A baby with a rare inherited disorder became the first child in the U.K. to receive a new gene therapy for the condition.
A 19-month-old girl named Teddi recently became the first child in the U.K. outside a clinical trial to receive a new gene therapy for metachromatic leukodystrophy (MLD), a fatal genetic disorder, the National Health Service (NHS) announced (opens in new tab).
Roughly six months out from treatment, "Teddi is a happy and healthy toddler showing no signs of the devastating disease she was born with," the NHS statement reads.
The genetic disorder MLD disrupts cells' ability to break down sulfatides, a fatty material used to insulate the wiring that runs through the white matter of the brain and much of the nervous system beyond the brain. Sulfatide buildup destroys brain and nerve cells, resulting in cognitive problems, a loss of motor control and sensation, seizures, paralysis and blindness, according to the Genetic and Rare Diseases Information Center (opens in new tab). Eventually, the disorder leads to death.
Typically, MLD treatment is aimed at managing symptoms of the disease, although several experimental therapies, including bone marrow transplants and cord blood stem cell transplants, have sometimes been used to slow the disorder's progression in infants, according to the Centers for Disease Control and Prevention (opens in new tab). The new gene therapy, called Libmeldy (generic name atidarsagene autotemcel), was only recently cleared for use by the NHS and works by inserting into the body working copies of the genes that are faulty in MLD, thus restoring the ability to break down sulfatides.
Next up for CRISPR: Gene editing for the masses?
Last year, Verve Therapeutics started the first human trial of a CRISPR treatment that could benefit most people—a signal that gene editing may be ready to go mainstream.
New research is starting to write the rulebook on how to effectively use CRISPR activation technology.
Researchers from the Wellcome Sanger Institute and collaborators have used human stem cells and neurons to investigate the features that influence how well CRISPR activation works for different sets of genes.
Published today (March 13, 2023) in Molecular Cell, the study explains the rules determining to what extent genes respond to CRISPR activation, ensuring that future research can be designed as efficiently as possible.
CRISPR activation (CRISPRa) is a type of CRISPR gene editing that is used to overexpress certain genes. Although this technique is broadly used, predicting its efficiency when aimed at certain points in the genome can be challenging, making it hard to reliably overexpress certain genes.
This new study integrated a marker gene at thousands of points in the genome of a human stem cell line, which was then activated with CRISPRa, to see where this was successful. The stem cell line used differentiates into neurons, allowing the team to also gather information on CRISPRa efficiency in different cell types.
The team uncovered multiple features that impact CRISPRa efficiency, including expression level, chromatin status, cell state, and gene location. They found that bivalent genes, which are key developmental regulator genes that have both repressing and activating marks in the same region, can be robustly activated by CRISPRa. They also discovered that CRISPRa could achieve the same overexpression levels that are necessary to drive significant changes in cell state and cause them to differentiate.
Commercial development of gene-edited food now legal in England
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Gene-edited food can now be developed commercially in England following a change in the law.
Supporters of the technology say it will speed up the development of hardier crops that will be needed because of climate change.
Critics say that the change could bring ''disaster'' to our food production and the environment.
Gene editing involves making precise changes to an organism's DNA to enhance certain characteristics.
The new law also opens the door to the development of gene-edited farm animals, but a further vote by MPs will be required before it is allowed, again only in England.
The Scottish, Welsh and Northern Irish governments have not permitted the commercial use of gene editing.
A team of medical researchers affiliated with a host of institutions in the U.S. has used base editing to restore the natural production of the SMN protein in mice, effectively curing spinal muscular atrophy (SMA) in the rodents. In their paper published in the journal Science, the group describes their base editing approach and its performance in restoring natural SMN production in mice afflicted with SMA.
SMA is one of the leading causes of infant mortality in humans. Babies born with the condition have a mutation in the SMN1 gene, resulting in production of insufficient amounts of the protein SMN, leading to neural deterioration and death. Many babies born with the condition who are diagnosed early enough are given drugs to increase production of SMN artificially, which slows progression of the disease, but cannot stop it completely. Thus, other therapies are needed.
In this new effort, the researchers used base editing, a kind of gene editing that is done chemically, to treat the disease in mice. Base editing is typically used to make single-nucleotide changes in a genome, as was done in this case.
Developing effective treatments for genetic lung diseases such as cystic fibrosis has proven challenging. That might not be the case for much longer, with scientists developing a new type of nanoparticle that can carry gene-editing technology directly into the lungs of mice.
With the mapping of the human genome and subsequent genome-wide association studies linking defined genetic mutations with known diseases, the focus of much research has been on developing gene therapies to target the genetic causes of disease.
