New Therapies for Inherited Retinal Disease LCA16?

A new grant from the National Institutes of Health’s National Eye Institute Audacious Goals Initiative will allow Bikash Pattnaik, PhD, to identify new therapeutic pathways for Leber's Congenital Amaurosis (LCA), an inherited retinal degenerative disease that accounts for 20 percent of childhood blindness.

Gene Editing to Study Cell Mutations

Diseased areas of the retinas of a patient with LCA16.
Diseased areas of the retinas of a patient with LCA16.

In the four-year, $1.5 million project, entitled "Molecular Therapies for Leber’s Congenital Amaurosis Caused by KCNJ13 Mutations," Dr. Pattnaik’s team will first generate induced pluripotent stem cell-derived retinal pigment epithelium cells (iPSC-RPEs) from the somatic cells of patients with LCA16, the most recently identified form of LCA.

The team will then use an innovative gene editing technology called Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR) to create in vitro models of different LCA16 mutations in those cells. They’ll study the pathophysiology of the mutations, specifically focusing on a gene called KCNJ13.

They hypothesize that the mutated KCNJ13 gene may be associated with a potassium channel defect in the retinal pigment epithelium, which in turn may be a cause of LCA16.

Drug and Gene Therapies

In the second part of the study, the team will test whether “read-through” drugs, such as gentamycin, can overcome the KCNJ13 gene mutation, promote full protein synthesis in the iPSC-RPEs and slow disease progression.

Clinical trials elsewhere are investigating similar drug-based approaches for the treatment of other genetic disorders, such as muscular dystrophy and cystic fibrosis, Dr. Pattnaik explained.

Finally, the team will investigate viral vectors to deliver a corrected version of the KCNJ13 gene into the induced iPSC-RPEs, thereby resolving the potassium channel defect and ultimately, treating the disease.

Expanding Options for More Patients

The new grant expands on Dr. Pattnaik’s earlier LCA research, which focused on only one specific mutation of the disease.

“This grant gives us options to explore the other mutations of LCA and take a personalized medicine approach,” Dr. Pattnaik explained.

“If we can develop therapies to target specific mutations of the LCA16 gene, we can potentially help a wider group of patients.”