Precision medicine the future for retinal dystrophies

Translational Pediatrics April 2015

In a recent paper appearing in Translational Pediatrics (Transl Pediatr 2015; 4(2):139-163), researchers from Save Sight Institute review the known disease genes of conditions such as retinitis pigmentosa (RP), congenital stationary night blindness (CSNB), human cone and cone-rod dystrophy and lebers congenital amaurosis (LCA).

Retinal dystrophies are degenerative diseases of the retina, commonly presenting as night or colour blindness, tunnel vision and subsequent progression to complete blindness. It is estimated that 1 in 4,000 individuals are affected, and while more than 120 genes have already been proven responsible, there remains considerable complexity in the way in which mutations present across individuals and families. Previous techniques result in a molecular diagnosis of just 10-20%.

According to A/Professor Robyn Jamieson “There is currently no cure or treatment options for patients with retinal dystrophies, only ongoing vision loss and progression in the degenerative cases.”

Researchers from Save Sight Institute are working hard to utilise emerging Next Generation Sequencing (NGS) technology as the first step in improving therapeutic approaches to retinal dystrophies.

Advances in gene therapy, cell replacement and retinal implant strategies offer hope to people affected by retinal dystrophies.

Gene therapy is predicted to be more effective for children diagnosed early with the condition, since intervention is likely to be more effective in patients with less advanced disease progression. For older patients, retinal implants or prosthetics (commonly referred to as ‘bionic eyes’) are an area actively being explored.

Various types of stem cells have been applied, and have demonstrated regeneration in mice with retinal diseases. Induced pluripotent stem cells (iPSCs) are derived from skin from the patient, reducing ethical concerns and reducing the risk of host immune system rejection. IPSCs have been differentiated to retinal cells, delivering healthy retinal cells into the diseased retina of mice, facilitating the repair and restoration of function.

Further development of iPSC applications for treating retinal dystrophies in human patients requires the use of efficient genome engineering to reverse or alter the mutation. The most promising of these technologies is the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. Application of the CRISPR/Cas9 system, in conjunction with stem cell technologies, is likely to pave the way for ‘precision medicine’ and catalyse the future understanding and treatment of genetic disease.

A/Prof Jamieson says “It is anticipated that future work will be more individualised”, offering the following example. “A patient may have a blood and skin sample collected to identify the mutation and to generate a fibroblast cell line. Once the mutation is identified, various treatment approaches can be observed in the patients own skin cells that have been changed to iPSCs and then retinal cells. Genome editing techniques are under research to correct the DNA mutation, with the aim that corrected differentiated retinal cells may be transplanted into the affected retina.”

In highly complex and diverse genetics diseases such as retinal dystrophies, where the underlying genetic cause is likely to be unique, this approach is one of the most promising avenues of future research and exploration.

To review the full published article in Translational Pediatrics please click here.

To support the work of researchers at Save Sight Institute please click here and select the ‘Inherited and Paediatric Eye Disease’ research group.