For children born with a rare form of inherited blindness called Leber congenital amaurosis type 16 (LCA16), the genetic culprit can be a single miswritten instruction in their DNA known as a nonsense mutation. The mutation results in a truncated and nonfunctional form of a critical protein called Kir7.1, which plays a key role in the retinal pigment epithelium (RPE) — a layer of cells that supports and sustains the light-sensing photoreceptors. The mutation leads to deterioration of the RPE, death of photoreceptor cells and progressive loss of vision.
Using a mouse model of the disease and patient-derived cells, a research team led by Bikash Pattnaik, PhD, professor of pediatrics who is also affiliated with the Department of Ophthalmology and Visual Sciences, found a way to override the premature stop signal, restore the functional Kir7.1 protein and measurably improve retinal function, as reported in a paper co-authored by Pawan Shahi, PhD, a scientist in the Department of Pediatrics.
Pattnaik’s research group used an engineered form of transfer RNA, or tRNA. The specially designed tRNAs contained an anticodon-engineered suppressor tRNA (ACE-tRNA) that recognized the premature stop code and inserted the correct amino acid, allowing the protein to be produced correctly. In patient-derived stem cell models of LCA16, treatment with the ACE-tRNA restored the Kir7.1protein to approximately 40% of normal levels. The protein was also shown to be in its proper location in the cell membrane, a prerequisite for its function. The treated cells regained the ability to perform a critical housekeeping task: clearing away and recycling the worn-out tips of photoreceptor cells.
The impact could extend well beyond LCA16. Nonsense mutations account for an estimated 15% to 20% of all inherited disorders, including cystic fibrosis, Duchenne muscular dystrophy, hemophilia, and many rare diseases. Pattnaik’s vision is to create a “one-to-many” therapeutic platform that benefits multiple patient populations affected by nonsense mutations.
Read more about the experimental therapy for nonsense mutations
