FDA-approved Drugs Slow or Reverse Alzheimer’s

A research team at Washington University School of Medicine in St. Louis has identified potential new treatment targets for Alzheimer’s disease, as well as existing drugs that have therapeutic potential against these targets.

The potential targets are defective proteins that lead to the buildup of amyloid in the brain, contributing to the onset of problems with memory and thinking that are the hallmark of Alzheimer’s. The 15 existing drugs identified by the researchers have been approved by the Food and Drug Administration (FDA) for other purposes, providing the possibility of clinical trials that could begin sooner than is typical, according to the researchers.

In addition, the experiments yielded seven drugs that may be useful for treating faulty proteins linked to Parkinson’s disease, six for stroke and one for amyotrophic lateral sclerosis (ALS).

Scientists have worked for decades to develop treatments for Alzheimer’s by targeting genes rooted in the disease process but have had little success. That approach has led to several dead ends because many of those genes don’t fundamentally alter proteins at work in the brain. The new study takes a different approach, by focusing on proteins in the brain, and other tissues, whose function has been altered.

In this study, we used human samples and the latest technologies to better understand the biology of Alzheimer’s disease,” said principal investigator Carlos Cruchaga, the Reuben Morriss III Professor of Neurology and a professor of psychiatry. “Using Alzheimer’s disease samples, we’ve been able to identify new genes, druggable targets and FDA-approved compounds that interact with those targets to potentially slow or reverse the progress of Alzheimer’s.”

The scientists focused on protein levels in the brain, cerebrospinal fluid (CSF) and blood plasma of people with and without Alzheimer’s disease. Some of the proteins were made by genes previously linked to Alzheimer’s risk, while others were made by genes not previously connected to the disease. After identifying the proteins, the researchers compared their results to several databases of existing drugs that affect those proteins.

The new study, funded by the National Institute on Aging of the National Institutes of Health (NIH), is published in the journal Nature Neuroscience.

Source: https://source.wustl.edu/

AI Recognises the Biological Activity of Natural Products

Nature has a vast store of medicinal substances. “Over 50 percent of all drugs today are inspired by nature,” says Gisbert Schneider, Professor of Computer-​Assisted Drug Design at ETH Zurich. Nevertheless, he is convinced that we have tapped only a fraction of the potential of natural products. Together with his team, he has successfully demonstrated how artificial intelligence (AI) methods can be used in a targeted manner to find new pharmaceutical applications for natural products. Furthermore, AI methods are capable of helping to find alternatives to these compounds that have the same effect but are much easier and therefore cheaper to manufacture.

And so the ETH researchers are paving the way for an important medical advance: we currently have only about 4,000 basically different medicines in total. In contrast, estimates of the number of human proteins reach up to 400,000, each of which could be a target for a drug. There are good reasons for Schneider’s focus on nature in the search for new pharmaceutical agents.

Most natural products are by definition potential active ingredients that have been selected via evolutionary mechanisms,” he says.
Whereas scientists used to trawl collections of natural products on the search for new drugs, Schneider and his team have flipped the script: first, they look for possible target molecules, typically proteins, of natural products so as to identify the pharmacologically relevant compounds. “The chances of finding medically meaningful pairs of active ingredient and target protein are much greater using this method than with conventional screening,” Schneider says.

Source: https://www.weforum.org/

Simple Blood Test Detects Early Pancreatic Cancer

A test that spots pancreatic cancer from a single drop of blood could improve survival rates. The first blood test for early diagnosis of the hard-to-spot disease, it could be available within monthsPancreatic cancer has the lowest survival rate of the common cancers, with 7.3 per cent of patients alive five years after diagnosis, compared to 58.4 per cent of bowel cancer patients and 85 per cent of breast cancer patients.

The disease is one of the hardest to diagnose early. This is partly because the pancreas — a pear-shaped gland that makes digestive juices and hormones including insulin — is hidden behind the stomach, making it difficult for tumours to be felt or seen on scans. It also doesn’t usually cause symptoms in the early stages — when they do occur, the signs, such as stomach or back pain, weight loss and indigestion, can be vague and easily confused with conditions, such as irritable bowel syndrome.

