So far, one Usher gene is known with respect to Usher Syndrome type 3, being USH3A. The USH3A gene does the coding for the ‘clarin-1’ protein. The USH3A gene is sometimes also called CLRN1, an abbreviation of clarin-1. Usher Syndrome type 3A mainly occurs with people with a Finnish background and with people from Ashkenazi Jewish origin. The HARS gene is sometimes considered to be the gene causing Usher Syndrome type 3B, but the relation between the HARS gene and Usher Syndrome is still unclear.
Gene therapy for USH type 3A – Retina
Unlike many other genes related to Usher Syndrome, the USH3A gene is relatively small. A research group of the University of Florida (USA), led by Dr Astra Dinculescu, is working on the development of gene therapy for the retina in Usher Syndrome type 3A patients. In their research, Dr Dinculescu and her colleagues make use of mouse models with mutations in the USH3A gene. These mice do no longer produce the clarin-1 protein. Just like with people, mutations in the USH3A gene lead with mice to deterioration of the eyesight.
The researchers used adeno-associated viruses (AAV’s) to insert healthy copies of the USH3A gene into the rods and the cones of the retina of the USH3A mouse. Through this method the researchers succeeded in recovering the production of the clarin-1 protein in the retina. The treatment also improved the functioning of the retina with the USH3A mouse and inhibited the deterioration of the retina.
At this moment, the research group is working hard on improving the method of administration of this type of gene therapy for USH3A. For an optimum result it is important that the healthy copies of the USH3A gene end up in as many rods and cones as possible without side effects occurring in the retina.
Gene therapy for USH type 3A – Inner ear
Dr Kumar Alagramam of the University Hospital in Cleveland (Ohio, USA) is doing research into gene therapy for Usher Syndrome 3A. Initially, the study of Dr Alagramam is focused on the development of a treatment of the progressive loss of hearing with people suffering from Usher Syndrome type 3A. He expects that this type of therapy can also be applied to the eye in order to inhibit the degeneration of the retina.
Just like Dr Dinculescu, Dr Alagramam makes use of a mouse model with mutations in the USH3A gene in his study. He has demonstrated that these USH3A mice suffer from progressive loss of hearing.
This is the first time that this USH3A-related loss of hearing can be copied in mice models. This makes research into a treatment of USH3A-related loss of hearing possible.
Dr Alagramam administrated healthy copies of the USH3A gene to the USH3A mice at two different ages.
The first administration took place during the embryonic development. For this Dr Alagramam modified the genetic material of the mice with the result that certain cells of the inner ear produced the clarin-1 protein even from the embryonic development.
In order to reproduce the effect of the treatment at a later age, Dr Alagramam used adeno-associated viruses (AAVs) to insert healthy copies of the USH3A gene into the inner ears of mice of 1 month old. The mice already suffered from loss of hearing at that moment.
The first study results are cautiously positive. The administration of the healthy copies of the USH3A gene during the embryonic development slowed down the deterioration of the loss of hearing.
The administration of the healthy USH3A gene in young mice suffering from loss of hearing could not improve the hearing function or inhibit further deterioration of their hearing.
From these results, Dr Alagramam concluded that a gene therapy for loss of hearing with patients with mutations in the USH3A gene is to be administered before the loss of hearing is developed. With people suffering from Usher Syndrome type 3A the loss of hearing is congenital or it is developed at a young age. This makes the further development of this therapy more difficult, as it is presently not possible to test the gene therapy with people of a very young age.
Medicines for USH type 3 (N48K mutation)
Dr Yoshikazu Imanishi of Case Western Reserve University in Cleveland (Ohio, USA) is focusing on the development of therapy for Usher Syndrome 3A.
One of the most frequent mutations in USH3A is the N48K mutation.
Imanishi studies the clarin-1 protein with the N48K mutation in cultivated cells.
This study demonstrated that the N48K mutation makes the clarin-1 protein unstable and this leads to the cell quickly destroying the clarin-1 protein again. As a result of this instability, the rods and cones of patients with the N48K mutation in USH3A show a lack of functional clarin-1 protein.
Subsequently, Imanishi used cultivated cells to look for medicines that can stabilise the N48K clarin-1. The medicine BF844 appeared to stabilise N48K clarin-1 in the cultivated cells.
Imanishi then administrated this medicine to mice with the N48K mutation in the USH3A gene. It was shown that BF844 has a therapeutic effect on the loss of hearing in mice with the N48K mutation: the mice treated with BF844 could hear better than their brothers and sisters that carried the N48K mutation but were not treated with the medicine. The N48K mice do not show any retina degeneration. Therefore it is still unknown whether the medicine BF844 also has a positive effect on the eyesight for patients with the USH3A-N48K mutation.
Usher Syndrome and DNA diagnostics
From DNA to protein
Development of a therapy for USH type 1
Gene therapy for USH type 1
Development of a therapy for USH type 2
Gene 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 governments 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 find out how USHIE you can help 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)