH1G
Saaïd Safieddine and Christine Petit of the Institut Pasteur in France are busy developing gene therapy for the USH1G gene. The USH1C gene does the coding for the SANS protein. Patients with mutations in the USH1G gene do not correctly produce the SANS protein. Safieddine and Petit applied the USH1G gene with the help of an AAV vector to the cochlea and the organ of balance of newborn mice models for USH1G. Twelve weeks after the treatment, the hearing of these mice had slightly improved and the functioning of the organ of balance had almost fully recovered. Using a mouse model, scientists have succeeded in recovering the hearing and the balance with one single local injection.
Natural development studies
All developments in connection with a possible treatment for Usher Syndrome type 1 require natural development studies. Knowledge about the natural deterioration of the eyesight is necessary to be able to determine, after applying any type of therapy, whether the treatment works. A natural development study will also provide insight into which phase of the disease is best to apply the treatment.
At this moment, natural development studies are conducted all over the world. In the summer of 2018, a natural development study for USH1B was started in Oogziekenhuis Rotterdam with 15 – 20 patients. This study is financed by Foundazion Telethon and is part of a larger study. Apart from Rotterdam, this study is also conducted in Naples and Madrid.
All types of therapy mentioned are still in their development phases. Even if the first results of clinical studies are promising, such as with @UshStat, it can still take several years for these to be approved as treatment for Usher Syndrome.
Do you want to know which developments involve your form of Usher Syndrome type 1, but do you not know exactly which mutation you have? Consult your physician about the possibility for DNA diagnostics. Do you want to know what a DNA test is about and how you can apply for this with your physician? Read ‘Usher Syndrome and DNA diagnostics’
Development of a therapy for USH type 2
Research into unravelling and a treatment for Usher Syndrome costs a lot of money. As Usher Syndrome is a rare disease, the government makes little money available to stimulate research. The mission of the Usher Syndrome Foundation is: ‘A treatment for Usher Syndrome in 2025!’ Help us and donate for scientific research, giving all people suffering from Usher Syndrome a realistic prospect of treatment.
#stopUSH and make our dream come true!
Also read ‘Who knows USHIE?’ and read how USHIE you can help to collect a million euros for scientific research
This series was established thanks to:
Ivonne Bressers, Cindy Boer en Willem Quite (Ushersyndroom Foundation),
Ronald Pennings, Erwin van Wijk, Erik de Vrieze en Bas Hartel (Radboudumc),
Lisé Nijman (English translations)