We will also stream this seminar via Zoom. For the Zoom link, please contact Jessica Marcus: jmarcus@upenn.edu.

Bikash Pattnaik
Department of Pediatrics
Department of Ophthalmology and Visual Sciences
University of Wisconsin – Madison

Genomic medicine influxes ions through channels

The flow of charged ions through membrane proteins or ion channels is the electrical current that controls cellular membrane potential. Leber Congenital Amaurosis (LCA16) results from mutations in the KCNJ13 gene, which encodes the inwardly rectifying potassium channel (Kir7.1). This channel is vital for maintaining ionic balance in retinal pigment epithelial (RPE) cells and is essential for photoreceptor function and survival. Disruptions caused by KCNJ13 mutations lead to progressive retinal degeneration and early-onset blindness. The evolving field of genomic medicine, which leverages advances in genomics for diagnosing and treating genetic diseases, has positioned genomic medicine therapeutic approaches as promising treatment strategies for LCA16. Here, I will discuss the disease’s genetic defects and how therapy targets the root cause rather than merely managing symptoms. One of the novel approaches within this field is engineered transfer RNAs (tRNAs) to suppress nonsense mutations, which occur when a premature stop codon truncates the protein, rendering it nonfunctional. In LCA16, such mutations in KCNJ13 result in a nonfunctional Kir7.1 channel, leading to retinal dystrophy. Engineered tRNAs recognize these premature stop codons and insert the correct amino acids, allowing the ribosome to produce a full-length, functional protein. Our recent studies have demonstrated the efficacy of this approach, with human induced pluripotent stem cells (hiPSCs) from LCA16 patients showing restored Kir7.1 channel function after correction with engineered tRNAs. Animal models treated with these tRNAs have also exhibited significant improvements in retinal function, providing proof-of-concept for potential therapeutic applications in humans. In conclusion, the development of gene therapies for LCA16 underscores the transformative potential of genomic medicine in treating inherited retinal diseases.