Tag Archives: DNA

New Cancer Drug Halts Tumour Growth

A drug that could stop cancer cells repairing themselves has shown early signs of working. More than half of the 40 patients given berzosertib had the growth of their tumours halted. Berzosertib was even more effective when given alongside chemotherapy, the trial run by the Institute of Cancer Research (ICR) and the Royal Marsden NHS Trust in UK suggested. The trial was designed to test the safety of the drug. The drug is the first to be trialled of a new family of treatments, which block a protein involved in DNA repairBlocking this protein prevents cancers from mending damage to their cells. It’s part of a branch of treatment known as “precision medicine“, which targets specific genes or genetic changes.

The study involved patients with very advanced tumours, for whom no other treatment had worked. This was what is known as a “phase onetrial, which is only designed to test the safety of a treatment. But the ICR said the researchers did find some early indications that berzosertib could stop tumours growing. One of the study’s authors, Prof Chris Lord, a professor of cancer genomics at the ICR, said these early signs were “very promising”, adding that it was unusual in phase one trials to see a clinical response. Further trials will be needed to demonstrate the drug’s effectiveness, though.

This study involved only small numbers of patients…Therefore, it is too early to consider berzosertib a game changer in cancer treatment,” said Dr Darius Widera at the University of Reading. “Nevertheless, the unusually strong effects of berzosertib, especially in combination with conventional chemotherapy, give reasons to be optimistic regarding the outcomes of follow-up studies.”

One patient in the trial, with advanced bowel cancer, had his tumours completely disappear after treatment with berzosertib, and has remained cancer-free for two years. Another, whose ovarian cancer returned following a different course of treatment, saw her tumours shrink after combination treatment with the drug and chemotherapyChemotherapy works by damaging cancer cells’ DNA, so using it in conjunction with this new treatment, which stops the cells from repairing themselves, appears to give an even greater benefit. And berzosertib is able to target tumour cells without affecting other healthy cells, Prof Lord said.

Our new clinical trial is the first to test the safety of a brand-new family of targeted cancer drugs in people, and it’s encouraging to see some clinical responses even in at this early stage,” said Professor Johann de Bono, head of drug development at the ICR and the Royal Marsden.

Source: https://www.bbc.com/

Breakthrough Against COVID-19

A team of scientists from Stanford University is working with researchers at the Molecular Foundry, a nanoscience user facility located at the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab), to develop a gene-targeting, antiviral agent against COVID-19. Last year, Stanley Qi, an assistant professor in the departments of bioengineering, and chemical and systems biology at Stanford University and his team had begun working on a technique called PAC-MAN – or Prophylactic Antiviral CRISPR in human cells – that uses the gene-editing tool CRISPR to fight influenza.

But that all changed in January, when news of the COVID-19 pandemic emerged. Qi and his team were suddenly confronted with a mysterious new virus for which no one had a clear solution.

Lipitoids, which self-assemble with DNA and RNA, can serve as cellular delivery systems for antiviral therapies that could prevent COVID-19 and other coronavirus infections.

So we thought, ‘Why don’t we try using our PAC-MAN technology to fight it?’” said Qi.

Since late March, Qi and his team have been collaborating with a group led by Michael Connolly, a principal scientific engineering associate in the Biological Nanostructures Facility at Berkeley Lab’s Molecular Foundry, to develop a system that delivers PAC-MAN into the cells of a patient.

Like all CRISPR systems, PAC-MAN is composed of an enzyme – in this case, the virus-killing enzyme Cas13 – and a strand of guide RNA, which commands Cas13 to destroy specific nucleotide sequences in the coronavirus’s genome. By scrambling the virus’s genetic code, PAC-MAN could neutralize the coronavirus and stop it from replicating inside cells.

Qi said that the key challenge to translating PAC-MAN from a molecular tool into an anti-COVID-19 therapy is finding an effective way to deliver it into lung cells. When SARS-CoV-2, the coronavirus that causes COVID-19, invades the lungs, the air sacs in an infected person can become inflamed and fill with fluid, hijacking a patient’s ability to breathe.

