Mutations in three different genes may lead to Usher Syndrome 2. USH2a, ADGRV1 (= USH2c) and WHRN (= USH2d). Also, mutations in the USH2d gene have been described which only lead to non-syndromic loss of hearing with patients. People suffering from non-syndromic loss of hearing are hard of hearing, but do not experience loss of eyesight caused by retinitis pigmentosa (RP). Additionally, mutations within the USH2a gene have been described that are responsible for the development of non-syndromic RP. These patients do develop RP, but they hardly suffer any loss of hearing.
Additional information about these Usher 2 genes, the proteins involved and the various mutations is to be found in ‘Usher Syndrome and DNA diagnostics’.
Which developments, innovations and studies are presently going on for patients suffering from Usher Syndrome type 2?
In this article we will discuss the developments in the area of gene therapy.
Gene therapy or gene replacement therapy for USH type 2
Gene therapy is a treatment method for hereditary disorders in which healthy copies of genes of patients in which faults (= mutations) were found are replaced or added to cells. The replacement genes produce again the proteins that as a result of the mutations are no longer produced. This is meant to stop the deterioration of the functioning of the retina or cochlea.
Insert genes with the help of a virus.
With this therapy a healthy copy of a required gene is delivered at a specific place in the body, for instance the eye. This is usually done with the help of a molecular vehicle or means of transport: a virus. Not any virus can simply 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 type of virus is called a vector, a kind of ‘packaging’. Then the required gene is inserted into the DNA of the virus. Finally, the vector with its new content is injected in a certain area in the eye, after which the new gene in the particular cells are translated into a functional protein. The most commonly used vector is the adeno-associated viral vector (AAV).
Usher genes are large
One of the major challenges in the development of gene therapy for people suffering from Usher Syndrome lies in the fact that the genes in which most mutations are found are too large to be packed in the AAV vector. This forces researchers to come up with all kinds of creative solutions to still make these large Usher genes fit into in a viral vector or to develop alternative therapeutic strategies in which the size of the genes is not a problem.
The development of Usher Syndrome can in about 50% of the cases be explained by mutations in the USH2a gene. This gene is very large and it covers about 16.000 bases (number of letters of the genetic code forming the usherin protein). The ADGRV1 gene (= USH2c) is even larger!
The capacity of the presently available AAV vectors is only 4.800 bases and therefore way too small to deliver USH2a or ADGRV1 to the body.
The different gene sizes in base pairs are also to be found in the table set up by Cindy Boer: ‘Usher syndrome – 20 Entries’
Mini-genes for USH2a
Erwin van Wijk is researcher at the Radboudumc Nijmegen, the Netherlands, and studies the question whether the functionality of various artificial, short forms of the USH2a protein (coded by so-called “mini-genes”) is sufficient to inhibit or even stop the deterioration of the eyesight. This is tested in the USH2a zebrafish model, which has been developed for this purpose.
The exon-skipping study for USH2a has shown earlier that some variation in the length of the USH2a gene/protein is possible without affecting the functioning. See ‘Development of a therapy for Usher Syndrome type 2′
If this study is to show positive results, it may be possible to make a USH2a gene that is small enough to be packed in the present viral vectors for gene release.
Also see ‘Usher Syndrome Foundation finances mini-genes project’
Gene therapy for USH2d
Mutations in the whirlin gene lead to Usher syndrome type 2d (USH2d is rare) or non-syndromic hearing loss (DFNB31) in humans. In a study by the Wade Chien group (NIDCD, Bethesda, USA) a healthy copy of the whirlin gene was delivered via an AAV vector to the inner ear of newborn mouse models in which the whirlin gene was switched off. Addition of this new whirlin gene copy to the inner ear of neonatal mice (within 5 days after birth) resulted in an improvement in balance and hearing for at least 4 months (the treated mice were no longer followed in this study).
This study shows that gene therapy could be a possible treatment option for hereditary balance and hearing disorders. However, it is important to realize that there are significant differences between the development of human and mouse inner ears. For example, the human inner ear is fully developed and functional at birth, while the mouse’s hearing organ is only functional a few weeks after birth (from 20 days). Most of the published studies showing recovery of hearing function in mouse models after treatment with a form of genetic therapy are based on treatment of neonatal mice (<5 days after birth). However, the positive effect of these treatments is no longer observed if the administration takes place from 14 days after the birth of the mouse. In concrete terms, this means that in humans the treatment should take place on the unborn child (= in utero) in order to be effective. This results in both practical and medical-ethical objections and will therefore not be applied in patients for the time being. In addition, there are no indications (yet) that USH2d or DFNB31 patients have balance problems, in contrast to the published whirlin mouse models. Additional studies are therefore necessary to provide a detailed overview of the function of the equilibrium organ in patients with whirlin mutations.
Future research by this group will show whether this form of therapy could possibly be successfully applied to treat whirlin-related retinitis pigmentosa.
Natural development study for future trials
The detailed mapping out of the natural development of the functioning of eyesight and hearing in the different types of Usher Syndrome is essential in order to be able to determine the effectiveness of future therapy. Only after studies have demonstrated the effectiveness and safety of certain therapy types, these will be made available to patients on a large scale after a long process of market implementation.
Two natural development studies for Usher Syndrome were started: the RUSH2a and the CRUSH studies.
In the international RUSH2a study 70 patient spread over 9 different clinics are monitored for 4 years. In this study only syndromic and non-syndromic patients with mutations in the USH2a gene are included.
In the Dutch CRUSH study, 50 patient suffering from different types of Usher Syndrome are followed for a period of five years in the Radboudumc.
Additional information about these two natural development studies can be found in: ‘The RUSH2a and the CRUSH studies’
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)