Irish scientists develop gene therapy for inherited vision loss disorder

Neurological disorders associated with ageing could benefit from breakthrough

A fluorescent microscope image of a healthy cell with its mitochondria highlighted in gold. It shows a highly elaborate and well-connected network of mitochondria. Image:  Prof Jane Farrar and Dr Daniel Maloney, Trinity College Dublin

A fluorescent microscope image of a healthy cell with its mitochondria highlighted in gold. It shows a highly elaborate and well-connected network of mitochondria. Image: Prof Jane Farrar and Dr Daniel Maloney, Trinity College Dublin

 

A team of Irish scientists have developed a gene therapy that could potentially lead to a new treatment for an eye disease causing progressive loss of vision, which affects many thousands of people across the globe.

The breakthrough therapy, which offers hope for people with dominant optic atrophy (DOA), was devised by researchers at Trinity College Dublin in collaboration with clinicians at the Royal Victoria Eye and Ear Hospital and the Mater hospital in Dublin.

It also has implications for a much wider suite of neurological disorders associated with ageing which collectively affect millions of people worldwide.

DOA is an inherited disorder characterised by degeneration of optic nerves. It typically starts during the first decade of life. Affected people usually develop moderate visual loss and colour vision defects – but severity varies, symptoms can worsen over time and some people become blind. At present, there is no way to prevent or cure DOA.

The scientists published their results in Frontiers in Neuroscience on Thursday.

A gene (OPA1) provides instructions for making a protein found in cells and tissues throughout the body that is pivotal to the proper function of mitochondria, the energy generators in cells.

Without the protein, mitochondrial function is sub-optimal; the normally well-interconnected mitochondrial network in healthy cells becomes highly disrupted. For those with DOA, it is mutations in OPA1 and the dysfunctional mitochondria that are responsible for onset and progression of the disorder.

Led by research fellow Dr Daniel Maloney and Prof Jane Farrar from TCD School of Genetics and Microbiology, the gene therapy successfully protected the visual function of mice who were treated with a chemical targeting the mitochondria – and were consequently living with dysfunctional mitochondria.

Mutations

The scientists also found the gene therapy improved mitochondrial performance in human cells that contained mutations in the OPA1 gene.

“We used a clever lab technique that allows scientists to provide a specific gene to cells that need it using specially engineered non-harmful viruses,” Dr Maloney said.

“This allowed us to directly alter the functioning of the mitochondria in the cells we treated, boosting their ability to produce energy which, in turn, helps protect them from cell damage.

“Excitingly, our results demonstrate that this OPA1-based gene therapy can potentially provide benefit for diseases like DOA, which are due to OPA1 mutations, and also possibly for a wider array of diseases involving mitochondrial dysfunction.”

Mitochondrial dysfunction causes problems in neurological disorders such as Alzheimer’s and Parkinson’s disease. The impacts gradually build up over time, which is why many may associate such disorders with ageing.

Prof Farrar added: “We are very excited by the prospect of this new gene therapy strategy, although it is important to highlight that there is still a long journey to complete from a research and development perspective before this therapeutic approach may one day be available as a treatment.”

Because mitochondrial dysfunction was implicated in so many neurological disorders, there was great potential for this type of therapeutic strategy to make “a major societal impact”, she said.

The research was supported by Science Foundation Ireland, the Health Research Board of Ireland, Fighting Blindness Ireland, and Health Research Charities Ireland.