But my lab doesn’t work on delivery methods,” he said. So on March 14, they published a preprint of their paper, and even tweeted, in the hopes of catching the eye of a potential collaborator with expertise in cellular delivery techniques. Soon after, they learned of Connolly’s work on synthetic molecules called lipitoids at the Molecular Foundry. Lipitoids are a type of synthetic peptide mimic known as a “peptoid” first discovered 20 years ago by Connolly’s mentor Ron Zuckermann. In the decades since, Connolly and Zuckermann have worked to develop peptoid delivery molecules such as lipitoids. And in collaboration with Molecular Foundry users, they have demonstrated lipitoids’ effectiveness in the delivery of DNA and RNA to a wide variety of cell lines.

Today, researchers studying lipitoids for potential therapeutic applications have shown that these materials are nontoxic to the body and can deliver nucleotides by encapsulating them in tiny nanoparticles just one billionth of a meter wide – the size of a virus. Now Qi hopes to add his CRISPR-based COVID-19 therapy to the Molecular Foundry’s growing body of lipitoid delivery systems.

Source: https://newscenter.lbl.gov/

How To Reverse Cellular Aging Process

Central to a lot of scientific research into aging are tiny caps on the ends of our chromosomes called telomeres. These protective sequences of DNA grow a little shorter each time a cell divides, but by intervening in this process, researchers hope to one day regulate the process of aging and the ill health effects it can bring. A Harvard team is now offering an exciting pathway forward, discovering a set of small molecules capable of restoring telomere length in mice. Telomeres can be thought of like the plastic tips on the end of our shoelaces, preventing the fraying of the DNA code of the genome and playing an important part in a healthy aging process. But each time a cell divides, they grow a little shorter. This sequence repeats over and over until the cell can no longer divide and dies.

This process is linked to aging and disease, including a rare genetic disease called dyskeratosis congenita (DC). This is caused by the premature aging of cells and is where the team focused its attention, hoping to offer alternatives to the current treatment that involves high-risk bone marrow transplants and which offers limited benefits.

One of the ways dyskeratosis congenita comes about is through genetic mutations that disrupt an enzyme called telomerase, which is key to maintaining the structural integrity of the telomere caps. For this reason, researchers have been working to target telomerase for decades, in hopes of finding ways to slow or even reverse the effects of aging and diseases like dyskeratosis congenita.

Once human telomerase was identified, there were lots of biotech startups, lots of investment,” says Boston Children’s Hospital’s Suneet Agarwal, senior investigator on the new study. “But it didn’t pan out. There are no drugs on the market, and companies have come and gone.

Source: https://news.harvard.edu/
AND
https://newatlas.com/

New DNA-based Strategy To Fight Aggressive Cancers

Researchers from the University of Copenhagen have discovered that our cells replicate their DNA much more loosely than previously thought. The new knowledge might be useful for developing novel treatments against aggressive forms of cancers. This was found by inhibiting the essential gene DNA polymerase alpha, or POLA1, which initiates DNA replication during cell division. The discovery gives researchers new insights into DNA replication and may potentially be used for a new type of cancer treatment.

If we are visionaries, I would say that we might be at the birth of a whole new set of molecules that could be used in fighting cancer’, states  Research Leader and Associate Professor Luis Toledo of the Center for Chromosome Stability at the Department of Cellular and Molecular Medicine. ‘Basically, if we turn the finding on its head, this novel strategy aims at exploiting an in-built weakness in cancer cells and make them crash while they divide.

When a cell divides, the double DNA strand is opened lengthwise like a zipper that is unzipped. The new double strands are built at each of the separated strands, so that you gradually end up with two new “zippers”.

Before the new halfs of the zipper are made, a bit of DNA is temporally exposed in single stranded form. This process is required for the new zippers to form. Nevertheless, large amounts of single-stranded DNA have traditionally been considered by researchers to be a sign of pathological stress during cell proliferation. However, the researchers behind the new study discovered that DNA unzippers act more loosely than expected. This can generate large amounts of single-stranded DNA, which the researchers now show is no more than a form of natural stress that cells can actually tolerate in high quantities. Still, for this tolerance to exist, cells require a sufficient amount of the protective protein RPA to cover the single-stranded DNA parts.