Treatments include surgery, radiotherapy and chemotherapy but their effectiveness hinges on early diagnosis. Caught early, before the disease has spread to other organs, up to 25 per cent of patients will live for at least five years. If the disease has spread, average survival is two to six months.

The new test, developed by Swedish biotech firm Immunovia and being trialled on 2,000 people at University College London Hospital, and 20 other centres in the U.S., Spain and Sweden, looks for signs of the disease in patient’s blood. These include different levels of around 30 proteins and other compounds identified by the Swedish scientists.

They provide a distinct chemical fingerprint of the disease. The test picks out the compounds using antibodies that latch on to individual chemicals: sophisticated scanning equipment is then used to measure their levels. Previous research shows the test is 96 per cent accurate in spotting people with early-stage pancreatic cancers.

Source: https://immunovia.com/

Moderna to Trial HIV and Flu Vaccines With mRNA Technology

The astonishing success of COVID-19 vaccines may signal a breakthrough in disease prevention technologyModerna is developing influenza and HIV vaccines using mRNA technology, the backbone of its effective COVID-19 vaccine. The biotech company is expected to launch phase 1 trials for its mRNA flu and HIV vaccines this year. If successful, mRNA may offer a silver lining to the decades-long fight against HIV, influenza, and other autoimmune diseases. Traditional vaccines often introduce a weakened or inactive virus to one’s body. In contrast, mRNA technology uses genetic blueprints, which build proteins to train the immune system to fight off the virus. Since mRNA teaches the body to recognize a virus, it can be effective against multiple strains or variants as opposed to just one.

The mRNA platform makes it easy to develop vaccines against variants because it just requires an update to the coding sequences in the mRNA that code for the variant,”  said Rajesh Gandhi, MD, an infectious diseases physician at Massachusetts General Hospital and chair of HIV Medicine association.

Future mRNA vaccines have the potential to ward off multiple diseases with one shot, according to the Centers for Disease Control and Prevention (CDC).  Current mRNA vaccines, as demonstrated in their use against COVID-19, already appear to be less susceptible to new variants. “Based on its success in protecting against COVID-19, I am hopeful that mRNA technology will revolutionize our ability to develop vaccines against other pathogens, like HIV and influenza,” Gandhi says.

Moderna’s flu and HIV vaccines are still in early development stages, having yet to undergo their clinical trials. Still, if they prove successful, the mRNA-based treatment could dramatically change health care — both in expediting the route to immunity and by providing a solution to illnesses that have been around for decades. Scientists currently make annual alterations to the typical flu shot to keep up with the viruses in circulation. But a successful mRNA vaccine could provide a far more effective alternative.

An approved mRNA flu vaccine could be administered every other year rather than annually, explained virologist Andrew Pekosz, PhD. This is because mRNA accounts for variants and produces a stronger and longer-lasting immune response than that of the current flu vaccine, he says. The influenza vaccine is similar to the COVID-19 vaccine because the viruses have similar characteristics and necessary treatments, according to Pekosz.

However, a potential concern lies in the level of public immunity prior to receiving a vaccine. Since the flu has been around since the early 1900s, an mRNA vaccine could potentially boost older or less effective antibody responses rather than targeting current strains, Pekosz adds. “There’s no way to answer that question except to do some clinical trials, and see what the results tell us”.

Source: https://www.verywellhealth.com/

Holistic Immune Response Against Covid-19

Researchers say it’s the first real look at exactly what types of “red flags” the human body uses to enlist the help of T cells—killers the immune system sends out to destroy infected cells. Until now, COVID vaccines have focused on activating a different type of immune cell, B cells, which are responsible for creating antibodies. Developing vaccines to activate the other arm of the immune system—the T cells—could dramatically increase immunity against coronavirus, and importantly, its variants.

As reported in the journal Cell, the researchers say current vaccines might lack some important bits of viral material capable of triggering a holistic immune response in the human body.

