The results are a vital step towards gene therapy for a devastating cause of severe sight loss in early childhood. Leading charities Fight for Sight and RP Fighting Blindness co-funded the research.
Researchers at London's UCL Institute of Ophthalmology and Moorfields Eye Hospital have confirmed for the first time that specific variations in the AIPL1 gene cause a form of Leber congenital amaurosis (LCA). Many natural variations in AIPL1's DNA sequence exist in the population, and the ability of AIPL1 variations identified in LCA patients to cause harm may therefore be unknown. However, people who test positive for the specific variations investigated in this research will now be eligible to participate in clinical trials as patients who might benefit from treatment. The results are a vital step towards gene therapy for LCA due to faults in the AIPL1 gene.
Clinical trials have shown that gene therapy can temporarily restore some vision to people with another form of LCA, that's due to faults in the RPE65 gene. Research has also shown that gene therapy can rescue the light-detecting photoreceptor cells that are affected in LCA, preserving sight in mice with LCA-like sight loss caused by faults in AIPL1.
In the current study Dr Jacqueline van der Spuy and colleagues investigated AIPL1 variations suspected of causing LCA in a group of patients recruited at Moorfields. The AIPL1 gene provides instructions to make the AIPL1 protein, which works together with another protein, Hsp90, to build and maintain essential photoreceptor machinery.
Results turned up three types of malfunction caused by variations in AIPL1:
- Some variations code for AIPL1 protein with large sections missing from the end or within the protein. Incomplete proteins are unlikely to be produced by cells and result in loss of function.
- Other variations cause protein misfolding, which alters AIPL1's shape and leads to clumps of protein building-up inside the cell.
- Finally, a number of variations produced AIPL1 that was unable to bind together with the Hsp90 protein. AIPL1 cannot play its critical role in phototransduction - the process of turning light into an electrical signal the brain can use - without the interaction with Hsp90.
"Collectively, these findings provide unequivocal experimental evidence that the AIPL1 variations investigated led to significant and severe functional deficits in the resultant AIPL1 protein. Lab experiments like this allow us to draw conclusions about cause and effect," said Dr van der Spuy. "Therefore, these variations are confirmed disease-causing mutations, and patients that harbour them will be eligible for AIPL1-targeted gene therapy, or other potential therapies targeting AIPL1."
Dr Dolores M Conroy, Director of Research at Fight for Sight said: "These results not only tell us which LCA patients might benefit from targeted AIPL1 gene therapy, they will also lead to a much richer picture of the condition in terms of the signs and symptoms associated with different variants. This will mean better diagnosis for patients and genetic counselling for affected families."
Tina Houlihan, Chief Executive at RP Fighting Blindness said: "This research proves once again how collaborative funding within the sight loss sector can accelerate our understanding of specific conditions; these results are hugely encouraging and represent an important step forward in developing an effective targeted gene therapy treatment for LCA. The wider patient community should welcome these findings and look forward to this initial research being built upon."
On where next for the research, Dr van der Spuy added: "The next steps of this research are to expand the repertoire of newly identified and uncharacterised AIPL1 variations identified in LCA patients for inclusion in our functional analysis, ultimately ensuring validation of these AIPL1 variations as the underlying cause of the disease and inclusion of patients harbouring these mutations in clinical trials targeting AIPL1. Moreover, the next steps are to utilise the findings of this research that have led to significant novel insights into the function of AIPL1 to model the disease in order to develop supportive and complementary therapies for AIPL1 LCA."