From Darkness

Introducing a personalized antisense gene therapy for inherited retinal diseases

After decades of study into inherited retinal diseases (IRD), researchers at the Scheie Eye Institute at the University of Pennsylvania have tested  an antisense gene therapy-based approach for the treatment of Leber congenital amaurosis (LCA) caused by a specific mutation in the ciliopathy gene centrosomal protein 290 – CEP290 (1).  The intravitreal injection was developed by ProQR Therapeutics.

“LCA is the most severe form of IRD and thus has the greatest treatment potential,” says Artur Cideciyan, who led the clinical trial at the Scheie Eye Institute. “We were cautiously optimistic that successful pre-clinical experiments performed in the lab would translate into positive results in patients.” And the cautious optimism was justified: majority of the patients who  took part in the multi-center study experienced an improvement in visual acuity within the first three months  – with no serious adverse events. And one responder improved from barely being able to perceive light to 20/400.

Patients received intravitreal injections of a short RNA molecule designed to counter the mutation. Cideciyan explains in more detail: “The most common mutation in the CEP290 gene is a single nucleotide change in intron 26, which results in the introduction of aberrant exon and reduces the amount of CEP290 protein.” The oligonucleotide essentially blocks recognition of the aberrant exon, boosting the amount of non-mutant CEP290 protein in photoreceptors.

“We are in an era of personalized medicines and this is especially true for monogenic conditions, such as IRD. Many of the treatment avenues currently considered are specific to the gene involved – such as gene augmentation for recessive loss of function, or gene knockdown and replacement for dominant gain of function conditions,” explains Cideciyan. “Our current work takes this gene-specific personalized medicine for IRDs one step further by making the intervention mutation specific.”

Naturally, patients with different molecular mechanisms of the disease cannot benefit from such specific treatment, but does the research hold wider promise? According to Cideciyan: yes. “Our study showed for the first time that intravitreally injected oligonucleotides can modulate splicing in human photoreceptor cells and result in positive changes in vision. This work opens the door to evaluating similar approaches in other inherited retinal diseases.”