We have seen that cells can duplicate their genome, even with large amounts of single stranded DNA. They can divide and go on living healthily because they have a large excess of RPA molecules that acts as a protective umbrella.’ says the study’s first author and former postdoc at the University of Copenhagen Amaia Ercilla, adding: ‘But there is a flip side of the coin. When we make the cells generate single strand DNA faster than what they can protect, chromosomes literally shatter in hundreds of pieces, a phenomenon we call replication catastrophe. We always thought that we could use this for instance to kill cancer cells“.

Source: https://news.ku.dk/

How To Uncloak Cancer Cells And Reveal Them To The Immune System

Scientists at Johns Hopkins report they have designed and successfully tested an experimental, super small package able to deliver molecular signals that tag implanted human cancer cells in mice and make them visible for destruction by the animals’ immune systems. The new method was developed, say the researchers, to deliver an immune system “uncloaking” device directly to cancer cells.

Conventional immune therapies generally focus on manipulating patients’ immune system cells to boost their cancer-killing properties or injecting drugs that do the same but often have toxic side effectsA hallmark of cancer biology is a tumor cell’s ability to essentially hide from the immune system cells whose job is to identify and destroy cancer cells. Current cellular immunotherapies, notably CAR-T, require scientists to chemically alter and enhance a patient’s own harvested immune system T-cells — an expensive and time-consuming process, say the researchers. Other weapons in the arsenal of immunotherapies are drugs, including so-called checkpoint inhibitors, which have broad effects and often lead to unwanted immune-system-associated side effects, including damage to normal tissue.

By contrast, the Johns Hopkins team sought an immune system therapy that can work like a drug but that also individually engineers a tumor and its surrounding environment to draw the immune system cells to it, says Jordan Green, Ph.D, professor of biomedical engineering at the Johns Hopkins University School of Medicine.

A microscopic image of the nanoparticles used in the study. The black scale bar is 100 nm in size
 And our process happens entirely within the body,” Green says, “requiring no external manipulation of a patient’s cells.

To develop the new system, Green and his team, including Stephany Tzeng, Ph.D., a research associate in the Department of Biomedical Engineering at Johns Hopkins, took advantage of a cancer cell’s tendency to internalize molecules from its surroundings. “Cancer cells may be easier to directly genetically manipulate because their DNA has gone haywire, they divide rapidly, and they don’t have the typical checks and balances of normal cells,” says Green.

The team created a polymer-based nanoparticle — a tiny case that slips inside cells. They guided the nanoparticles to cancer cells by injecting them directly into the animals’ tumors. “The nanoparticle method we developed is widely applicable to many solid tumors despite their variability on an individual and tumor type level,” says Green, also a member of the Johns Hopkins Kimmel Cancer Center. Once inside the cell, the water-soluble nanoparticle slowly degrades over a day. It contains a ring of DNA, called a plasmid, that does not integrate into the genome and is eventually degraded as the cancer cell divides, but it stays active long enough to alter protein production in the cell.

The additional genomic material from the plasmid makes the tumor cells produce surface proteins called 4-1BBL, which work like red flags to say, “I’m a cancer cell, activate defenses.” The plasmid also forces the cancer cells to secrete chemicals called interleukins into the space around the cells. The 4-1BBL tags and interleukins are like magnets to immune system cells, and they seek to kill the foreign-looking cancer cells.

Results of the proof-of-concept experiments were published online in the Proceedings of the National Academy of Sciences.

Source: https://www.hopkinsmedicine.org/

Nano-Transistor From DNA-like Material

Computer chips use billions of tiny switches, called transistors, to process information. The more transistors on a chip, the faster the computer. A material shaped like a one-dimensional DNA helix might further push the limits on a transistor’s size. The material comes from a rare earth element called tellurium.

