Gene-Editing Successfully Cures Mice Genetic Disorder


Gene-Editing Successfully Cures Mice Genetic Disorder

A peptide nucleic acid developed at Carnegie Mellon is part of a gene editing system that has cured a blood disorder in mice. Credit: Carnegie Mellon University”

Gene-Editing Successfully Cures Mice Genetic Disorder


Identification of a Thermostable Cas9

Harrington L.B. et. al. (2017) Nature Communications 8:1424. https://www.ncbi.nlm.nih.gov/pubmed/29127284

The CRISPR/Cas systems used for genome editing to date have come from mesophilic bacteria, preferring temperatures of 20-45°C, preventing their use at higher temperatures. Harrington et. al. have identified a Cas9 protein from the thermophilic bacterium Geobacillus stearothermophilus (GeoCas9) that is active in temperature up to 70°C, providing a much wider range of possibilities. Additionally, GeoCas9 showed greater stability as an RNP complex in human plasma, opening the door to possible therapeutic uses.

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Could CRISPR/Cas Claims Inhibit Innovation?

Gray, B.N and Spruill, W.M. (2017) Nature Biotechnology 35:630-633. https://www.ncbi.nlm.nih.gov/pubmed/28700549

The ongoing patent battle between the Broad Institute and the University of California-Berkeley provides difficulties for researchers and companies wishing to develop CRISPR/Cas technology, though this is not the only barrier. This article describes the broad claims that have been granted or that are being investigated and presents the argument that these claims are overly broad and could limit the genome editing field.

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Using Gene Drives to Study Fungal Pathogenicity

GEN News Highlights, 30 October 2017, https://www.genengnews.com/gen-news-highlights/crispr-drives-out-fungal-resistance/81255106

Gene drives have been described as a way to eliminate pests, notably the mosquito, from the environment. However, they are a powerful research tool as well. Candida albicans can be notoriously difficult to study due to its diploid nature. By combining a newly discovered haploid C. albicans and CRISPR/Cas gene drive technology, researchers have been able to rapidly create diploid knockouts for study (https://www.ncbi.nlm.nih.gov/pubmed/29062088). The creation of these mutants could serve to increase the pace of drug discovery to combat this and other fungal pathogens.

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Model Predicts Relationship Between Editing Speed and Off-Target Effects

David Ruth, 17 October 2017, PHYS.org, https://phys.org/news/2017-10-genome-efficient.html

Researchers at Rice University have used computational models to predict the speed at which the CRISPR/Cas system identifies and cleaves the targeted location. The research, published in the Biophysical Journal (https://www.ncbi.nlm.nih.gov/pubmed/28978436), determined that by allowing CRISPR to cut at off-target sites the system could quickly find and cleave the targeted site. By limiting the system’s ability to cleave off-target sites, the dissociation of Cas9 from DNA greatly decreased the speed at which on-target sites were identified.

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Gold Nanoparticles Deliver CRISPR in Muscular Dystrophy Treatment

Sophia Ktori, GEN News Highlights, 04 October 2017, http://www.genengnews.com/gen-news-highlights/crispr-nanoparticles-repair-duchenne-muscular-dystrophy-gene/81255009

Scientists working on CRISPR delivery have developed a gold nanoparticle that encapsulates the CRISPR/Cas machinery for delivery to cells. This new technique, coined CRISPR-Gold, was published in Nature Biomedical Engineering (https://www.nature.com/articles/s41551-017-0137-2). In the paper the authors demonstrated CRISPR-Gold’s ability to correct the mutated dystrophin gene in a mouse model, with mice receiving CRISPR-Gold treatment displaying two-fold improvement in hanging time in a four-limb hanging test, compared to control mice.

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Chinese Research Team Fix Genetic Disorder in Human Embryos

David Cyranoski, 02 October 2017, Nature News, http://www.nature.com/news/chinese-scientists-fix-genetic-disorder-in-cloned-human-embryos-1.22694

A new report in Protein and Cell (https://www.ncbi.nlm.nih.gov/pubmed/28942539) is the latest in a string of human embryo CRISPR publications. Using a modified CRISPR/Cas9 system tethered to a second enzyme that can swap individual DNA bases, the researchers targeted an A to G point mutation that results in β-thalassemia. Eight of the 20 cloned embryos contained a corrected copy of the gene, possibly curing the recessive disorder. The scientists were careful to point out that not all cells in the embryo were modified, which could have unintended consequences.

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New Cas9 Mutations Increase Accuracy

Chen et. al. (2017) Nature. https://www.ncbi.nlm.nih.gov/pubmed/28931002

Researchers using FRET to study previously engineered high-fidelity Cas9 (SpCas9-HF1) and enhanced Cas9 (eSpCas9), identified that these versions are trapped in an inactive state when bound to off-target sites. Using this observation and rational protein engineering, the researchers made additional modifications to the REC3 domain to prevent activation of the HNH nuclease domain unless the guide RNA and target DNA match is very close. This new Cas9, coined Hyper Cas9 (HypaCas9) maintains the native Cas9 on target efficiency, but decreases the number of off-target events.