Messenger RNA (mRNA) is a relatively new therapeutic agent being used to prevent and treat certain genetic diseases. But to function effectively in the body, mRNA – which carries the genetic information that directs cells to make proteins – needs a stable delivery system that protects it from degradation and allows it to enter cells to deliver its gene-altering payload. Nanoparticles have proved effective vehicles for delivering mRNA.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal genetic disease—about a half million people in the United States alone suffer from the condition. There is no cure, but new research could open the door to new gene therapies for treating most cases of the disease.
For several decades, researchers have known that mutations in the PKD1 gene, which encodes the polycystin-1 (PC1) protein, can cause the disease in about 80% of cases. However, the protein is too big to be modified through gene therapy strategies.
Now, a research team led by Laura Onuchic, MD, postdoctoral researcher in the Yale Department of Cellular & Molecular Physiology and Michael Caplan, MD, Ph.D., chair and C.N.H. Long Professor of Cellular & Molecular Physiology and professor of cell biology, has found that just a small piece of this protein might hold the key to preventing the disease. This finding could lead to opportunities to develop a new class of therapeutics. The team published its findings on March 30 in Nature Communications.
"Our research shows that a tiny fragment of the PC1 protein—just 200 amino acids from the very tail end of that protein—is enough to suppress the disease in a mouse model," says Caplan, who was principal investigator of the study. "Our work will provide new insights into the underlying disease mechanisms for polycystic kidney disease and reveal new avenues for developing therapies."
Researchers from Kyushu University and Nagoya University School of Medicine have developed an optimized genome-editing method that significantly reduces unwanted mutations and toxicity in CRISPR-Cas9. The new technique, called “safeguard gRNA” ([C]gRNA), demonstrates potential for safe and efficient gene therapy, with applications in treating genetic diseases like fibrodysplasia ossificans progressiva.
CRISPR-Cas9 is a prevalent genome-editing technique utilized for investigating specific genes and modifying genes related to diseases. However, it comes with drawbacks such as unintended mutations and toxicity, necessitating the development of a technology that minimizes these side effects to enhance its applicability in industry and medicine.
Scientists from Kyushu University in southern Japan and Nagoya University School of Medicine in central Japan have now created an enhanced genome-editing approach that significantly reduces mutations, paving the way for more effective treatment of genetic disorders with reduced undesired mutations. Their research has been published in Nature Biomedical Engineering.
The high eye pressure seen in glaucoma slowly leads to blindness. For some, the first-line treatment, eye drops, doesn’t work. Researchers have used gene therapy to develop a promising new way of treating the high eye pressure associated with glaucoma.
Affecting up to 80 million people worldwide, glaucoma is usually caused by raised intraocular pressure (IOP). The number of people with glaucoma is expected to rise to 110 million by 2040.
The eye constantly produces a liquid called aqueous humor, which helps the eye hold its shape and nourishes the eye. The fluid is drained out of the eye through the anterior chamber angle or drainage angle. If the drainage angle is damaged, the eye produces more aqueous humor than it can drain, causing high IOP that can irreversibly damage the optic nerve, leading to blindness.
The first-line treatment for glaucoma is eye drops made of a prostaglandin analog, which lowers IOP. However, 25% to 50% of people don’t respond to the treatment, and their eye pressure remains elevated.
Researchers at Trinity College Dublin have collaborated with the biotechnology company Exhaura Ltd to develop a novel gene-therapy-based approach to decreasing IOP that shows great promise in the treatment of glaucoma.
“This exciting project allowed us to bridge the gap between academia and industry and work very closely with a gene therapy company to develop a cutting-edge therapy that we believe holds immense promise for patients in the future,” said Matthew Campbell, corresponding author of the study.
A new approach to the genetic engineering of cells promises significant improvements in speed, efficiency, and reduction in cellular toxicity compared to current methods. The approach could also power the development of advanced cell therapies for cancers and other diseases, according to a study from researchers in the Perelman School of Medicine at the University of Pennsylvania.
In the study, which appeared this week in Nature Biotechnology, researchers found that protein fragments used by some viruses to help them get into cells could also be used to get CRISPR-Cas gene editing molecules into cells and their DNA-containing nuclei with extraordinarily high efficiency and low cellular toxicity.
The scientists expect the new technique to be particularly useful for modifying T cells and other cells from a patient's own body to make cell therapies. One such application could be CAR T (chimeric antigen receptor T cell) therapy, which uses specially modified immune cells from a patient to treat cancer. The T cells—a type of white blood cell—are removed from the patient and reprogrammed to find and attack cancer cells when reintroduced to the bloodstream.
The first FDA-approved CAR T therapy was developed at Penn Medicine, and received Food & Drug Administration approval in 2017. There are now six FDA-approved CAR T cell therapies in the United States. The therapies have revolutionized the treatment of certain B cell leukemias, lymphomas, and other blood cancers, putting many patients who otherwise had little hope into long-term remission.
