The secrets of permanent blindness have finally been revealed by stem-cell research. This could lead to significant discoveries because not only can scientists develop more tailored drugs, but they could potentially use the stem-cell models to test hundreds of drugs in pre-clinical assays.
The world’s most common cause of lifelong blindness, glaucoma, has been linked to certain genetic markers in research on the retina and optic nerve using stem cell models. These findings may lead to the development of novel treatments for the disease.
A series of eye diseases together referred to as glaucoma cause damage to the retinal ganglion cells, or neurons close to the inner eye that make up the optic nerve. Because the optic nerve of the eye receives light and sends it to the brain, glaucoma damage results in irreversible blindness. By 2040, the illness is expected to afflict almost 80 million individuals, yet there are very few effective treatments.
This study correlated 97 genetic clusters to the damage caused by the most prevalent kind of glaucoma, primary open-angle glaucoma (POAG), identifying critical genetic components that determine how the condition strikes. POAG is a genetically complex disorder that is almost certainly hereditary and, for the time being, cannot be prevented or corrected. The sole treatment for POAG is to relieve pressure on the eye, which will only slow the progression of the disorder.
The Garvan Institute of Medical Research, the University of Melbourne, and the Centre for Eye Research Glaucoma collaborated on the study.
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“We saw how the genetic causes of glaucoma act in single cells, and how they vary in different people,” stated Prof. Joseph Powell, co-lead author of the study and a Melbourne University scholar, in a Garvan Institute media release.
“Current treatments can only slow the loss of vision, but this understanding is the first step towards drugs that target individual cell types,” Powell said.
The Contribution of Stem-cell Modelling
The study, which was published in the journal Cell Genomics (read below), was the outcome of a long partnership between Australian medical research centers encompassing the investigation of complex diseases and their underlying genetic causes using stem-cell modeling, which the researchers said demonstrated the study’s accomplishment and the power of this approach.
Previously, glaucoma research was limited because non-invasive samples of the optic nerve could not be collected from volunteers. However, stem-cell modeling solved this problem by allowing researchers to create optic nerve samples from skin, which is a much easier area of the body to extract.
The researchers performed skin biopsies on 183 people, 91 of whom had advanced primary open-angle glaucoma, in order to collect skin cells that could be programmed to revert to stem cells and then guided into becoming retinal cells. Of the 183 samples collected, 110 were successfully converted from skin cells to retinal, 54 from POAG participants, and almost 200,000 of these transformed cells were sequenced to establish “molecular signatures.”
To analyze individual cells, the researchers in this work used single-cell RNA genetic sequencing. This type of sequencing generates an extremely precise genomic map that searches for genetic variants that affect the expression of one or more genes (the process of converting instructions from DNA into functional products such as proteins). By identifying these critical genes, researchers can make further inferences about the impact of genetic variants on glaucoma.
The profiles of people with and without glaucoma were examined in order to identify critical genetic components that govern how glaucoma damages the retina.
The researchers first found 312 genetic variations related with the ganglion cells that subsequently deteriorate in a person living with POAG using the signatures of both those with and without glaucoma. Further investigation of the genes related with POAG linked the 97 clusters indicated above to glaucoma damage.
What This Research Means For People With Glaucoma
Alice Pébay, a Melbourne University professor and another co-lead author of the report, stated that by investigating glaucoma in retinal cells, a context-specific profile of the disease was produced.
“We wanted to see how glaucoma acts in retinal cells specifically—rather than in a blood sample, for instance—so we can identify the key genetic mechanisms to target,” Pébay said.
“Equally, we need to know which genetic variations are healthy and normal, so we can exclude them from a treatment.”
To better understanding of complicated disorders such as glaucoma, researchers underlined the importance of developing a disease profile that promotes understanding of disease causes, risks, and fundamental mechanisms. Furthermore, genetic studies are important in drug development and pre-clinical trials since they aid in the construction of comprehensive human models of diseases.
Alex Hewitt, a University of Tasmania professor and a third co-lead author on the publication, stated that the outcomes of this study pave the way for future research into innovative glaucoma treatments.
“Not only can scientists develop more tailored drugs, but we could potentially use the stem-cell models to test hundreds of drugs in pre-clinical assays,” said Hewitt.
“This method could also be used to assess drug efficacy in a personalised manner to assess whether a glaucoma treatment would be effective for a specific patient.”
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