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CRISPR Allows for Target Mapping in Rare Cancers

Sharifnia, T., et. al. (2017) Cell Chemical Biology. 24:1075-1091. https://www.ncbi.nlm.nih.gov/pubmed/28938087

Rare cancers have traditionally been difficult to study due to low incidence and limited sample availability. However, new technologies, such as sequencing, have allowed for a greater understanding of the underlying genetic causes. In tandem with sequencing technologies, CRISPR/Cas and small molecule screens have allowed researchers to rapidly screen rare cancers for possible mechanisms and treatments.

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CRISPR Reveals How Butterflies Get Their Color

Rachael Lallensack, Nature News, 18 September 2017, http://www.nature.com/news/crispr-reveals-genetic-master-switches-behind-butterfly-wing-patterns-1.22628

Two new studies in the Proceedings of the National Academy of Sciences (http://www.pnas.org/content/early/2017/08/29/1709058114, http://www.pnas.org/content/early/2017/08/29/1708149114) provide insight into butterfly wing color. The studies identified two genes, WntA is responsible for creation of the coloring pattern and borders, while optix fills the color within the borders. Understanding butterfly coloration could provide insights into adaptations such as mimicry.

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Reversing CRISPR Gene Drives

Vella, M.R. et. al. (2017) Scientific Reports 7:11038. https://www.ncbi.nlm.nih.gov/pubmed/28887462

CRISPR/Cas gene drives could be used to eliminate vector-borne diseases such as malaria and Lyme disease. However, release of modified organisms is controversial in part due to unforeseen consequences. Developing strategies for gene drive reversal could prove useful if such problems arise. This paper develops models to evaluate the effectiveness of gene drive counter-measures in order to evaluate their potential use.


Gene-Editing Successfully Cures Mice Genetic Disorder, unlocking new possibilities for genetic editing.


A peptide nucleic acid developed at Carnegie Mellon is part of a gene editing system that has cured a blood disorder in mice. Credit: Carnegie Mellon University.123

Gene-Editing Successfully Cures Mice Genetic Disorder: In recent years, CRISPR has made waves, sparkling hundreds of studies after researchers understood its huge potential.

Gene-Editing Successfully Cures Mice Genetic Disorder: Clustered regularly interspaced short palindromic repeats (CRISPR, pronounced crisper) are basically segments of prokaryotic DNA which can be cut with a “genetic scissors,” eliminating unwanted elements from genes.

Gene-Editing Successfully Cures Mice Genetic Disorder: The technique could herald a new age for genetic editing, but there’s a catch: it’s really difficult to apply it in complex, living creatures.

Gene-Editing Successfully Cures Mice Genetic Disorder: The difficulty stems from the fact that you need to be careful and apply it in cells all throughout the body, otherwise, there’s a high mutation risk.

Gene-Editing Successfully Cures Mice Genetic Disorder: This new technique on the other hand significantly decreases unwanted, off-target gene mutations making it much easier to apply directly to complex organisms – including humans.

Gene-Editing Successfully Cures Mice Genetic Disorder: The method relies on state-of-the-art technology revolving around peptide nucleic acid (PNA) molecules, a synthetic nucleotide technology. Nucleotides are subunits of DNA.



“We have developed a system that uses FDA-approved nanoparticles to deliver our PNA molecule along with a donor DNA to repair a malfunctioning gene in living mice. This has not been achieved with CRISPR,” said Danith Ly, professor of chemistry in Carnegie Mellon’s Mellon College of Science and an expert in PNA chemistry.

Gene-Editing Successfully Cures Mice Genetic Disorder: There is also another issue with CRISPR. CRISPR relies on DNA-cutting enzymes to slice open DNA at a target site to edit a specific gene.

Gene-Editing Successfully Cures Mice Genetic Disorder: The thing is, these enzymes are pretty big and hard to administer in situ – in live organisms. What researchers usually do is harvest some cells, administer the enzymes in the lab and then re-implant the cells.

The new system consists of biocompatible nanoparticles containing PNAs, small nano-sized synthetic molecules which are much more easily applied to the body.

In order to test this approach, aside from lab tests, researchers attempted to cure a genetic blood disorder in mice.

They were successful in 7 percent of all cases which doesn’t really sound like much, but it’s a huge improvement from the 0.1% success rate usually seen in genetic editing.

Furthermore, when you consider that this is still in its early stages, it’s even more impressive.

“The effect may only be 7 percent, but that’s curative,” Ly said. “In the case of this particular disease model, you don’t need a lot of correction. You don’t need 100 percent to see the phenotype return to normal.”

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