"This new approach—building on Penn Medicine's history of cell and gene therapy innovation—has the potential to be a major enabling technology for engineered cellular therapies," said co-senior author E. John Wherry, Ph.D., Richard and Barbara Schiffrin President's Distinguished Professor and chair of Systems Pharmacology & Translational Therapeutics at Penn Medicine.
CRISPR-Cas molecules are derived from ancient bacterial antiviral defenses, and are designed to precisely remove DNA at desired locations in a cell's genome. Some CRISPR-Cas-based systems combine the deletion of old DNA with the insertion of new DNA for versatile genome editing. This approach can be used to replace faulty genes with corrected ones or delete or modify genes to enhance cellular function. Some systems can also add genes that confer new properties to CAR T cells such as the ability to recognize tumors or withstand the harsh tumor microenvironment that normally exhausts T cells.
Major genetics breakthrough could herald new era of tests and treatments reflecting ethnic diversity
Wednesday 10 May 2023 16:08, UK
Scientists have unveiled the first draft of a genetic blueprint that more accurately reflects diversity in the human population.
They say the major advance could open up a new era of genetic-based tests and treatments to everybody, regardless of their ethnic origin.
The current "official" DNA code of the human species, which was published as the Human Genome Project in 2001, has since been used as the reference against which all other genetic sequences have been compared.
But the genome was largely based on an anonymous American man of white European descent, creating a bias that's likely to exclude people with other ancestries from genetic advances.
Now, in a major scientific undertaking, a consortium of scientists has produced a more representative genetic manual, called a "pan-genome", that was based on samples taken from 47 diverse individuals.
Gene editing is a powerful method for both research and therapy. Since the advent of the Nobel Prize-winning CRISPR/Cas9 technology, a quick and accurate tool for genome editing discovered in 2012, scientists have been working to explore its capabilities and boost its performance.
Researchers in UC Santa Barbara biologist Chris Richardson's lab have added to that growing toolbox, with a method that increases the efficiency of CRISPR/Cas9 editing without the use of viral material to deliver the genetic template used to edit the target genetic sequence. According to their new paper published in the journal Nature Biotechnology, their method stimulates homology-directed repair (a step in the gene editing process) by approximately threefold "without increasing mutation frequencies or altering end-joining repair outcomes."
"We've found a chemical modification that improves non-viral gene editing and also discovered an intriguing new type of DNA repair," Richardson said.
Find, cut and paste
The CRISPR/Cas9 method works by capitalizing on a defense technique employed by bacteria against viral attackers. To do this, the bacteria snip a piece of the invading virus's genetic material, and incorporate it into their own in order to recognize it later. Should the bacteria get reinfected, they can target the now-familiar genetic sequences for destruction.
In gene editing, this process uses the enzyme Cas9 as molecular "scissors" to snip sequences it recognizes, guided by the CRISPR system. This cut is also an opportunity to replace the severed genes with similar (homologous) but improved ones, utilizing the cell's natural repair mechanisms. If successful, the cell should have modified expressions and functions thereafter.
Modified viruses have proven a handy way to get CRISPR/Cas9 gene editing materials into the nucleus of cells – but they're expensive, difficult to scale and potentially toxic. Now, researchers have found a non-viral approach that does the job better.
Most have heard of CRISPR/Cas9, the gene-editing technology that’s revolutionized biomedical research. Now, researchers have added another tool to the gene-editing toolbox after discovering a new way of using the technology that improves its editing efficiency and provides a new way to repair DNA.
CRISPR/Cas9 tech was adapted from a naturally occurring genome editing system bacteria use as an immune defense. When bacteria are infected by a virus, they ‘cut off’ a small piece of the virus’s DNA and insert it into their own in a particular arrangement known as a CRISPR array. This means the virus can be recognized later and, if it re-invades the bacteria, can be targeted for destruction.
Gene editing in humans relies on the Cas9 enzyme which, guided by CRISPR, ‘snips out’ a fragment of DNA. The removed section can be replaced with a similar (homologous) but improved DNA template by a process called homology-directed repair, which initiates the cell’s natural DNA repair mechanisms. Viruses – modified so they can’t cause disease – are commonly used to deliver the template DNA to the cell’s nucleus because of their effectiveness at entering cells.
Evolution experiment yields yeast 20,000x bigger and 10,000x tougher
By Michael Irving
May 15, 2023
Scientists are conducting a long-term experiment on evolution in the lab, to investigate how single-celled organisms could evolve into multicellular lifeforms. After thousands of generations, their yeast grew 20,000 times bigger and 10,000 times tougher.
