CRISPR & Genetic Engineering News and Discussions

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Xyls
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Last-gasp gene therapy saved a Syrian refugee’s life. Five years later, the boy is thriving and a clinical trial is starting

https://www.statnews.com/2021/12/08/las ... QzoBYvqgGs
In the summer of 2015, a 7-year-old named Hassan was admitted to the burn unit of the Ruhr University Children’s Hospital in Bochum, Germany, with red, oozing wounds from head to toe.

It wasn’t a fire that took his skin. It was a bacterial infection, resulting from an incurable genetic disorder. Called junctional epidermolysis bullosa, the condition deprives the skin of a protein needed to hold its layers together and leads to large, painful lesions. For kids, it’s often fatal. And indeed, Hassan’s doctors told his parents, Syrian refugees who had fled to Germany, the young boy was dying.
weatheriscool
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A new way to find genetic variations removes bias from human genotyping
https://phys.org/news/2021-12-genetic-v ... yping.html
by University of California - Santa Cruz
Since the first sequencing of the human genome more than 20 years ago, the study of human genomes has relied almost exclusively on a single reference genome to which others are compared to identify genetic variations. Scientists have long recognized that a single reference genome cannot represent human diversity and that using it introduces a pervasive bias into these studies. Now, they finally have a practical alternative.

In a paper published December 16 in Science, researchers at the UC Santa Cruz Genomics Institute have introduced a new tool, called Giraffe, that can efficiently map new genome sequences to a "pangenome" representing many diverse human genome sequences. They show that this approach allows a more comprehensive characterization of genetic variations and can improve the genomic analyses used by a wide range of researchers and clinicians.

"We've been working toward this for years, and now for the first time we have something practical that works fast and works better than the single reference genome," said corresponding author Benedict Paten, associate professor of biomolecular engineering at UC Santa Cruz and associate director of the Genomics Institute. "It's important for the future of biomedicine that genomics helps everyone equally, so we need tools that account for the diversity of human populations and are not biased."
weatheriscool
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Fastest DNA sequencing technique helps undiagnosed patients find answers in mere hours
https://medicalxpress.com/news/2022-01- ... nosed.html
by Stanford University Medical Center

A new ultra-rapid genome sequencing approach developed by Stanford Medicine scientists and their collaborators was used to diagnose rare genetic diseases in an average of eight hours—a feat that's nearly unheard of in standard clinical care.

"A few weeks is what most clinicians call 'rapid' when it comes to sequencing a patient's genome and returning results," said Euan Ashley, MB ChB, DPhil, professor of medicine, of genetics and of biomedical data science at Stanford.

Genome sequencing allows scientists to see a patient's complete DNA makeup, which contains information about everything from eye color to inherited diseases. Genome sequencing is vital for diagnosing patients with diseases rooted in their DNA: Once doctors know the specific genetic mutation, they can tailor treatments accordingly.

Now, a mega-sequencing approach devised by Ashley and his colleagues has redefined "rapid" for genetic diagnostics: Their fastest diagnosis was made in just over seven hours. Fast diagnoses mean patients may spend less time in critical care units, require fewer tests, recover more quickly and spend less on care. Notably, the faster sequencing does not sacrifice accuracy.

A paper describing the researchers' work will publish Jan.12 in The New England Journal of Medicine. Ashley, associate dean of the Stanford School of Medicine and the Roger and Joelle Burnell Professor in Genomics and Precision Health, is the senior author of the paper. Postdoctoral scholar John Gorzynski, DVM, Ph.D., is the lead author.
weatheriscool
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Discovery of a 'hidden gem' enables gene editing with a small but mighty CRISPR-Cas3 system
https://phys.org/news/2022-01-discovery ... -gene.html
by University of Michigan

Nearly a decade ago, scientists discovered the power of CRISPR, a tool employed by bacteria to protect themselves against viral invaders. This system is now a fundamental research tool used for editing genomes. One of most popular CRISPR tool is CRISPR-Cas9, with which researchers can identify and then cut out or replace the targeted DNA within a cell.

"However, the ability of cas9 tools to engineer large-scale, gene-sized edits is really limited," said Yan Zhang, Ph.D., assistant professor in the Department of Biological Chemistry at the University of Michigan Medical School.

That's where another editing tool, CRISPR-Cas3, comes in.

