Potential treatment of newborns via amniotic fluid?
A breakthrough study offers promise for therapeutic treatment of congenital diseases — in utero — using designer gene sequences.
Breakthrough research by teams at Rosalind Franklin University of Medicine (RFU), and the Oregon Health & Science University (OHSU), offers promise for therapeutic management of congenital diseases by in utero treatment.
Researchers made designer nucleotide sequences — specific nucleotide chains arranged from the GACT "letters" of DNA and on RNA using the GACU "letters", organized into molecules called antisense oligonucleotides (ASOs). These ASOs are then injected into the amniotic fluid surrounding each developing fetal mouse. The objective of the experiment being the treatment of disabling-to-lethal congenital genetic defects.
Recently published in the journal Nucleic Acids Research, the study showed that these antisense oligonucleotides (ASOs), short strands of engineered nucleic acid designed to bind to specific gene sequences, were able to be safely injected into the amniotic cavity of mice. The procedure resulted in the intended alteration to genes relevant to the tissues intended, with affected genes still being expressed one month following birth.
"A major barrier to the development of treatments for congenital disorders is the risk to the developing fetus such an intervention may pose.
"Our demonstration that this promising type of therapeutic can be delivered to the amniotic cavity is an important advance for fetal treatment of disease."
Michelle Hastings PhD, Associate Professor - and team leader, Cell Biology and Anatomy, Rosalind Franklin University of Medicine, Chicago, Illinois, USA.
An ASO is engineered to stick to a particular nucleic acid sequence. Researchers in this project targeting a class of molecules within RNA, that influences when, where, and how strongly specific genes are expressed (or produced). One ASO had properties to initiate the destruction of a targeted RNA, another ASO altered the way pre-messenger RNA was snipped and pasted together to make a more mature RNA. Researchers' aim was to destroy mutated RNA that can cause harm — or to correct the processing of pre-messenger RNA and restore healthy protein production. In the latter option, they tested an ASO on mice for Usher syndrome, a condition in which babies are born deaf with balance abnormalities and lose their vision by early adolescence.
The researchers injected the constructed ASO into the amniotic cavity of mice and discovered the treatment process worked exactly as predicted: (1) it was delivered safely and efficiently through the amniotic cavity and absorbed by the fetus, (2) it delivered an altered RNA molecule to the liver, kidney, and inner ear of postnatal mice with Usher syndome.
"This could be really useful in the future to treat all types of genetic diseases," said study co-author Lingyan Wang PhD, a researcher with the Oregon Hearing Research Center at OHSU.
Congenital diseases are estimated to cause the death of almost 300,000 infants within the first month of life each year across the globe. They can also cause childhood illnesses and long-term disability. Prenatal screening techniques now make early diagnosis of some congenital diseases possible — which may present an opportunity for developed techniques to intervene in the disease process before birth.
The authors add: "We predict that fetal ASO pharmacotherapy has the potential to safely enable therapeutic strategies for the treatment of fetal and congenital genetic disease."
Combining a potentially low-risk delivery approach — amniotic injection — with a promising antisense drug platform, is an exciting breakthrough. But, more work must be done to improve drug uptake efficiency and distribution.
"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."
John Brigande PhD, Associate Professor, Otolaryngology, Cell and Developmental Biology, Oregon Hearing Research Center, and principal investigator.
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.
This study was conducted by a team of researchers from around the country, including lead author Frederic Depreux, Ph.D., with Francine Jodelka and Michelle Hastings, Ph.D, at RFU; John Brigande, Ph.D., Lingyan Wang, Ph.D., and Han Jiang, Ph.D., at OHSU; Frank Rigo, Ph.D., of Ionis Pharmaceuticals; 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.)
Oregon Health & Science University is a nationally prominent research university and Oregon’s only public academic health center. It serves patients throughout the region with a Level 1 trauma center and nationally recognized Doernbecher Children’s Hospital. OHSU operates dental, medical, nursing and pharmacy schools that rank high both in research funding and in meeting the university’s social mission. OHSU’s Knight Cancer Institute helped pioneer personalized medicine through a discovery that identified how to shut down cells that enable cancer to grow without harming healthy ones. OHSU Brain Institute scientists are nationally recognized for discoveries that have led to a better understanding of Alzheimer’s disease and new treatments for Parkinson’s disease, multiple sclerosis and stroke. OHSU’s Casey Eye Institute is a global leader in ophthalmic imaging, and in clinical trials related to eye disease.
About Rosalind Franklin University
Formed in 1912 as the Chicago Hospital-College of Medicine, today RFU brings together five colleges and over 30 graduate health profession and science programs. The range of disciplines being taught on a single campus allows for team-based, interdisciplinary learning and practice opportunities—an approach that has made RFU a national leader in Interprofessional medical and healthcare education and research.
Our students are further prepared for their careers through our state-of-the-art network of simulation and skills labs and a wide variety of clinical opportunities. Located 36 miles north of Chicago in the city’s North Shore suburbs, RFU students have access to a greater number and wider range of clinical and service learning experiences.
Finally, RFU’s 2,000+ students enjoy an engaged, supportive sense of community with peers who share their academic interests and goals, and faculty who know them by name and are committed to their individual success.
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Oct 14, 2016 Fetal Timeline Maternal Timeline News News Archive
Transuterine microinjection into amniotic cavity surrounding a mouse embryo.
BLUE microinjection pipette crossing the uterus. RED: yolk sac cavity (ysc);
BLACK: visceral yolk sac; GREEN: (vys) - exocoelomic cavity (ec) - amnion cavity.
Image Credit: Rosalind Franklin University