Antisense oligonucleotides delivered to the amniotic cavity in utero modulate gene expression in the postnatal mouse

Frederic F. Depreux, Lingyan Wang, Han Jiang, Francine M. Jodelka, Robert F. Rosencrans, Frank Rigo, Jennifer J. Lentz, John Brigande, Michelle L. Hastings

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9519-9529
Number of pages11
JournalNucleic Acids Research
Volume44
Issue number20
StatePublished - Nov 16 2016
Externally publishedYes

Fingerprint

Antisense Oligonucleotides
Gene Expression
Fetus
Prenatal Diagnosis
Usher Syndromes
Inborn Genetic Diseases
Microinjections
Inner Ear
Pharmaceutical Preparations
Therapeutics
Parturition
RNA
Pediatrics
Drug Therapy
Mutation

ASJC Scopus subject areas

  • Genetics

Cite this

Depreux, F. F., Wang, L., Jiang, H., Jodelka, F. M., Rosencrans, R. F., Rigo, F., ... Hastings, M. L. (2016). Antisense oligonucleotides delivered to the amniotic cavity in utero modulate gene expression in the postnatal mouse. Nucleic Acids Research, 44(20), 9519-9529.

Antisense oligonucleotides delivered to the amniotic cavity in utero modulate gene expression in the postnatal mouse. / Depreux, Frederic F.; Wang, Lingyan; Jiang, Han; Jodelka, Francine M.; Rosencrans, Robert F.; Rigo, Frank; Lentz, Jennifer J.; Brigande, John; Hastings, Michelle L.

In: Nucleic Acids Research, Vol. 44, No. 20, 16.11.2016, p. 9519-9529.

Research output: Contribution to journalArticle

Depreux, FF, Wang, L, Jiang, H, Jodelka, FM, Rosencrans, RF, Rigo, F, Lentz, JJ, Brigande, J & Hastings, ML 2016, 'Antisense oligonucleotides delivered to the amniotic cavity in utero modulate gene expression in the postnatal mouse', Nucleic Acids Research, vol. 44, no. 20, pp. 9519-9529.
Depreux FF, Wang L, Jiang H, Jodelka FM, Rosencrans RF, Rigo F et al. Antisense oligonucleotides delivered to the amniotic cavity in utero modulate gene expression in the postnatal mouse. Nucleic Acids Research. 2016 Nov 16;44(20):9519-9529.
Depreux, Frederic F. ; Wang, Lingyan ; Jiang, Han ; Jodelka, Francine M. ; Rosencrans, Robert F. ; Rigo, Frank ; Lentz, Jennifer J. ; Brigande, John ; Hastings, Michelle L. / Antisense oligonucleotides delivered to the amniotic cavity in utero modulate gene expression in the postnatal mouse. In: Nucleic Acids Research. 2016 ; Vol. 44, No. 20. pp. 9519-9529.
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