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Developmental biology - Gene Therapy

Cured! A genetic blood disorder stopped in utero

A gene-editing technique cures the blood disorder Beta Thalassemia while mouse pup is in the womb...

Carnegie Mellon and Yale researchers have for the first time used a gene editing technique to successfully cure a genetic condition. The study was conducted in mice and shows promise for treating genetic conditions during embryonic development. Their findings, published in Nature Communications, represent a new avenue for therapies.

An estimated 8 million children are born each year with severe genetic disorders. Although some can be detected during pregnancy using amniocentesis, there are no treatment options to correct any before birth. "Early in embryonic development, there are a lot of stem cells dividing at a rapid pace. If we can go in and correct a genetic mutation early, we could dramatically reduce the impact that mutation has on fetal development or even cure the condition," says Danith Ly, professor of chemistry in Carnegie Mellon's Mellon College of Science.

In the current study, researchers used a peptide nucleic acid-based gene editing technique (PNAs) to cure beta thalassemia, a genetic blood disorder that reduces production of hemoglobin. Peptide nucleic acids combine a synthetic protein backbone with nucleobases found in DNA and RNA. The PNAs used in this study are created by Ly at Carnegie Mellon's Center for Nucleic Acids Science and Technology (CNAST), a leading center for PNA science. Their technique uses an FDA-approved nanoparticle to deliver PNA molecules paired with donor DNA to the site of a genetic mutation.
When the PNA-DNA complex identifies a designated mutation, the PNA molecule binds to the DNA and unzips its two strands. The donor DNA binds with the faulty DNA and spurs the cell's DNA repair pathways into action, correcting the error.

Using a technique similar to amniocentesis, researchers injected the PNA complex into the amniotic fluid of pregnant mice whose fetuses carry a mutation in the beta-globin gene causing beta thalassemia.

Just one injection of the PNA during gestation corrected 6 percent of the mutations. This 6 percent correction was enough to cause dramatic improvements in the pup's symptoms of beta thalassemia - and enough for them to be considered cured. Mice treated using PNA while in utero, had levels of hemoglobin within the normal range, less spleen enlargement and increased survival rates.

There were no off-target effects from the treatment, a finding that suggests this method would be preferable over other gene editing techniques like CRISPR/Cas9, which can sometimes damage off-target DNA.

"CRISPR is much easier to use, which makes it ideal for laboratory research. But the off-site errors make it less useful for therapeutics," explains Ly. "The PNA technique is more ideal for therapeutics. It doesn't cut the DNA, it just binds to it and repairs things that seem unusual. We looked at 50 million samples and couldn't find one offsite error when we used our PNA gene editing technique."

The researchers believe that their technique might be able to achieve even higher success rates if they can administer it multiple times during gestation. They also hope to see if their technique can be applied to other conditions.

Genetic diseases can be diagnosed early during pregnancy, but many monogenic disorders continue to cause considerable neonatal and pediatric morbidity and mortality. Early intervention through intrauterine gene editing, however, could correct the genetic defect, potentially allowing for normal organ development, functional disease improvement, or cure. Here we demonstrate safe intravenous and intra-amniotic administration of polymeric nanoparticles to fetal mouse tissues at selected gestational ages with no effect on survival or postnatal growth. In utero introduction of nanoparticles containing peptide nucleic acids (PNAs) and donor DNAs corrects a disease-causing mutation in the ß-globin gene in a mouse model of human ß-thalassemia, yielding sustained postnatal elevation of blood hemoglobin levels into the normal range, reduced reticulocyte counts, reversal of splenomegaly, and improved survival, with no detected off-target mutations in partially homologous loci. This work may provide the basis for a safe and versatile method of fetal gene editing for human monogenic disorders.

Authors: Adele S. Ricciardi, Raman Bahal, James S. Farrelly, Elias Quijano, Anthony H. Bianchi, Valerie L. Luks, Rachael Putman, Francesc López-Giráldez, Süleyman Co?kun, Eric Song, Yanfeng Liu, Wei-Che Hsieh, Danith H. Ly, David H. Stitelman, Peter M. Glazer and W. Mark Saltzman .

This work was made possible by the support of the DSF Charitable Foundation, who has donated $7 million to CNAST, enabling the center to engage in fundamental research aimed at developing synthetic chemistry solutions for the diagnosis and treatment of disease.

Additional study authors include Adele S. Ricciardi, Raman Bahal, James S. Farrelly, Elias Quijano, Anthony H. Bianci, Valerie L. Luks, Rachel Putman, Francesc Lopez-Giraldez, Suleyman Coskun, Eric Song, Yanfeng Liu, David H. Stitelman, Peter M. Glazer and W. Mark Saltzman from Yale, and Wei-Che Hsieh from Carnegie Mellon.

The research was funded by the Brain Research Foundation Scientific Innovations Award, the NIGMS Medical Scientist Training Program (GM07205), the National Heart, Lung and Blood Institute (HL134252), the Ohse Research Grant, Yale School of Medicine, the American Pediatric Surgical Association Foundation Grant and the DSF Charitable Foundation.

Prof Bik Tye is Visiting Professor in LIFS at HKUST. Her interest in the mechanisms for DNA replication dated from when she established her own laboratory at Cornell University as Assistant Professor. Her group published the initial paper in 1983 that identified the MCM2-7 genes as key components in DNA replication. Dr Yuanliang Zhai formerly worked as Research Assistant Professor in LIFS and Junior Fellow of Jockey Club IAS, and currently is Assistant Professor in School of Biological Sciences in HKU. The co-authors in the ORC paper also include Dr Wai Hei Lam, Post-doctoral fellow of LIFS and Dr Yongqian Zhao, Research Assistant Professor in LIFS and Junior Fellow of Jockey Club IAS.

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Jul 13, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

3D model of the Gamma-PNA molecule. Image credit: Carnegie Mellon Institute.

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