Researchers at the Great Ormond Street Institute of Child Health (UCL GOS ICH) have grown ‘mini-eyes’ for the first time to study and better understand the development of blindness in a rare genetic condition called Usher syndrome.
The 3D mini-eyes, known as organoids, were grown from stem cells obtained from skin samples donated by patients at Great Ormond Street Children’s Hospital (GOSH). In a healthy eye, rod cells—cells that detect light—are located at the back of the eye in an important area responsible for processing images called the retina. In this study, published in Stem Cell Reports1the team discovered that they could make the rod cells organize themselves into layers that mimic their organization in the retina, creating a “mini-eye.”
These “mini-eyes” are an important step forward because previous studies using animal cells could not mimic the same kind of vision loss seen in Usher syndrome.
Usher syndrome is the most common genetic cause of combined deafness and blindness, affecting approximately three to ten people per 100,000 worldwide. Children with Usher syndrome type 1 are often born profoundly deaf, while their vision gradually deteriorates until they become blind by adulthood.
Although cochlear implants can help with hearing loss, there are currently no treatments for retinitis pigmentosa, which causes vision loss in Usher syndrome. Although this research is in its early stages, these steps toward understanding the condition and how to develop future treatments may offer hope to those facing vision loss.
The “mini-eyes” developed during this research allow scientists to study the light-sensitive cells of the human eye at an individual level and in more detail than ever before. For example, using powerful single-cell RNA sequencing, this is the first time researchers have been able to see tiny molecular changes in rod cells before they die. Using “mini-eyes,” the team discovered that Müller cells, responsible for the metabolic and structural support of the retina, are also involved in Usher syndrome. They found that stress response and protein breakdown genes are abnormally turned on in the cells of people with Usher syndrome. Canceling them can be the key to preventing the progression and worsening of the disease.
Because the “mini-eyes” are grown from cells donated by patients with and without the genetic “error” that causes Usher syndrome, the team can compare healthy cells and cells that will lead to blindness.
Understanding these differences can provide clues to the changes that occur in the eye before a child’s vision begins to deteriorate. In turn, this could provide clues to the best targets for early treatment – which is crucial for achieving the best outcomes.
Dr Yeh Chwan Leong, UCL GOS ICH Research Fellow and first author, said: ‘It is difficult to study the inaccessible tiny nerve cells of a patient’s retina as they are so intricately connected and delicately located at the back of the eye. skin biopsies, we now have the technology to reprogram the cells into stem cells and then create a lab-grown retina with the same DNA and therefore the same genetic conditions as our patients.”
Professor Jane Sowden, Professor of Developmental Biology and Genetics at UCL and senior author, said: “We are very grateful to the patients and families who donate these samples for research so that together we can improve our understanding of genetic eye diseases such as Usher Syndrome.
Although some time away, we hope that these models can help us one day develop treatments that could save the sight of children and young adults with Usher syndrome.”
The “mini-eye” model for eye diseases may also help the teams understand other inherited diseases in which rod cells in the eye die, such as forms of retinitis pigmentosa without deafness. In addition, the technology used to grow precise models of disease from human skin cells can be used for a number of other diseases – this is the area of expertise of the Zayed Pediatric Rare Disease Research Center at UCL GOS ICH.
Future studies will create “mini-eyes” from more patient samples and use them to identify treatments, for example by testing different drugs. In the future, it may be possible to edit a patient’s DNA in specific cells in their eyes to avoid blindness.
This research was funded by the National Institute for Health and Care Research, Great Ormond Street Hospital Biomedical Research Centre, the Medical Research Council, the children’s charity GOSH and the disabled children’s charity Newlife.