Companies should reevaluate their vaccine designs,” says Mohsan Saeed, a virologist at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) and co-corresponding author of the paper.

Saeed, an assistant professor of biochemistry at the School of Medicine, performed experiments on human cells infected with coronavirus. He isolated and identified those missing pieces of SARS-CoV-2 proteins inside one of the NEIDL’s Biosafety Level 3 (BSL-3) labs.

This was a big undertaking because many research techniques are difficult to adapt for high containment levels [such as BSL-3],” Saeed says. “The overall coronavirus research pipeline we’ve created at the NEIDL, and the support of our entire NEIDL team, has helped us along the way.”

Saeed got involved when computational geneticists Pardis Sabeti and Shira Weingarten-Gabbay contacted him. They hoped to identify fragments of SARS-CoV-2 that activate the immune system’s T cells.

The emergence of viral variants, an active area of research in my lab, is a major concern for vaccine development,” says Sabeti, a leader in the Broad Institute’s Infectious Disease and Microbiome Program. She is also a Harvard University professor of systems biology.

We swung into full action right away because my laboratory had [already] generated human cell lines that could be readily infected with SARS-CoV-2,” Saeed says. The group’s efforts were spearheaded by two members of the Saeed lab: Da-Yuan Chen, a postdoctoral associate, and Hasahn Conway, a lab technician.

Source:  https://www.futurity.org/

RNA Could Be The Future of Cancer Treatment

Cells are the basic building blocks of all living things. So, in order to treat or cure almost any disease or condition – including cancer – you first need to have a fundamental understanding of cell biology. While researchers have a pretty good understanding of what each component of a cell does, there are still things we don’t know about them – including the role that some RNAs molecules play in a cell.

Finding the answer to this may be key in developing further cancer treatments, which is what our research has sought to uncover. Three types of molecules carry information in a cell, and each of these molecules performs its own important function. The first is DNA, which contains hard-wired genetic information (like a book of instructions). . The second, RNA, is a temporary copy of one particular instruction that is derived from DNA. Last are the proteins produced thanks to the information provided by the RNA. These proteins are the “workhorses” of the cells, which perform specific functions, such as helping cells move, reproduce, and generate energy.

In line with this model, RNA has long been seen as nothing more than an intermediary between DNA and proteins. But researchers are starting to discover that RNA is much more than an intermediary. In fact, this overlooked molecule may hold the secret to cancer progression. The scientists group recently discovered a new type of RNA that drives cancer progression without producing any protein. We think that this type of discovery may pave the way for an entirely new way of targeting cancer cells. But to understand how this is possible, it’s first important to know the different types of RNA we have in our body. Only about 1% of DNA is copied into RNAs that make proteins. Other RNAs help the production of proteins. The rest (known as non-coding RNAs) were long assumed to serve no function in the human body. But recent studies are challenging these assumptions, showing these “uselessRNAs actually performvery specific purpose. In fact, these “non-coding” RNAs regulate the functions of many genes, thereby controlling key aspects of the cells’ lives (such as their ability to move around).

The most abundant type of non-coding RNAs are long non-coding RNAs (lncRNAs). These are long molecules which interact with many different molecules in the cell. And, as researchers have now discovered, these complex structures allow many different functions to take place between cells.

For example, some lncRNAsgrab” different proteins and gather them to work in a specific cellular space – such as the same gene segment. This function is essential for controlling the inactivation of some genes during development.

Source: https://nationalinterest.org/

Reversible Gene Editing

The gene-editing system, CRISPR-Cas9, is truly revolutionizing medicine: in the future, it may help us eradicate ailments from sickle cell, cancer, and even blindness. While this system allows scientists to make changes to DNA, the changes are permanent. On the one hand, this is useful, because it could potentially cure genetic diseases without requiring a lifetime of treatment. The downside is that unintended consequences of the edits are difficult to fix — especially “off-targetedits, where CRISPR changes the wrong stretch of DNA. This is a huge concern for the scientific community — no one wants to be responsible for genetic mutations that go awry.