The idea of an evolutionary “missing link” usually conjures images of a hairy ape-like hominid, but there are actually much more profound missing links in the chain. One of the biggest gaps sits between single-celled and multicellular organisms, which marks a key step in the development of complex life on Earth.
Now, scientists from Georgia Tech have reported the first results of an experiment that they hope to continue running for decades, with a pretty lofty goal – evolving single-celled lifeforms into brand new multicellular lifeforms. Directed evolution experiments have been conducted for decades, even winning the Nobel Prize for Chemistry in 2018, but those are usually focused on making new drugs or solving other problems, not plugging holes in our distant family tree.
By 2050, one in 10 individuals are expected to live with some form of hearing loss. Of the hundreds of millions of cases of hearing loss affecting individuals worldwide, genetic hearing loss is often the most difficult to treat.
While hearing aids and cochlear implants offer limited relief, no available treatment can reverse or prevent this group of genetic conditions, prompting scientists to evaluate gene therapies for alternative solutions.
Age-related hearing loss impacts one in three adults between the ages of 64 and 75 in the US, and around half of these numbers are down to genes.
The extra kicker, though, is that because hearing involves a complex genetic toolkit, it also makes this kind of hearing loss incredibly difficult to treat.
A team of researchers has for the first time targeted age-related genetic hearing loss in a much older cohort of mice, which had a mutation of the human transmembrane serine protease 3 (TMPRSS3) gene that results in autosomal recessive deafness 8/10 (DFNB8/DFNB10).
As global food insecurity climbed to a perilous high in 2022, scientists ramped up their efforts to perfect best practices for protecting the yields of major crops that are essential in combating this issue. And, while rice makes up a small portion of Missouri's annual harvest, it—along with corn and soybeans—are key staples that help address food insecurity not only in the United States, but across the world.
In a recent study that examined how diseases function in rice crops, University of Missouri researchers might have found critical answers.
In this study, Bing Yang, a plant biology professor in the MU College of Agriculture, Food and Natural Resources and the Donald Danforth Plant Science Center used genome editing as a tool to identify problematic pathogens present in certain bacteria that lead to prolific infections in rice crops. His research helps scientists understand how these pathogens function and, thus, can determine how to guard against widespread infections that destroy yields.
This research provides insight into the host-pathogen relationship, allowing scientists to better genetically engineer plants to survive crop diseases.
A research team from the Hefei Institutes of Physical Science of the Chinese Academy of Sciences (CAS) has developed an analysis service platform called CRISPRimmunity, which was an interactive web server for identifying important molecular events related to CRISPR and regulators of genome editing systems. The study is published in Nucleic Acids Research.
The new CRISPRimmunity platform was designed for integrated analysis and prediction of CRISPR-Cas and anti-CRISPR systems. It includes customized databases with annotations for known anti-CRISPR proteins, anti-CRISPR-associated proteins, class II CRISPR-Cas systems, CRISPR array types, HTH structural domains and mobile genetic elements. These resources allow the study of molecular events in the co-evolution of CRISPR-Cas and anti-CRISPR systems.
CRISPR gene editing is a breakthrough that has been used to treat diseases such as sickle cell anemia, leukemia and genetic disorders, but it has challenges that limit its broad utility.
Identifying the root of those issues led a research team at Duke Health to find an improved approach to gene editing that expands its functionality.
In work published online June 29 in the journal Cell Chemical Biology, the researchers lay out a new way to identify diverse CRISPR RNA variants that can specifically home in on challenging areas of DNA to target for editing. The new approach opens up more of the genome for editing, enabling the repair of mutations associated with more diseases.
"CRISPR is great, but there are a lot of places within the human genome that can't be edited well," said senior author Bruce Sullenger, Ph.D., the Joseph W. and Dorothy W. Beard Distinguished Professor of Experimental Surgery at Duke University School of Medicine. Sullenger is also a professor in the departments of Pharmacology and Cancer Biology, Neurosurgery, Cell Biology and Biomedical Engineering.
CRISPR-Cas9 has been the household name of genetic engineering tools over the past decade, but there might be other, better ways. MIT scientists have now demonstrated an alternative called Fanzor, which is naturally found in animals so could be a better fit for human use.
The CRISPR gene-editing system was originally isolated from bacteria, which use an enzyme called Cas9 to snip out a section of a virus’s DNA and store it for later, to help them fight off that infection in the future. In 2012, scientists made the Nobel Prize-winning discovery that this process could be hijacked to edit DNA in living cells, which has since been used to treat diseases, grow better crops, and tweak bacteria to do some important things.
As successful as CRISPR has been so far, scientists have wondered if there are other similar systems at play in some of our closer relatives – after all, bacteria are about as far from us on the tree of life as it’s possible to get. And now, researchers at MIT have found a group of proteins that function much the same way, but in animals.
