Tag Archives: Alzheimer’s

Base Editing Could Cure a Host of Genetic Diseases

Picture the familiar double helix of human DNA — a long, twisted ladder with 3 billion rungs on it, each made of a pair of genetic bases (A, T, C, and G). A mistake in just one base along that ladderan A where there should be a G — can be enough to cause a disease. In fact, researchers have linked over 31,000 different mistakes, known as “point mutations,” to human diseases. Now, an advanced form of gene therapy — called base editing — could make it possible to safely correct them.

Base editing is a type of gene editing technology, just like CRISPR. However, while CRISPR cuts through both strands of the DNA ladder to swap in different genes, a base editor makes precise changes to individual letters along the genome — a much less invasive kind of DNA surgery.

It’s like your spell-checker,” neuroscientist Jeffrey Holt said. “If you type the wrong letter, spell checker fixes it for you.” Base editing was first developed by Broad Institute researcher David Liu in 2016, and it’s not perfect — the best base editors still make off-target edits and aren’t 100%  efficient. However, the technique is more efficient than CRISPR and causes fewer errors, which has made it the focus of considerable research into correcting disease-causing point mutations.

Base editing is like your spell-checker. If you type the wrong letter, it fixes it for you,” explained Jeffrey Holt. Holt was part of a team that used base editing to partially restore the hearing of mice with a point mutation that causes deafness in people. Earlier in 2020, University of Illinois researchers used base editing to slow the progression of ALS in mice. More recently, Liu was part of a group that used base editing to correct the point mutation that causes progeria, a premature-aging syndrome, in mice. By changing a T to a C in a single gene, they were able to more than double the lifespan of mice with the disease.

There’s no guarantee that a therapy that works in mice will translate to humans (although gene editing is conceptually much simpler than drugs that rely on complex chemistry). To find out whether base editing can live up to its promise as a disease-curing technology, we need human studies — and now, one is just on the horizon.

On January 12, Massachusetts-based biotech company Verve Therapeutics announced the promising results of a study testing a base editing treatment for heterozygous familial hypercholesterolemia (HeFH), a genetic heart diseaseHeFH is fairly common, affecting about one in 500 people, and it causes consistently high levels of “badcholesterol (LDL-C) — that makes people with the disease susceptible to heart attacks or strokes at a relatively young age. In primates with HeFH, Verve used base editing to change an A to a G in a single gene. Within two weeks, the animals’ blood LDL-C levels had dropped by 59%. Six months later, they were still just as low.The treatment, dubbed “VERVE-101,” was well-tolerated, with no adverse effects reported.

When we started, we had no idea this would work,” Verve CEO Sekar Kathiresan said in a press release, adding, “It works, and we expect this to be durable for the lifetime of the animals.” Now, Verve wants to find out if VERVE-101 works in humans.

Source: https://www.freethink.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/

Alzheimer’s Is Actually 3 Distinct Disease Subtypes

Alzheimer’s Disease (AD) is probably more diverse than our traditional models suggest. Postmortem, RNA sequencing has revealed three major molecular subtypes of the disease, each of which presents differently in the brain and which holds a unique genetic risk.  Such knowledge could help us predict who is most vulnerable to each subtype, how their disease might progress and what treatments might suit them best, potentially leading to better outcomes. It could also help explain why effective treatments for AD have proved so challenging to find thus far.

The mouse models we currently have for pharmaceutical research match a particular subset of AD,  but not all subtypes simultaneouslyThis may partially explain why a vast majority of drugs that succeeded in specific mouse models do not align with generalised human trials across all AD subtypes,”  say the authors. “Therefore,” the authors conclude, “subtyping patients with AD is a critical step toward precision medicine for this devastating disease.

Traditionally, AD is thought to be marked by clumps of amyloid-beta plaques (), as well as tangles of tau proteins (NFTs) found in postmortem biopsies of the brain. Both of these markers have become synonymous with the disease, but in recent years our leading hypotheses about what they actually do to our brains have come under question. Typically, accumulations of and NFT are thought to drive neuronal and synaptic loss, predominantly within the cerebral cortex and hippocampus. Further degeneration then follows, including inflammation and degeneration of nerve cells‘ protective coating, which causes signals in our brains to slow down.

