Pediatric Focus: Inherited retinal disease

Inherited retinal diseases (IRDs) encompass an array of diverse conditions, each with a specific genetic makeup. Currently, IRDs are linked to over 270 distinct genes and manifest in varying degrees of clinical severity and inheritance patterns – from blindness in infancy and early childhood to progressive vision loss throughout adulthood. “We have very limited options for pediatric IRDs. At present, there is only one approved gene therapy for mutations in RPE65, which accounts for about 10 percent of the cases of Leber congenital amaurosis (LCA; the most severe pediatric IRD),” says Mark Pennesi, Director of Ophthalmic Genetics at the Retina Foundation and Professor of Ophthalmology at Oregon Health and Science University.

The development of comprehensive and effective therapeutic options against IRDs has proven to be a challenge for scientists. Though AAV-derived vectors and gene therapies have several advantages, they cannot accommodate large genes. Plus, the generation of neutralizing antibodies against AAV may attenuate the efficacy of AAV-mediated gene therapy. “Luxturna was approved in 2017 and has improved vision in patients with RPE65 mutations, but it affects only a small subset of the population,” Pennesi adds. In a recent study, he and a team of researchers evaluated the safety and effectiveness of EDIT-101 – an experimental gene editing treatment that uses CRISPR technology – in patients born with a form of LCA driven by CEP290 mutations. CRISPR allows scientists to address mutations in larger genes that might not be candidates for AAV gene therapy; one major issue with CEP290 is that it is too big to fit into the typical AAV vector.

Notably, 79 percent of their participants experienced a measurable improvement after receiving treatment, and there were no procedure-related adverse events. “Our recent study examined gene editing for CEP290 mutations, which account for 20–30 percent of patients with LCA. It is also a more severe disease and often results in vision loss earlier in life. There are at least 25 other genes that can cause early onset retinal degenerations and we do not have a universal treatment that can address these genes,” says Pennesi. “Eleven out of 14 patients demonstrated an improvement in at least one measurement of vision, while five out 14 showed improvements in at least two domains of visual function.”

CRISPR-Cas9 offers several advantages over previous gene editing technologies as it facilitates targeted gene editing in an efficient, specific, and modifiable manner. Progress with CRISPR-Cas9 research now means that gene editing is a feasible strategy for the treatment of IRDs. However, it is important to remember this is not a cure. “Patients who improved did not return to normal vision, but had important improvements that improved their quality of life,” says Pennesi.

Gene replacement therapy, gene editing, and antisense oligonucleotides could all help these diseases in a gene dependent manner. Scientists are also exploring gene agnostic therapies, such as neuroprotection, as well as regenerative therapies, like stem cells or optogenetics. Pennesi concludes, “This is an exciting time for patients with IRDs. The demonstration that CRISPR can work in this field will inspire further research in this area and the development of even more potent therapies.”