But what if the changes were not permanent? What if we could simply turn CRISPR off whenever we wanted?  A team of researchers at MIT and UCSF has developed a new gene-editing system that they call “CRISPRoff.” According to the researchers, this system can change how specific genes behave, much like CRISPR, while leaving the DNA strand unaltered — and even better, these modifications are completely reversible.

The traditional CRISPR system invented in 2012 relies on a protein called Cas9, which is found in bacterial immune systems. Cas9 can target specific genes and cut the DNA strand, removing or replacing defective genes. The DNA then self-repairs and continues functioning after the gene has been removed. Because this system alters the DNA sequence, the changes are permanent, and even though CRISPR is one of the most accurate ways to change DNA, it can be difficult to ensure that the modification will always be limited to that one gene.

As beautiful as CRISPR-Cas9 is, it hands off the repair to natural cellular processes, which are complex and multifaceted,MIT‘s Jonathan Weissman and coauthor of the study, said in a press release. “It’s very hard to control the outcomes.”

CRISPRoff is a new kind of gene-editing technology that doesn’t modify the DNA sequence, but instead changes the way those sequences are read. With this system, scientists can silence or activate various genes by adding chemical tags onto the DNA strand, without making any permanent changes. The tags cause the DNA to become unreadable by the cell’s messenger RNA, the molecule responsible for carrying instructions from the DNA to make proteins.

Source: https://news.mit.edu/

A Cannabis Molecule Reduces Plaque, Improves Cognition in Alzheimer’s

A two-week course of high doses of CBD helps restore the function of two proteins key to reducing the accumulation of beta-amyloid plaque, a hallmark of Alzheimer’s disease, and improves cognition in an experimental model of early onset familial Alzheimer’s, investigators report. The proteins TREM2 and IL-33 are important to the ability of the brain’s immune cells to literally consume dead cells and other debris like the beta-amyloid plaque that piles up in patients’ brains, and levels of both are decreased in Alzheimer’s.

The investigators report for the first time that CBD normalizes levels and function, improving cognition as it also reduces levels of the immune protein IL-6, which is associated with the high inflammation levels found in Alzheimer’s, says Dr. Babak Baban, immunologist and associate dean for research in the Dental College of Georgia (DCG) and the study’s corresponding author. There is a dire need for novel therapies to improve outcomes for patients with this condition, which is considered one of the fastest-growing health threats in the United States, DCG and Medical College of Georgia (MCG) investigators write in the Journal of Alzheimer’s Disease.

Right now we have two classes of drugs to treat Alzheimer’s,” says Dr. John Morgan, neurologist and director of the Movement and Memory Disorder Programs in the MCG Department of Neurology. “One class increases levels of the neurotransmitter acetylcholine, which also are decreased in Alzheimer’s, and another works through the NMDA receptors involved in communication between neurons and important to memory. But we have nothing that gets to the pathophysiology of the disease,” says Morgan, a study coauthor.

The DCG and MCG investigators decided to look at CBD’s ability to address some of the key brain systems that go awry in Alzheimer’s.

They found CBD appears to normalize levels of IL-33, a protein whose highest expression in humans is normally in the brain, where it helps sound the alarm that there is an invader like the beta-amyloid accumulation. There is emerging evidence of its role as a regulatory protein as well, whose function of either turning up or down the immune response depends on the environment, Baban says. In Alzheimer’s, that includes turning down inflammation and trying to restore balance to the immune system, he says.

CBD also improved expression of triggering receptor expressed on myeloid cells 2, or TREM2, which is found on the cell surface where it combines with another protein to transmit signals that activate cells, including immune cells. In the brain, its expression is on the microglial cells, a special population of immune cells found only in the brain where they are key to eliminating invaders like a virus and irrevocably damaged neurons.