Strangely enough, however, recent evidence has shown up to a third of patients with a confirmed, clinical diagnosis have no Aβ plaques in postmortem biopsies. What’s more, many of those found with plaques at death did not show cognitive impairment in life. Instead of being an early trigger of AD, setting off neurodegeneration and driving memory loss and confusion, in some people, Aβ plaques appear to be latecomers. On the other hand, recent evidence suggests tau proteins are there from the very earliest stages.

In light of all this research, it’s highly likely there are specific subtypes of AD that we simply haven’t teased apart yet. The new research has helped unbraid three major strands. To do this, researchers analysed 1,543 transcriptomes – the genetic processes being express in the cellacross five brain regions, which were collected post mortem from two AD cohorts.

Source: https://advances.sciencemag.org/

Blocking Enzymes Reverse Alzheimer’s Memory Loss

Inhibiting certain enzymes involved in abnormal gene transcription may offer a way to restore memory loss associated with Alzheimer’s disease, a new study in mice suggests.

The findings could pave the way toward new treatments for Alzheimer’s disease (AD).

“By treating AD mouse models with a compound to inhibit these enzymes, we were able to normalize gene expression, restore neuronal function, and ameliorate cognitive impairment,” says senior author Zhen Yan, a professor in the department of physiology and biophysics in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo.

Alzheimer’s disease alters the expression of genes in the prefrontal cortex, a key region of the brain controlling cognitive processes and executive functions.

When they focused on gene changes caused by epigenetic processes (those not related to changes in DNA sequences) such as aging, the researchers could reverse elevated levels of harmful genes that cause memory deficits in AD.

The current research extends the work the team reported in 2019 in the journal Brain, in which they reversed the loss or downregulation of genes beneficial to cognitive function in AD.

In the new paper in Science Advances, the team reports they reversed the upregulation of genes involved in impairing cognitive function.

http://www.buffalo.edu/

Nanoparticle Drug-Delivery To Treat Brain Disorders

In the past few decades, researchers have identified biological pathways leading to neurodegenerative diseases and developed promising molecular agents to target them. However, the translation of these findings into clinically approved treatments has progressed at a much slower rate, in part because of the challenges scientists face in delivering therapeutics across the blood-brain barrier (BBB) and into the brain.

To facilitate successful delivery of therapeutic agents to the brain, a team of bioengineers, physicians, and collaborators at Brigham and Women’s Hospital and Boston Children’s Hospital created a nanoparticle platform, which can facilitate therapeutically effective delivery of encapsulated agents in mice with a physically breached or intact BBB. In a mouse model of traumatic brain injury (TBI), they observed that the delivery system showed three times more accumulation in brain than conventional methods of delivery and was therapeutically effective as well, which could open possibilities for the treatment of numerous neurological disorders.

It’s very difficult to get both small and large molecule therapeutic agents delivered across the BBB,” said corresponding author Nitin Joshi, PhD, an associate bioengineer at the Center for Nanomedicine in the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine. “Our solution was to encapsulate therapeutic agents into biocompatible nanoparticles with precisely engineered surface properties that would enable their therapeutically effective transport into the brain, independent of the state of the BBB.”

The technology could enable physicians to treat secondary injuries associated with TBI that can lead to Alzheimer’s, Parkinson’s, and other neurodegenerative diseases, which can develop during ensuing months and years once the BBB has healed.

To be able to deliver agents across the BBB in the absence of inflammation has been somewhat of a holy grail in the field,” said co-senior author Jeff Karp, PhD, of the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine. “Our radically simple approach is applicable to many neurological disorders where delivery of therapeutic agents to the brain is desired.”

Findings were published in Science Advances.

https://www.eurekalert.org/

How to Protect Neurons and Encourage Their Growth

Many neurodegenerative conditions, from glaucoma to Alzheimer’s disease, are characterized by injury to axons — the long, slender projections that conduct electrical impulses from one nerve cell to another, facilitating cellular communications. Injury to axons often leads to neuronal impairment and cell death.

Researchers know that inhibiting an enzyme called dual leucine zipper kinase (DLK) appears to robustly protect neurons in a wide range of neurodegenerative diseases models, but DLK also inhibits axonal regeneration. Until now, there have been no effective methods to modify genes to improve both the long-term survival of neurons and promote regeneration.

In a paper published December 14, 2020 in PNAS, a multi-university team led by researchers at University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health identified another family of enzymes called germinal cell kinase four kinases (GCK-IV kinases) whose inhibition is robustly neuroprotective, while also permitting axon regeneration, making it an attractive therapeutic approach for treating at some neurodegenerative diseases.

