A breakthrough study published online this week in the journal Nucleic Acids Research suggests that it may be possible to treat genetic disease detected in the womb by safely and efficiently delivering gene-altering therapies through a kind of reverse amniocentesis. The study was published online on Sept. 28.
Congenital disease and anomalies are estimated to cause 276,000 deaths worldwide within the first month of life. Prenatal diagnosis of disease has been advanced by new molecular techniques, which opens the possibility of developing therapeutic treatments to restore function in the womb.
“This could be really useful in the future to treat all types of genetic diseases,” said co-author Lingyan Wang, Ph.D., a researcher with the Oregon Hearing Research Center at Oregon Health & Science University.
Mouse models were used to evaluate the usefulness of a specific synthetic molecule called an antisense oligonucleotide (ASO). ASO sticks to precise nucleic acid sequences with extraordinary precision. Researchers developed an ASO to target RNA, a class of molecules that influences when, where, and how strongly genes are expressed in a cell. One ASO was made with special properties that lead to the destruction of the targeted RNA, and another that altered the way pre-messenger RNA is snipped and pasted together to make mature RNA. The idea is to destroy mutated RNA that may cause harm or to correct the processing of pre-messenger RNA to restore healthy protein production. In the latter case, the ASO was tested on a mouse model of Usher syndrome, a condition in which children are born deaf with balance abnormalities and vision loss by early adolescence.
Researchers injected ASO into the amniotic cavity, the space surrounding the fetus. They discovered that the treatment worked exactly as predicted: It was delivered safely and efficiently through the amniotic cavity to the fetus. The study demonstrated that ASOs delivered this way can alter expression of targeted RNA molecules in the liver, kidney, and inner ear of postnatal mice.
“The best way to treat a disease that we know will emerge at birth is to deliver a therapy in utero to the developing fetus before irreparable damage occurs,” said co-author John Brigande, Ph.D., a principal investigator in the Oregon Hearing Research Center at OHSU.
Nucleic Acids Research tagged the study as a breakthrough article, a designation ascribed to no more than 3 percent of the papers published by the journal. Wang and Brigande noted that the work opens the door for fetal drug therapy to treat congenital disease.
In addition to Wang and Brigande, authors included Han Jiang, Ph.D., of OHSU; Frederic F. Depreux, Ph.D., Francine M. Jodelka, Ph.D. and Michelle L. Hastings, Ph.D., , with the Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science in Chicago; Frank Rigo, Ph.D., of Ionis Pharmaceuticals in Carlsbad, California; and Robert F. Rosencrans, Ph.D. and Jennifer J. Lentz, Ph.D., with the Neuroscience Center and Department of Otorhinolaryngology, LSU Health Sciences Center in New Orleans.
The research was funded by the National Institutes of Health [R01-DC012596 to M.L.H., R21-DC012916 to J.V.B., R01-DC014160 to J.V.B., P30-DC005983 to J.V.B., 1 U54 GM104940 to J.J.L., P30-GM103340 to J.J.L.]; and Foundation Fighting Blindness (to J.J.L., M.L.H.).