Understanding Usher Syndrome Research

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Natural history (NH) studies are used to track the progression of a disease in a patient over time. USH NH studies usually requires many trips by a patient to a designated centre for regular tests such as eye exams, balance tests, hearing tests, and more, depending on the predefined set of data required by the study. These studies, especially for rare diseases, are important as their results may provide better understanding to both patient and clinicians of what a patient may expect from their disease. They may also be valuable for use in clinical trials as researchers would be able compare the results of the NH studies to data from clinical trials.  

 Gene replacement modifies a specific gene by replacing the faulty gene with a functional copy using AAV. This method is gene-specific and would mean many different gene therapy trials would need to be undertaken to find a treatment for each sub-type of Usher syndrome. There is also the issue that currently this approach may only work for some USH sub-types due to some of the USH genes being too large for a single AAV. 

 What are AAV? AAV are sdeno-associated viruses! These are harmless viruses that have been adapted into a viral vector to carry a functional copy of an affected gene to the targeted area. To overcome their limited packaging capability, researchers are quickly working on ways to create a dual-AAV vector which may hold bigger genes.

Stem cell therapy focuses on using cells, rather than genetic materials as used in gene therapy, to treat a range of diseases. 

 In IRDs therapies, these stem cells are programmed into induced pluripotent stem cells (iPSCs) which are then differentiated into retinal cells for research. Scientists hope this approach may one day replace lost photoreceptors for USH patients and perhaps restore vision.

Antisense oligonucleotide (AON) is a therapy that is designed to target RNA of a faulty gene. 

The role of RNA is convert the information stored on a DNA into proteins. Therefore, when the RNA tries to reads a faulty gene it can result in faulty expressions in protein making, possibly leading to severe consequences, such as hearing and sight loss associated with USH. AON approach is to “silence” the fault in order for the RNA to skip over it and begin creating the protein needed thus stabilising against further loss. 

When all of the photoreceptor cells in the retina have degenerated with no vision remaining, gene replacement tends to be no longer a viable option to restore vision. However, despite the death of these cells it is known that the retinal ganglion cells (a layer of cells behind the photoreceptors) remain active in many cases. 

Optogenetics involves delivering a gene that expresses a light-sensitive protein to these retinal ganglion cells to work a somewhat similar role of the lost photoreceptors. With the help of special glasses, it's hoped that this method may one day restore some sight to those who are completely blind by an IRD.