Researchers found that the material, encapsulated in a nanotube made of boron nitride, helps build a field-effect transistor with a diameter of two nanometers. Transistors on the market are made of bulkier silicon and range between 10 and 20 nanometers in scale.  Engineers at Purdue University performed the work in collaboration with Michigan Technological University, Washington University in St. Louis, and the University of Texas at Dallas.

Over the past few years, transistors have been built as small as a few nanometers in lab settings. The goal is to build transistors the size of atomsPeide Ye’s lab at Purdue is one of many research groups seeking to exploit materials much thinner than silicon to achieve both smaller and higher-performing transistors.

These silver, wiggling lines are strings of atoms in tellurium behaving like DNA. Researchers have not seen this behavior in any other material.

This tellurium material is really unique. It builds a functional transistor with the potential to be the smallest in the world,” said Ye, Purdue’s Richard J. and Mary Jo Schwartz Professor of Electrical and Computer Engineering.

The research is published in the journal Nature Electronics.

Source: https://www.purdue.edu/

How To Reengineer Viruses To Cure Bacterial Infections

The world is in the midst of a global “superbug crisis. Antibiotic resistance has been found in numerous common bacterial infections, including tuberculosis, gonorrhoea and salmonellosis, making them difficult – if not impossibleto treat. We’re on the cusp of a post-antibiotic era, where there are fewer treatment options for such antibiotic-resistant strains. Given estimates that antibiotic resistance will cause 10 million deaths a year by 2050, finding new methods for treating harmful infections is essential.

Strange as it might sound, viruses might be one possible alternative to antibiotics for treating bacterial infections. Bacteriophages (also known as phages) are viruses that infect bacteria.

They’re estimated to be the most abundant organisms on Earth, with probably more than 1031 bacteriophages on the planet. They can survive in many environments, including deep sea trenches and the human gut. While phages are efficient killers of bacteria, they don’t infect human cells and are harmless to humans.

Although phage therapy was used in the 1930s, it has since become a forgotten cure in the west. Although the treatment became commonplace in the former Soviet Union, it wasn’t adopted by western countries largely because of the discovery of antibiotics, which became widespread after World War II.

Bacteriophages are effective against bacteria because they’re able to attach themselves to the cell if they recognise specific molecules called receptors. This is the first step in the “infection” process. After attaching to the bacterial cell, the phage then injects its DNA inside the bacteria.

This causes one of two things to happen. After being injected with the phage’s DNA, the virus will take over the bacterial cell’s replication mechanism and start producing more phages. This process is known as a “lytic infection”. This disintegrates the cell, allowing the newly produced viruses to leave the host cell to infect other bacterial cells.

But sometimes, the phage DNA gets incorporated into the bacterial host’s chromosome instead, becoming a “prophage. It usually remains dormant but environmental factors, such as UV radiation or the presence of certain chemicals such as those found in sunscreen, can cause the phage to “wake up”, start a lytic infection, take over the host cell and destroy it.

Lytic bacteriophages are preferred for treatment because they don’t integrate into the bacterial host’s chromosome. But it’s not always possible to develop lytic bacteriophages that can be used against all types of bacteria. As each type of phage is only able to infect specific types of bacteria, they can’t infect a bacterial cell unless the bacteriophage can find specific receptors on the bacterial cell surface.

However, engineering techniques can remove the bacteriophage’s ability to integrate into the host’s genome, making them useful for treatment. Engineered phages have even successfully treated a drug-resistant Mycobacterium abscessus infection in a 15-year-old girl.

Source: https://www.realclearscience.com/

Aggressive cancers in ‘evolutionary arms race’ with the immune system

Aggressive and highly-mutated cancers are engaged in an “evolutionary arms race” with the immune system, new research suggests. Gullet and stomach cancers with faults in their systems for repairing DNA build up huge numbers of genetic mutations which make them resistant to treatments like chemotherapy. But these numerous mutations mean they appear foreign to the immune system, leaving them vulnerable to attack, and susceptible to new immunotherapies.

Scientists at the Institute of Cancer Research, London (ICR), found that these “hyper-mutant” tumours rapidly evolve strategies to disguise themselves from the immune system and evade attack. They hope that in the future, the findings could help optimise treatment with immunotherapy, and other drugs such as chemotherapy.

