Antisense oligonucleotides delivered to the amniotic cavity in utero modulate gene expression in the postnatal mouse.
Congenital diseases account for a large portion of pediatric illness. Prenatal screening and diagnosis permit early detection of many genetic diseases. Fetal therapeutic strategies to manage disease processes in utero represent a powerful new approach for clinical care. A safe and effective fetal pharmacotherapy designed to modulate gene expression ideally would avoid direct mechanical engagement of the fetus and present an external reservoir of drug. The amniotic cavity surrounding the fetus could serve as an ideal drug reservoir. Antisense oligonucleotides (ASOs) are an established tool for the therapeutic modulation of gene expression. We hypothesize that ASOs administered to the amniotic cavity will gain entry to the fetus and modulate gene expression. Here, we show that an ASO targeting MALAT1 RNA, delivered by transuterine microinjection into the mouse amniotic cavity at embryonic day 13-13.5, reduces target RNA expression for up to 4 weeks after birth. A similarly delivered ASO targeting a causal splice site mutation for Usher syndrome corrects gene expression in the inner ear, a therapeutically relevant target tissue. We conclude that intra-amniotic delivery of ASOs is well tolerated and produces a sustained effect on postnatal gene expression. Transuterine delivery of ASOs is an innovative platform for developing fetal therapeutics to efficaciously treat congenital disease.
Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
Frederic F
FF
Depreux
Department of Otolaryngology, Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR 97239, USA.
Lingyan
L
Wang
Department of Otolaryngology, Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR 97239, USA.
Han
H
Jiang
Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
Francine M
FM
Jodelka
Neuroscience Center of Excellence, LSU Health Sciences Center, New Orleans, LA 70112, USA.
Robert F
RF
Rosencrans
Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
Frank
F
Rigo
Neuroscience Center of Excellence, LSU Health Sciences Center, New Orleans, LA 70112, USA.|Department of Otorhinolaryngology, LSU Health Sciences Center, New Orleans, LA 70112, USA.
Jennifer J
JJ
Lentz
Department of Otolaryngology, Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR 97239, USA brigande@ohsu.edu.
John V
JV
Brigande
Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA michelle.hastings@rosalindfranklin.edu.
Michelle L
ML
Hastings
D000650:Amnion / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D005260:Female; D005333:Fetus; D015870:Gene Expression; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008845:Microinjections; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D009928:Organ Specificity / Q000235:genetics; D011247:Pregnancy; D062085:RNA, Long Noncoding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C557040:Malat1 long non-coding RNA, mouse; D016376:Oligonucleotides, Antisense; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; C492262:Ush1c protein, mouse
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