Usher Syndrome type 1 knows six different genes (USH 1B, 1C, 1D, 1F, 1G and 1J) and many different mutations. Additional information about these genes, the proteins involved and the various mutations in these USH1-genes is to be found in ‘Usher Syndrome and DNA diagnostics’.
Which developments, studies and clinical trials are presently going on for people suffering from Usher Syndrome type 1? Today we will discuss the development of medicines.
Medicines for improved release of neurotransmitters with USH1B
USH1B is caused by mutations in the MYO7A gene. In the USA Alaa Koleilat is, under supervision of Dr Lisa Schimmenti (Mayo Clinic, USA), working on the development of a medicine for treating USH1B. She makes use of zebrafishes with mutations in the MYO7A gene, because this zebrafish model for USH1B shows serious deafness and balance problems. Because of their balance problems, these zebrafishes swim in circles. Apart from this, these USH1B zebrafishes do not react to sound stimuli. The hair cells of the USH1B zebrafishes no longer have a nice bundle of cilia, just like the hair cells of USH patients. It is expected that as a result of this the hair cells cannot properly pass on sounds to the brains. Passing on information from the ear takes place through neurotransmitters. Expectations are that the release of neurotransmitters has been decreased in the ear of the USH1B zebrafish.
Alaa Koleilat studied three already existing and by the FDA approved medicines that can increase the release of neurotransmitters. When administering these medicines to USH1B zebrafishes their swimming behaviour improved. This indicates a better functioning of the organ of balance. One medicine resulted in an improved reaction to sound stimulation. Although the results with USH1B zebrafishes are promising, these medicines cannot be administered to patients right away. As these medicines have been developed for other diseases, their effectiveness and safety in the ear is still unclear. Presently, studies are conducted to see whether these medicines also have a positive effect on the hearing and the organ of balance in a mouse model for USH1B.
The ‘genetic patch’ for USH1C
Jennifer Lentz from New Orleans (LSU School of Medicine, USA) is working on a treatment for USH1C patients who have a specific mutation in the USH1C gene, the c.216G>A mutation. The USH1C gene is translated into the harmonin protein, which plays an important role in the eye, ear and balance organ. The c.216G>A mutation influences the pre-mRNA splicing (see Splicing mutations in ‘From DNA to protein’). As a consequence of this mutation a part of the USH1C gene is not included in the mRNA. If this part of the USH1C gene is missing in the mRNA, the production of the harmonin protein stops prematurely. This incomplete harmonin protein is not functional, which leads to retina degeneration, loss of hearing and imbalance problems.
Lentz and colleagues have developed an antisense oligonucleotide for this specific mutation. An antisense oligonucleotide, abbreviated by ASO or AON, is also called a ‘genetic patch’. Dependent on the design an antisense oligonucleotide may have different functions. The ‘genetic patch’ can skip the stop coding (exon skipping) or correct the splicing (splice correction). ASO29, the antisense oligonucleotide of Lentz, corrects the pre-mRNA splicing. All important information of the USH1C gene is included in the mRNA again and the cell can restart the production of the harmonin protein.
A schematic representation of the “AON Therapy” can be viewed here (made by Erwin van Wijk, Radboudumc). Here is step-by-step explained how AON therapy works and how the “genetic patch” is applied mutation or exon specifically.
A few years ago, Jennifer Lentz was able to demonstrate that the balance of new-born mice with the c.216G>A mutation in the USH1C gene was recovered after administration of ASO29. The hearing of these mice improved as well after treatment with the genetic patch. The cochlea and the organ of balance of people are difficult to reach using medicines. Currently, a study is being conducted into how to best administer the genetic patches. Recently, the effect of the genetic patch on retina degeneration was studied as well. A local injection of this medicine in the vitreous of the eye also seems to improve the visual function. All studies are presently still conducted on animal models and they are promising in particular with respect to the eye.
‘Translational read-through’ therapy voor USH1C
Kerstin Nagel-Wolfrum from Mainz (Johannes Gutenberg University, Germany) is doing research into ‘translational read-through’ therapy for USH1C as a result of stop (nonsense) mutations in the USH1C gene.
Many mutations causing Usher Syndrome are ‘nonsense mutations’. This means that the mutation prematurely stops the protein production process, a so-called ‘stop sign’. Nagel-Wolfrum studied read-through medicines (abbreviated by TRID = Translational Readthrough Inducing Drug), as a possible therapy for USH1C. These ‘read-through’ medicines can make the protein production machine ignore the ‘stop sign’ and so make the machine produce the complete protein. TRID medicines have existed for some time already, but they often have adverse effects on the body.
Nagel-Wolfrum is looking for new TRID medicines with fewer side effects. She studied the medicine Ataluren in cultivated cells with a USH1C mutation. Without treatment these cells are unable to produce the USH1C protein harmonin. When Ataluren is administered to the cultivated cells with a USH1C mutation, the complete harmonin protein is produced again. In order to investigate whether Ataluren is also effective in the eye, studies are presently conducted into pigs with a mutation in the USH1C gene. Nagel-Wolfrum also treated mice with another form of retina degeneration with Ataluren eye drops. This slowed down the retina degeneration. At this moment clinical trials are conducted with Ataluren for Aniridia, an eye disease which prevents the proper forming of the iris. For USH1C the studies with the pigs will have to demonstrate whether Ataluren can also slow down the retina degeneration before clinical studies can be done.
Study into medicines for reducing ER stress with Usher Syndrome
The group of Monte Westerfield and Jennifer Phillips (University of Oregon, USA) demonstrated in zebrafish models for Usher Syndrome that mutations in various Usher genes affect the health of cells. In the cell proteins are produced in the endoplasmic reticulum (ER) and then transported to the correct place in the cell. In the ER, Usher proteins forma complex of proteins, which is transported as a whole. It seems that different Usher mutations, each type in its own way, prevent the forming of the correct (Usher) protein complex in the endoplasmic reticulum. This incomplete or not functioning protein complex cannot be transported and accumulates in the ER. This is called ER stress, because this accumulation is a heavy burden on the cell. It is expected that prolonged ER stress leads to the rods and cones in the retina as well as the hair cells in the inner ear dying slowly. It was also demonstrated that intense or bright light can accelerate the dying of cells in the retina. Therefore Monte Westerfield advises to wear sunglasses when the light is intense in order to protect the cells of the retina.
Westerfield and colleagues want to test various medicines against Parkinson’s disease and Alzheimer’s disease in their zebrafish models for Usher Syndrome in follow-up studies. This medication has demonstrated that it can reduce ER stress. Expectations are this this will slow down the deterioration of the hearing and eyesight of the zebrafish. The development of this possible form of therapy is still in an early phase. Possibly, the findings can also be applied to Usher types 2 and 3. If this therapy appears to work, application of this may be possible prior to or in support of gene therapy.
Gene therapy for Usher Syndrome type 1
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.
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)