Dr Marco Gerlinger, team Leader in translational oncogenomics at the ICR, said: “Our new study has shown that in highly mutated tumours, cancer and the immune system are engaged in an evolutionary arms race in which they continually find new ways to outflank one another.

Watching hyper-mutated tumours and immune cells co-evolve in such detail has shown that the immune system can keep up with changes in cancer, where current cancer therapies can become resistant – and that we could use immunotherapies to shift the balance of this arms race, extending patients’ lives.

“Next, we plan to study the evolutionary link between hyper-mutant tumours and the immune system as part of a new clinical trial looking at the possible benefit of immunotherapy in bowel cancer.

The study has been published in Nature Communications.

Source: https://www.sciencefocus.com/

Human Genetic Enhancement Might Soon Be Possible

The first genetically edited children were born in China in late 2018.Twins Lulu and Nana had a particular gene – known as CCR5modified during embryonic development. The aim was to make them (and their descendants) resistant to HIV. By some definitions, this would be an example of human enhancement.

Although there is still a long way to go before the technology is safe, this example has shown it’s possible to edit genes that will continue being inherited by genetic offspring for generations. However, we don’t yet know what effect these genetic changes will have on the overall health of the twins throughout life. Potential unintended changes to other genes is a grave concern which is limiting our use of gene editing technology at the moment – but this limit won’t always be present.

As we increasingly become less limited by what is scientifically achievable in the realm of gene editing for enhancement, we rely more heavily on ethical – rather than practical – limits to our actions. In fact, the case of Lulu and Nana might never have happened if both scientific and ethical limits had been more firmly established and enforced.

But in order to decide these limits, the expert community needs one important contribution: public opinion. Without the voice of the people, regulations are unlikely to be followed. In a worst-case scenario, a lack of agreed-upon regulations could mean the emergence of dangerous black markets for genetic enhancements. These come with safety and equity issues. In the meantime, experts have called for a temporary international ban on the use of gene editing technologies until a broad societal consensus has been established.

What should this broad consensus be? Current guidance in the UK is theoretically in favour of gene editing for treatment purposes in the future – if certain requirements regarding safety and the intentions of editing are met. This includes eliminating unintentional changes to other genes as a result of genetic enhancements, and that edits serve the welfare of the individuals involved. But when it comes to enhancement, ethical limits are harder to determine as people have different views on what’s best for ourselves and society.

One thing to consider with a technology like gene editing is that it affects more people than just the individual whose genes have been edited – and in some cases, those with edited genes could be unfairly better off than those who haven’t had their genes enhanced.

For example, if it were possible to enhance genes to improve facial symmetry or make a person more confident, it might mean these people are more likely to find employment in a competitive market, compared to those who haven’t had their genes edited for these characteristics. Future generations will also inherit and carry these enhancements in their DNA. In these ethical dilemmas, in order for one person to win, many people must (often unwittingly) lose.

Source: https://theconversation.com/

The Rising Of Gene Therapy

After false starts, drugs that manipulate the code of life are finally changing lives. The idea for gene therapy—a type of DNA-based medicine that inserts a healthy gene into cells to replace a mutated, disease-causing variant—was first published in 1972. After decades of disputed results, treatment failures and some deaths in experimental trials, the first gene therapy drug, for a type of skin cancer, was approved in China in 2003. The rest of the world was not easily convinced of the benefits, however, and it was not until 2017 that the U.S. approved one of these medicines. Since then, the pace of approvals has accelerated quickly. At least nine gene therapies have been approved for certain kinds of cancer, some viral infections and a few inherited disorders. A related drug type interferes with faulty genes by using stretches of DNA or RNA to hinder their workings. After nearly half a century, the concept of genetic medicine has become a reality.

These treatments use a harmless virus to carry a good gene into cells, where the virus inserts it into the existing genome, canceling the effects of harmful mutations in another gene.

