David R. Corey, PhD, JAMA Neurol. Published online August 01, 2016. doi:10.1001/jamaneurol.2016.2089
OPEN
EMERGING TARGET: FRATAXIN/FRIEDREICH’S ATAXIA
Friedreich’s ataxia is a multiorgan disease that affects the central nervous system, heart, pancreas, and other diseases.25 Antisense oligonucleotides efficiently inhibit gene expression in liver and the central nervous system. Using them to treat the broad range of tissues necessary to fully treat Friedreich’s ataxia will require more potent compounds and more effective strategies for delivering oligonucleotides in to all tissues that are affected.
The expanded RNA binds to chromosomal DNA to form an R-loop. This R-loop induces histone modifications and reduces transcription. The antisense oligonucleotide binds the expanded repeat, prevents the RNA from binding to the DNA, and releases the break on transcription. The expression of FXN increases to normal levels.
Further testing of anti-AAG oligonucleotides will focus on generalizing the findings to a wider variety of patient-derived cell lines with various numbers of repeats. In the longer term, preclinical and clinical testing will likely benefit from the lessons learned developing nucleic acid drugs for the treatment of other diseases.