In 2019, the Zhang lab was among the first wave of researchers to describe the new tool, which has the capability of processive DNA degradation and thereby making large scale genome deletions. The average human gene is 10 to 15 kilobases long, well within the ability of CRISPR-Cas3 to cut out.
weatheriscool
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CRISPR-Cas13 technique targets proteins causing ALS and Huntington's disease in the mouse nervous system
https://medicalxpress.com/news/2022-01- ... ngton.html
by Liz Ahlberg Touchstone, University of Illinois at Urbana-Champaign
A single genetic mutation can have profound consequences, as demonstrated in neurodegenerative diseases such as amyotrophic lateral sclerosis or Huntington's disease. A new study by University of Illinois Urbana-Champaign researchers used a targeted CRISPR technique in the central nervous systems of mice to turn off production of mutant proteins that can cause ALS and Huntington's disease.

Rather than the popular DNA-editing CRISPR-Cas9 technique, the new approach uses CRISPR-Cas13, which can target mRNA—the messenger molecule that carries protein blueprints transcribed from DNA. The Illinois team developed Cas13 systems to target and cut RNAs that code for mutant proteins that trigger ALS and Huntington's disease, effectively silencing the mutant genes without disturbing the cell's DNA, said study leader Thomas Gaj, an Illinois professor of bioengineering. The team published its results in the journal Science Advances.
weatheriscool
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Scientists use CRISPR activation method to reveal 'Rosetta Stone' of immune cell function
https://medicalxpress.com/news/2022-02- ... setta.html
by Gladstone Institutes
CRISPR genome editing has served as a powerful tool for deleting or altering DNA sequences and studying the resulting effect. Now, researchers at Gladstone Institutes and UC San Francisco (UCSF) have co-opted the CRISPR-Cas9 system to forcibly activate genes—rather than edit them—in human immune cells. The method, known as CRISPRa, let them discover genes that play a role in immune cell biology more thoroughly and rapidly than previously possible.

"This is an exciting breakthrough that will accelerate immunotherapy research," says Alex Marson, MD, Ph.D., director of the Gladstone-UCSF Institute of Genomic Immunology and senior author of the new study. "These CRISPRa experiments create a Rosetta Stone for understanding which genes are important for every function of immune cells. In turn, this will give us new insight into how to genetically alter immune cells so they can become treatments for cancer and autoimmune diseases."

The study, published in the journal Science, is the first to successfully use CRISPRa at a large scale in primary human cells, which are cells isolated directly from a person.

The scientists activated each gene in the genome in different cells, enabling them to test almost 20,000 genes in parallel. This allowed them to quickly learn the rules about which genes provide the most powerful levers to reprogram cell functions in ways that could eventually lead to more powerful immunotherapies.
weatheriscool
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Study in mice shows potential for gene-editing to tackle mitochondrial disorders
https://phys.org/news/2022-02-mice-pote ... drial.html
by University of Cambridge

Defective mitochondria—the 'batteries' that power the cells of our bodies—could in future be repaired using gene-editing techniques. Scientists at the University of Cambridge have shown that it is possible to modify the mitochondrial genome in live mice, paving the way for new treatments for incurable mitochondrial disorders.

Our cells contain mitochondria, which provide the energy for our cells to function. Each of these mitochondria is coded for by a tiny amount of mitochondrial DNA. Mitochondrial DNA makes up only 0.1% of the overall human genome and is passed down exclusively from mother to child.

Faults in our mitochondrial DNA can affect how well the mitochondria operate, leading to mitochondrial diseases, serious and often fatal conditions that affect around 1 in 5,000 people. The diseases are incurable and largely untreatable.

There are typically around 1,000 copies of mitochondrial DNA in each cell, and the percentage of these that are damaged, or mutated, will determine whether a person will suffer from mitochondrial disease or not. Usually, more than 60% of the mitochondria in a cell need to be faulty for the disease to emerge, and the more defective mitochondria a person has, the more severe their disease will be. If the percentage of defective DNA could be reduced, the disease could potentially be treated.
weatheriscool
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Advancing genome editing through studying DNA repair mechanisms
https://phys.org/news/2022-02-advancing ... nisms.html
by Austrian Academy of Sciences
Since the discovery of CRISPR/Cas9, also known as molecular scissors, scientists around the world have been working to improve the revolutionary technique for altering DNA that earned Emmanuelle Charpentier and Jennifer Doudna the Nobel Prize in 2020. The method enables deep exploration of the human genome and shows enormous potential for curing genetic diseases. While the precise alterations made by CRISPR/Cas9 were initially less predictable, scientists around the world are now working on further developments that enable precise changes to be made within DNA. A recent study by the group of Joanna Loizou, Group Leader at the Center for Cancer Research at MedUni Vienna and CeMM Adjunct Principal Investigator, was devoted to understanding how prime editing, a technique that promises greater targeting accuracy and efficiency in introducing DNA changes, can be made more efficient and precise.