Example of retinal ganglion cells with axons and dendrites in the retina of a healthy eye.

We basically figured out that there are a set of genes that, when inhibited, allow optic nerve cells to survive and regenerate,” said senior author Derek Welsbie, MD, PhD, associate professor of ophthalmology in the Viterbi Family Department of Ophthalmology at Shiley Eye Institute.

Prior to this work, the field knew how to get these cells to survive, but not regenerate. Conversely, there are ways to promote regeneration, but then the survival was rather modest. Of course, for a successful strategy of vision restoration, you need both and this is a step in that direction.”

Source: https://ucsdnews.ucsd.edu/

Human Brain Cells Gene-edited To reduce The Risk Of Developing Alzheimer’s Disease

Cells in the human brain could one day be edited by scientists to prevent the development of Alzheimer’s disease, a new study suggests. The causes of Alzheimer’s are still not well understood, but a leading theory is that it is triggered by the build-up of a protein called beta-amyloid outside the brain cells. Researchers from Laval University in Canada have been investigating how a key gene in human nerve cells could reduce the formation of this protein. Many variants of this gene increases beta-amyloid production, but one variant, called A673T, instead reduces it.

A673T was first discovered in 2012, and is only active in one in 150 people in Scandinavia, but those that have it are four times less likely to get Alzheimer’s. The researchers believe that switching on this gene variant in brain cells could reduce the production of beta-amyloid and thereby reduce Alzheimer’s risk. As the A673T variant doesn’t become relevant until later in life, it isn’t selected for by evolution, according to the study authors. It differs from other variants of the gene by a single DNA letter. Researchers showed that, by editing this one DNA letter, they were able to activate the A673T variant in brain cells growing in a culture dish. Jacques Tremblay and colleagues say this is the first step to proving that engineering the variant into brains could have the same benefits as inheriting it.

The team are still refining the technique before they try it on animals. The researchers initially used a CRISPR technique called base editing, which allows the direct, irreversible conversion of a DNA base into another, targeted base. However, they have now switched to a relatively new method called prime editing – a ‘search and replace‘ technique for editing genomes that directly writes new genetic information into a targeted DNA site using a fusion protein.  Working with cells in a dish they managed to edit about 40 per cent of the cells, but they think a higher proportion might be needed for it to work in a human brain.

The researchers  worked with a process known as base editing, a relatively new method that allows the direct, irreversible conversion of a DNA base into another, targeted base
Source: https://www.dailymail.co.uk/

AI Detects In Your Language Early Sign Of Alzheimer’s Disease

An artificial intelligence program analyzing language predicted whether people with no memory or thinking problems would develop Alzheimer’s disease later in life, researchers said. The study by IBM, funded by drug giant Pfizer, found a computerized model analyzing language patterns accurately predicted up to 74% of participants diagnosed with Alzheimer’s disease later in lifeEarly detection of Alzheimer’s disease is crucial, as the memory-robbing disease  afflicts about 5.8 million Americans.

Many researchers are working to develop blood tests to detect Alzheimer’s before memory and thinking problems occur. Blood tests can potentially be more precise than memory and cognitive tests now used to diagnose the disease. The tests also could be a less expensive way to conduct clinical studies.

IBM officials say their study of language patterns show another possible tool for early detection of Alzheimer’s disease and other forms of dementia. Ajay Royyuru, IBM’s vice president of health care and life sciences research, said IBM‘s research efforts to track language shows the potential for a noninvasive test that “presents a better window for targeted interventions.”

The research analyzed more than 700 written samples from 270 participants in the decades-old Framingham Heart Study, which has collected detailed medical histories, physical exams and lab tests from thousands of participants. Participants were shown a cookie-theft picture and asked to write a description of the image. The samples were collected when participants showed no signs of memory loss. The datas predicted Alzheimer’s disease an average of 7.6 years before participants were diagnosed.

The findings are reported in the journal EClinicalMedicine.

