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posted by martyb on Saturday December 09 2017, @11:22AM   Printer-friendly
from the CRISPR-bacon dept.

Instead of using CRISPR/Cas9 for gene editing, Salk Institute researchers have used gene-activating CRISPR/Cas9 to regulate gene activity in mice:

A new twist on gene editing makes the CRISPR/Cas9 molecular scissors act as a highlighter for the genetic instruction book. Such highlighting helps turn on specific genes. Using the new tool, researchers treated mouse versions of type 1 diabetes, kidney injury and Duchenne muscular dystrophy [open, DOI: 10.1016/j.cell.2017.10.025] [DX], the team reports December 7 in Cell. The new method may make some types of gene therapy easier and could be a boon for researchers hoping to control gene activity in animals, scientists say.

CRISPR/Cas9 is a two-part molecular scissors. A short, guide RNA leads the DNA-cutting enzyme Cas9 to specific places in the genetic instructions that scientists want to slice. Snipping DNA is the first step to making or fixing mutations. But researchers quickly realized the editing system could be even more versatile.

In the roughly five years since CRISPR/Cas9 was first wielded, researchers have modified the tool to make a variety of changes to DNA (SN: 9/3/16, p. 22). Many of those modifications involve breaking the Cas9 scissors so they cannot cut DNA anymore. Strapping other molecules to this "dead Cas9" allows scientists to alter genes or change the genes' activities.

Gene-activating CRISPR/Cas9, known as CRISPRa, could be used to turn on dormant genes for treating a variety of diseases. For instance, doctors might be able to turn on alternate copies of genes to compensate for missing proteins or to reinvigorate genes that grow sluggish with age. So far, researchers have mostly turned on genes with CRISPRa in cells growing in lab dishes, says Charles Gersbach, a biomedical engineer at Duke University not involved in the new study.

Also at GenomeWeb and New Atlas.


Original Submission

Related Stories

2017: Gene Therapy's Milestone Year 4 comments

In a milestone year, gene therapy is finding a place in medicine

After decades of hope and high promise, this was the year scientists really showed they could doctor DNA to successfully treat diseases. Gene therapies to treat cancer and even pull off the biblical-sounding feat of helping the blind to see were approved by U.S. regulators, establishing gene manipulation as a new mode of medicine.

Almost 20 years ago, a teen's death in a gene experiment put a chill on what had been a field full of outsized expectations. Now, a series of jaw-dropping successes have renewed hopes that some one-time fixes of DNA, the chemical code that governs life, might turn out to be cures. "I am totally willing to use the 'C' word," said the National Institutes of Health's director, Dr. Francis Collins.

[...] The advent of gene editing — a more precise and long-lasting way to do gene therapy — may expand the number and types of diseases that can be treated. In November, California scientists tried editing a gene inside someone's body for the first time using a tool called zinc finger nucleases for a man with a metabolic disease. It's like a cut-and-paste operation to place a new gene in a specific spot. Tests of another editing tool called CRISPR to genetically alter human cells in the lab may start next year. "There are a few times in our lives when science astonishes us. This is one of those times," Dr. Matthew Porteus, a Stanford University gene editing expert, told a Senate panel discussing this technology last month.

Previously: Gene Therapy Cure for Sickle-Cell Disease
Gene Therapy to Kill Cancer Moves a Step Closer to Market
U.S. Human Embryo Editing Study Published
FDA Approves a Gene Therapy for the First Time
Gene Editing Without CRISPR -- Private Equity Raises $127 Million
FDA Committee Endorses Gene Therapy for a Form of Childhood Blindness
FDA Approves Gene Therapy for Non-Hodgkin's Lymphoma
Gene Therapy and Skin Grafting for Junctional Epidermolysis Bullosa
Gene Therapy for Spinal Muscular Atrophy Type 1
Biohackers Disregard FDA Warning on DIY Gene Therapy
CRISPR Used to Epigenetically Treat Diseases in Mice
Gene Therapy Showing Promise for Hemophilia B
Gene Therapy for Retinal Dystrophy Approved by the FDA
CRISPR Treatment for Some Inherited Forms of Lou Gehrig's Disease Tested in Mice


Original Submission

CRISPR Epigenetic Cholesterol Reduction in Mice 2 comments

CRISPR study reduces cholesterol in mice without "editing" DNA

Rather than hacking away with genetic scissors, recent work has instead used CRISPR to temporarily turn certain genes on and off through epigenetic modulation. In that vein, the new study developed a CRISPR-Cas9 repressor system that can silence a gene called Pcsk9, which regulates cholesterol levels. The Duke researchers managed to package this system and deliver it into the livers of adult mice.

