Brief Lay Background
Aniridia is a rare genetic disorder characterised by improper eye development due to mutations in a gene called PAX6. While patients are born with eye abnormalities, the most severe manifestations of the disease often emerge later in life. Typically, during adolescence or early adulthood, the cornea—the transparent front part of the eye—begins to deteriorate, leading to pain, inflammation, and loss of transparency. This progression significantly impacts patients' quality of life, with the majority ultimately being registered as legally blind.
What problem/knowledge gap does it help address?
Corneal damage in aniridia lacks effective treatments that address the root cause of this disease. Current supportive measures, including corneal transplants, ultimately fail not long after the surgery as the stem cells needed to maintain the transplanted cornea are not functional.
Crucially, the gradual development of corneal problems presents a "therapeutic window"—a period during which an effective treatment targeting the cause of the disease could halt or slow its progression. This opportunity requires a safe intervention, such as something called self-amplifying RNA (saRNA). This is a type of therapy that works by carrying instructions to specific cells. Once it has been delivered to the cells, it has the ability to replicate itself (i.e. “self-amplify”), meaning it can be effective at smaller doses.
By intervening earlier in the disease course, the saRNA-based therapies could offer a promising approach to preserve vision and improve long-term outcomes for individuals with aniridia. This novel strategy holds promise for restoring corneal health and vision in aniridia patients by addressing the fundamental genetic cause rather than merely managing symptoms.
Aim of the research project
The team have developed an innovative saRNA technology that precisely upregulates PAX6 gene expression to normal levels. This method circumvents traditional gene therapy limitations, offering improved delivery and dosage control.
The team aims to determine and validate saRNA therapy as a new therapeutic option for treating corneal disease in aniridia. The team will develop and test a novel eye drop formulation in an established mouse model of the disease; determining optimal dosing and administration while investigating its impact on disease progression.
Potential impact on people with sight loss
If it is established that saRNAs can effectively stop/slow aniridia associated keratopathy progression in a very well validated mouse model, then there will be confidence that they can also be used in humans. As such, at the completion of this project, the team would be ready to progress to doing safety and toxicology studies as the last step before human clinical trials.
In the longer term, the team hope to develop an eye drop formulation that patients can use to prevent their disease from progressing, removing the need for regular painful, invasive, and ultimately ineffective surgical intervention.
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