Source: https://www.ibm.com/
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https://eu.usatoday.com/

 

Artificial Intelligence Detects 100% Of Asymptomatic COVID-19 Coughs

Scientists at the Massachusetts Institute of Technology developed an artificial intelligence model that could distinguish between a healthy cough and one that comes from an asymptomatic coronavirus patient. The differences are nonexistent to the naked human ear, but the AI was able to accurately identify nearly 99% of coughs from people with COVID-19, including all of the coughs from individuals without symptoms. The model was trained by listening to more than 200,000 recordings of coughs and spoken words, the “largest cough dataset that we know of.”  The team said it’s working on incorporating the model into apps, and eventually smart speakers and other listening devices, so that people can consistently and conveniently be screened for coronavirus infection. This, researchers say, can help prevent asymptomatic individuals from unknowingly spreading the virus to others. What’s more, the method would be free and save you from having a cotton swab poked up your nose.

The effective implementation of this group diagnostic tool could diminish the spread of the pandemic if everyone uses it before going to a classroom, a factory, or a restaurant,” study co-author Brian Subirana, a research scientist in MIT’s Auto-ID Laboratory, said in the release. “We think this shows that the way you produce sound changes when you have COVID, even if you’re asymptomatic,” Subirana added.
When the pandemic began, the MIT scientists thought it would be an interesting experiment to see if an AI model they invented to detect signs of Alzheimer’s disease could also work to detect COVID-19. The team felt confident the model could work because there’s growing evidence that coronavirus patients experience similar symptoms associated with Alzheimer’s such as neuromuscular impairment that affects the vocal cords.

The sounds of talking and coughing are both influenced by the vocal cords and surrounding organs. This means that when you talk, part of your talking is like coughing, and vice versa,” Subirana said in the release. “It also means that things we easily derive from fluent speech, AI can pick up simply from coughs, including things like the person’s gender, mother tongue, or even emotional state. There’s in fact sentiment embedded in how you cough.”

In April, the team collected 70,000 recordings of people forcibly coughing into their cell phones or laptops, which amounted to about 200,000 cough audio samples. About 2,500 of those were submitted by people with COVID-19. Participants also had to answer surveys about symptoms they were experiencing, their COVID-19 diagnosis, gender, geographical location and native language. After using a couple thousand recordings to “train” the AI, 1,000 audio samples were used to officially test if the model can discern between a healthy and sick cough, even if the person is asymptomatic.

By listening for “vocal cord strength, sentiment, lung and respiratory performance, and muscular degradation” specific to COVID-19, the AI model identified 98.5% of coughs from coronavirus patients, and 100% of asymptomatic coughs.

Blood Test For Alzheimer’s Detects Signs 20 years Before Falter

A new blood test detected Alzheimer’s disease as accurately as expensive brain scans or spinal taps, raising the possibility for a new, inexpensive option to diagnose the most common form of dementia, researchers said. Researchers at the Alzheimer’s Association International Conference presented the results of multiple studies of whether a blood test could distinguish Alzheimer’s disease from other forms of dementia.

In one study published in JAMA, researchers said the blood test could could identify Alzheimer’s disease and even detected signs of disease 20 years before cognitive problems were expected in a group of people who carry a rare genetic mutation. A blood test to detect Alzheimer’s disease early could be more precise than memory and thinking tests now used to diagnose the disease. Invasive and expensive brain scans and spinal taps that measure spinal fluid are used, but insurance does not always cover those tests. Researchers reported the blood test measuring the protein tau accurately distinguished Alzheimer’s from other forms of dementia in 89% to 98% of cases.

It is a promising blood test that seems to be highly accurate and seems to detect (Alzheimer’s) relatively early,” said Dr. Eric Reiman, a researcher in one of the studies and executive director of Banner Alzheimer’s Institute in Phoenix

But experts warned it could take a few years to validate a blood test as a reliable option for both doctors and researchers. And would patients want to know they are destined to develop memory and thinking problems if there are no reliable medications to slow the deadly disease?

Randall J. Bateman, a Washington University neurology professor and Alzheimer’s researcher, said blood tests could be useful both for patients and doctors as well scientists studying new drugs to slow the mind-robbing disease. Doctors might use the test to accurately diagnose Alzheimer’s earlier and begin treatments with existing Food and Drug Administration-approved drugs that ease symptoms, if not mental decline. But perhaps the bigger payoff would come for accelerating research for new drugs that seek to slow or halt a disease that afflicts 5.8 million older Americans. Drug companies for decades have developed therapies targeting amyloid proteins on the theory it is responsible for scuttling memory and thinking in Alzheimer’s patients. Some recent studies have sought to administer drugs targeting these proteins before memory and thinking problems emerge.

Source: https://jamanetwork.com/ 
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