"We previously used these same types of tools to turn genes on and off in cultured cells, and we wanted to see if we could also deliver them to animal models with an approach that is relevant for gene therapy," says Charles Gersbach, lead researcher on the study. "We wanted to change the genes in a way that would have a therapeutic outcome, and Pcsk9 is a useful proof-of-concept given its role regulating cholesterol levels, which in turn affect health issues like heart disease."

The researchers started with a Cas9 enzyme taken from the bacteria species Staphylococcus aureus, and to keep it from making cuts to the target DNA, they created a "dead" version dubbed dCas9. This was bundled with a KRAB protein that silences gene expression, and the combination was then packaged inside adeno-associated viral (AAV) vectors – viruses that are engineered to carry the active ingredients to the right DNA target.

In their tests, the Duke researchers delivered the system to adult mice, where it activated in their livers. Compared to a control group that had simple saline injections, the Pcsk9 genes in the test mice were successfully repressed and the animals' cholesterol levels dropped as a result. Better yet, the effects of a single treatment lasted six months.

RNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors (open, DOI: 10.1038/s41467-018-04048-4) (DX)

Related: CRISPR Used to Reduce Tissue Inflammation and Damage
CRISPR Used to Epigenetically Treat Diseases in Mice


Original Submission

CRISPR Used to Cure Duchenne Muscular Dystrophy in Dogs... by Further Damaging DNA 7 comments

Gene editing of dogs offers hope for treating human muscular dystrophy

Fighting fire with fire, researchers working with dogs have fixed a genetic glitch that causes Duchenne muscular dystrophy (DMD) by further damaging the DNA. The unusual approach, using the genome editor CRISPR, allowed a mutated gene to again make a key muscle protein. The feat—achieved for the first time in a large animal—raises hopes that such genetic surgery could one day prevent or treat this crippling and deadly disease in people. An estimated 300,000 boys around the world are currently affected by DMD.

The study monitored just four dogs for less than 2 months; more animal experiments must be done to show safety and efficacy before human trials can begin. Even so, "I can't help but feel tremendously excited," says Jennifer Doudna of the University of California, Berkeley, who heard the results last week at a CRISPR meeting she helped organize. "This is really an indication of where the field is heading, to deliver gene-edited molecules to the tissues that need them and have a therapeutic benefit. Obviously, we're not there yet, but that's the dream."

[...] The study offers little evidence that dogs regained muscle function, however, and that, coupled with the short duration of the study and the small number of animals studied, left some scientists less enthusiastic. One researcher in the tight-knit DMD field who asked not to be named wonders whether the study was rushed to help draw investment in Exonics Therapeutics, a Boston-based company Olson launched last year to develop the potential treatment.

[...] Another challenge was to alter billions of muscle cells throughout a living animal. So the team enlisted a helper: a harmless adeno-associated virus that preferentially infects skeletal muscle and heart tissue. Two 1-month-old dogs received intramuscular injections of the virus, engineered to carry CRISPR's molecular components. Six weeks later, those muscles were making dystrophin again. Those results led the researchers to give an intravenous infusion to two more dogs, also 1 month old, to see whether the CRISPR-carrying viruses could add the genome editor to muscles throughout the body. By 8 weeks, Olson told the meeting, dystrophin levels climbed to relatively high levels in several muscles, reaching 58% of normal in the diaphragm and 92% in the heart. But because the dogs were euthanized, Olson could show little evidence that they had avoided DMD symptoms, save for a dramatic video of a treated dog walking and jumping normally.

Also at Science News.

Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy (DOI: 10.1126/science.aau1549) (DX)

More about Duchenne muscular dystrophy at Wikipedia.

Related: Scientists Create Extra-Muscular Beagles
FDA Panel Recommends Rejection of Duchenne Muscular Dystrophy Treatment
Nonviral CRISPR-Gold Editing Technique Fixes Duchenne Muscular Dystrophy Mutation in Mice
CRISPR Used to Epigenetically Treat Diseases in Mice


Original Submission

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  • (Score: 0) by Anonymous Coward on Saturday December 09 2017, @02:53PM

    by Anonymous Coward on Saturday December 09 2017, @02:53PM (#607693)

    Too bad about all the dystopian prophecies coming true as well.

  • (Score: 1, Informative) by Anonymous Coward on Saturday December 09 2017, @07:16PM

    by Anonymous Coward on Saturday December 09 2017, @07:16PM (#607750)

    It looks like they are finally getting away from the DSB (double strand break) "editing" thing and actually using this tech for something plausible.

  • (Score: 1) by rylyeh on Sunday December 10 2017, @03:59AM

    by rylyeh (6726) <{kadath} {at} {gmail.com}> on Sunday December 10 2017, @03:59AM (#607890)

    This is a HUGE step forward!
    Many genetic problems are simply due to the lack of expression of a few genes/proteins.
    In addition, this method does not require altering the genome in a permanent way.

    --
    "a vast crenulate shell wherein rode the grey and awful form of primal Nodens, Lord of the Great Abyss."
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