Prime editing is a powerful genome engineering tool that allows for replacement, insertions, and deletion of DNA into any given genomic locus. However, to date, the efficiency of prime editing has been highly variable and depends not only on the targeted genomic region but also on the genetic background of the edited cell. Leading authors Joana Ferreira da Silva, CeMM Ph.D. student, and Gonçalo Oliveira from the Center for Cancer Research of the MedUni Vienna, devoted their study to the question of which factors influence the success of prime editing, taking a close look at DNA repair processes. Since genome editing relies on the intrinsic DNA repair machinery within a cell, it is imperative to know which DNA repair pathways are engaged and how this impacts the outcome of editing. Yet the underlying DNA repair machinery involved in prime editing is largely unknown. The study authors explain that "depending on the type of DNA damage, a cell has different cellular repair mechanisms. To find out which of these are active in prime editing, we performed a targeted genetic screening for DNA repair factors covering all known repair pathways."
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R8Z
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CRISPR-Cas9-mediated nuclear transport and genomic integration of nanostructured genes in human primary cells
https://pubmed.ncbi.nlm.nih.gov/35104875/
2022 Feb 1
Abstract
DNA nanostructures are a promising tool to deliver molecular payloads to cells. DNA origami structures, where long single-stranded DNA is folded into a compact nanostructure, present an attractive approach to package genes; however, effective delivery of genetic material into cell nuclei has remained a critical challenge. Here, we describe the use of DNA nanostructures encoding an intact human gene and a fluorescent protein encoding gene as compact templates for gene integration by CRISPR-mediated homology-directed repair (HDR). Our design includes CRISPR-Cas9 ribonucleoprotein binding sites on DNA nanostructures to increase shuttling into the nucleus. We demonstrate efficient shuttling and genomic integration of DNA nanostructures using transfection and electroporation. These nanostructured templates display lower toxicity and higher insertion efficiency compared to unstructured double-stranded DNA templates in human primary cells. Furthermore, our study validates virus-like particles as an efficient method of DNA nanostructure delivery, opening the possibility of delivering nanostructures in vivo to specific cell types. Together, these results provide new approaches to gene delivery with DNA nanostructures and establish their use as HDR templates, exploiting both their design features and their ability to encode genetic information. This work also opens a door to translate other DNA nanodevice functions, such as biosensing, into cell nuclei.
And, as always, bye bye.
weatheriscool
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Gene editing gets safer thanks to redesigned Cas9 protein
https://phys.org/news/2022-03-gene-safe ... otein.html
by University of Texas at Austin

One of the grand challenges with using CRISPR-based gene editing on humans is that the molecular machinery sometimes makes changes to the wrong section of a host's genome, creating the possibility that an attempt to repair a genetic mutation in one spot in the genome could accidentally create a dangerous new mutation in another.

But now, scientists at The University of Texas at Austin have redesigned a key component of a widely used CRISPR-based gene-editing tool, called Cas9, to be thousands of times less likely to target the wrong stretch of DNA while remaining just as efficient as the original version, making it potentially much safer. The work is described in a paper published today in the journal Nature.

"This really could be a game changer in terms of a wider application of the CRISPR Cas systems in gene editing," said Kenneth Johnson, a professor of molecular biosciences and co-senior author of the study with David Taylor, an assistant professor of molecular biosciences. The paper's co-first authors are postdoctoral fellows Jack Bravo and Mu-Sen Liu.

Other labs have redesigned Cas9 to reduce off-target interactions, but so far, all these versions improve accuracy by sacrificing speed. SuperFi-Cas9, as this new version has been dubbed, is 4,000 times less likely to cut off-target sites but just as fast as naturally occurring Cas9. Bravo says you can think of the different lab-generated versions of Cas9 as different models of self-driving cars. Most models are really safe, but they have a top speed of 10 miles per hour.
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