Source: https://jagwire.augusta.edu/

Soon a Vaccine to Prevent Melanoma

A personalized “cancer vaccine” may help keep a deadly form of skin cancer from growing for years, a small new study in humans suggests. Unlike vaccines that prevent infections, such as measles and influenza, cancer vaccines are a form of immunotherapy that take down cancer cells that already exist. The vaccines train immune cells, called T cells, to better recognize cancer and target it for destruction, while sparing healthy cells in the body. For example, the new experimental vaccine works by training T cells to spot specific proteins on melanoma cells, a type of skin cancer. In the study, scientists found that the T cells continue to “remember” these proteins for at least four years after the vaccination — and they even learn to recognize more melanoma-related proteins over time.

The only way that could have happened is if there was actually killing of the tumor cells. And presumably it was the T cells induced by the vaccine that did that killing,” said study author Dr. Catherine Wu, a physician-scientist with the Dana-Farber Cancer Institute and Harvard Medical School in Boston and the Broad Institute in Cambridge, Massachusetts. That’s because, once killed, tumor cells fall apart and spill their contents; T cells then swoop in to examine these remains and log that information away for future attacks, Wu said.

While the results are promising, the new study only included eight patients, and more trials need to be conducted to pin down exactly how effective the vaccine is, she added. But as of now, the limited data hint that the vaccine triggers a persistent immune response and can help keep cancer under control, especially when combined with other immunotherapies, the authors noted. The new study, published Jan. 21 in the journal Nature Medicine, included patients with advanced melanoma who had recently undergone surgery for the cancer. The researchers took samples of the patients’ removed tumors and used them to craft personalized vaccines for each of the eight participants.

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

Immune System Killer Cells Controlled By Circadian Rhythms

An analysis of an exhaustive dataset on cells essential to the mammalian immune system shows that our ability to fight disease may rely more heavily on daily circadian cycles than previously assumed.

Malfunctions in , the process that keeps our bodies in tune with the day/night cycles, are increasingly associated with diabetes, cancer, Alzheimer’s, and many other diseases. An investigation published today in Genome Research shows that the activity of macrophagescells within us that seek and destroy intruders like bacteria—may time daily changes in their responses to pathogens and stress through the circadian control of metabolism. In this study, Jennifer Hurley, the Richard Baruch M.D. Career Development Assistant Professor of Biological Sciences at Rensselaer Polytechnic Institute and senior author on this study, and her team investigated how the levels of RNA and proteins in macrophages change over two days.

We have shown there is an incredible amount of circadian timing of macrophage behavior, but the clock is timing macrophages in unexpected ways” said Hurley.

The circadian system is comprised of a set of core clock proteins that anticipate the day/night cycle by causing daily oscillations in levels of enzymes and hormones, and ultimately affecting physiological parameters such as body temperature and the immune response. This molecular clock marks time through a self-regulating cycle of  production and decay. The “positive” element proteins of the clock trigger production of the “negative” element proteins, which in turn block production of positive element proteins until the negative element proteins decay, thus creating a negative feedback cycle that occurs once every 24 hours.

Positive element proteins also regulate fluctuations in a substantial number of gene products, known as messenger RNA or mRNA. Genetic instructions are transcribed from DNA to mRNA, which are then used as a recipe for assembling proteins, the functional building blocks of the cell. It has long been assumed that the levels of each subsequent step could be predicted from the previous. If that were the case, oscillating mRNA would correspond with oscillating levels of cellular proteins, and therefore, if one could track mRNA, they would know what proteins the circadian clock controlled in the cell.

However, this investigation showed that this paradigm may not always be true. The analysis of the macrophage dataset revealed that there was a substantial mismatch between the proteins and mRNAs that are controlled by the circadian clock. This data paralleled research published in Cell Systems in 2018 by the Hurley lab, showing that about 40% of oscillating proteins in the fungus and circadian model system, Neurospora crassa, had no corresponding oscillating mRNA.

But the scale of the difference in macrophages really surprised us,” Hurley said. “Eighty percent of the proteins that oscillate don’t have associated oscillating mRNA in macrophages. That means we were really missing how the clock was timing immunity.”

Source: https://medicalxpress.com/