GENDICINE: China’s regulatory agency approved the world’s first commercially available gene therapy in 2003 to treat head and neck squamous cell carcinoma, a form of skin cancer. Gendicine is a virus engineered to carry a gene that has instructions for making a tumor-fighting protein. The virus introduces the gene into tumor cells, causing them to increase the expression of tumor-suppressing genes and immune response factors.The drug is still awaiting FDA approval.

GLYBERA: The first gene therapy to be approved in the European Union treated lipoprotein lipase deficiency (LPLD), a rare inherited disorder that can cause severe pancreatitis. The drug inserted the gene for lipoprotein lipase into muscle cells. But because LPLD occurs in so few patients, the drug was unprofitable. By 2017 its manufacturer declined to renew its marketing authorization; Glybera is no longer on the market.

IMLYGIC: The drug was approved in China, the U.S. and the E.U. to treat melanoma in patients who have recurring skin lesions following initial surgery. Imlygic is a modified genetic therapy inserted directly into tumors with a viral vector, where the gene replicates and produces a protein that stimulates an immune response to kill cancer cells.

KYMRIAH: Developed for patients with B cell lymphoblastic leukemia, a type of cancer that affects white blood cells in children and young adults, Kymriah was approved by the FDA in 2017 and the E.U. in 2018. It works by introducing a new gene into a patient’s own T cells that enables them to find and kill cancer cells.

LUXTURNA: The drug was approved by the FDA in 2017 and in the E.U. in 2018 to treat patients with a rare form of inherited blindness called biallelic RPE65 mutation-associated retinal dystrophy. The disease affects between 1,000 and 2,000 patients in the U.S. who have a mutation in both copies of a particular gene, RPE65. Luxturna delivers a normal copy of RPE65 to patients’ retinal cells, allowing them to make a protein necessary for converting light to electrical signals and restoring their vision.

STRIMVELIS: About 15 patients are diagnosed in Europe every year with severe immunodeficiency from a rare inherited condition called adenosine deaminase deficiency (ADA-SCID). These patients’ bodies cannot make the ADA enzyme, which is vital for healthy white blood cells. Strimvelis, approved in the E.U. in 2016, works by introducing the gene responsible for producing ADA into stem cells taken from the patient’s own marrow. The cells are then reintroduced into the patient’s bloodstream, where they are transported to the bone marrow and begin producing normal white blood cells that can produce ADA.

YESCARTA: Developed to treat a cancer called large B cell lymphoma, Yescarta was approved by the FDA in 2017 and in the E.U. in 2018. It is in clinical trials in China. Large B cell lymphoma affects white blood cells called lymphocytes. The treatment, part of an approach known as CAR-T cell therapy, uses a virus to insert a gene that codes for proteins called chimeric antigen receptors (CARs) into a patient’s T cells. When these cells are reintroduced into the patient’s body, the CARs allow them to attach to and kill cancer cells in the bloodstream.

ZOLGENSMA: In May 2019 the FDA approved Zolgensma for children younger than two years with spinal muscular atrophy, a neuromuscular disorder that affects about one in 10,000 people worldwide. It is one of the leading genetic

causes of infant mortality. Zolgensma delivers a healthy copy of the human SMN gene to a patient’s motor neurons in a single treatment.

ZYNTEGLO: Granted approval in the E.U. in May 2019, Zynteglo treats a blood disorder called beta thalassemia that reduces a patient’s ability to produce hemoglobin, the protein in red blood cells that contains iron, leading to life-threatening anemia. The therapy has been approved for individuals 12 years and older who require regular blood transfusions. It employs a virus to introduce healthy copies of the gene for making hemoglobin into stem cells taken from the patient.The cells are then reintroduced into the bloodstream and transported to the bone marrow, where they begin producing healthy red blood cells that can manufacture hemoglobin.

The approach called ‘Gene Interference‘ uses a synthetic strand of RNA or DNA (called an oligonucleotide) that, when introduced into a patient’s cell, can attach to a specific gene or its messenger molecules, effectively inactivating them. Some treatments use an antisense method, named for one DNA strand, and others rely on small interfering RNA strands, which stop instruction molecules that go from the gene to the cell’s protein factories.

Source: https://www.nature.com/