Groundbreaking study opens door for treating congenital disease before birth

Congenital diseases account for nearly a quarter of perinatal deaths and are important causes of childhood illness and long-term disability. Prenatal screening techniques now make early diagnosis possible, presenting the opportunity to intervene in disease processes before birth. The rapid proliferation of stem cells in the fetus and its immature immune system make in utero gene therapy an attractive target for gene therapy, but ethical considerations and the consequences of disrupting fetal development have so far prohibited human trials.

A breakthrough study by a team of researchers at OHSU and collaborators suggests it may be possible to deliver prenatal gene therapy safely and efficiently in the womb, using the amniotic cavity as a drug reservoir. The study, published in the journal Nucleic Acids Research on Sept. 28, opens the door to potential therapeutic treatments.

The team used a mouse model to determine whether antisense oligonucleotides (ASO), synthetic molecules engineered to target and alter RNA sequences, could be delivered to the amniotic cavity to target gene expression in utero.

A well-characterized ASO was injected into the amniotic fluid and successfully altered expression of a targeted RNA transcript in the liver, kidney, and inner ear of postnatal mice for up to four weeks after birth. The treatment was well tolerated, with 94% of injected mice surviving. The team successfully demonstrated the general ability of ASOs to deliver gene therapy by testing a second ASO.

Further investigation is needed to better understand ASO transport in order to maximize fetal uptake and broaden distribution, but this work establishes that the amniotic cavity has the necessary characteristics to serve as an efficient reservoir for sustained ASO delivery to the developing fetus.

Authors included Lingyan Wang, Ph.D., Han Jiang, Ph.D., and John Brigande, Ph.D., of OHSU’s Oregon Hearing Research Center; 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.

This 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.)