Tag Archives: therapeutic

Scientists Reveal New Potential Therapeutic Targets for Mental and Neurological Disorders

January 31, 2023 Admin Leave a comment

Cilia are small, hair-like structures found on the surface of cells in the body. They are known to play important roles in various bodily functions, such as sensing the environment and moving fluids. In the brain, cilia have been found to play a crucial role in the striatum, a region that is involved in movement, motivation, and time perception. Recent research has revealed that cilia in the striatum play a key role in our ability to perceive time,

UCI researchers have discovered the crucial role of cilia in the striatum of the brain in time perception.

A recent study from researchers at the University of California, Irvine found that the removal of cilia from the striatum region of the brain negatively impacted time perception and judgement, opening the possibility for new therapeutic targets for mental and neurological conditions such as schizophrenia, Parkinson’s and Huntington’s diseases,

The study, which was recently published in the journal Molecular Neurobiology, uncovered the first evidence of the important role cilia play in timing-dependent dysfunction.

“Our findings may revolutionize our understanding of brain functions and mental disorders in the context of the critical task performed by these previously unappreciated organelles in the brain’s ‘central clock’ function,” said Amal Alachkar, Ph.D., corresponding author, and professor of teaching in UCI’s Department of Pharmaceutical Sciences. “Our results may open new avenues for effective intervention through cilia-targeted therapies for treatment.”

The striatum is part of the brain’s circuitry that performs central clock processes, essential in controlling executive functions such as motor coordination, learning, planning, and decision-making, as well as working memory and attention. Cilia protrude from the brain cell surfaces like antennae, working as a signaling hub that senses and transmits signals to generate appropriate reactions.

To examine their physiological role, the researchers removed cilia from the striatum in mice using conditional gene manipulation technology. These rodents were not able to learn new motor tasks, showed repetitive motor behavior, and exhibited delays in decision-making. They were also deficient in rapidly recalling information about their location and orientation in space and in their ability to filter irrelevant environmental sensory information. However, the mice maintained habitual or already learned motor skills and long-term memories.

“Successful performance of working memory, attention, decision-making, and executive function requires accurate and precise timing judgment, usually within a millisecond to a minute,” Alachkar said. “When that capacity is impaired, it means losing the ability to quickly adjust behavior in response to changes in external stimuli and failing to sustain appropriate, goal-oriented motor responses. Our ongoing work is aimed at understanding the mechanisms by which cilia regulate time perception and developing targeted therapies to improve behavioral deficits.”

Reference: “Cilia in the Striatum Mediate Timing-Dependent Functions” by Wedad Alhassen, Sammy Alhassen, Jiaqi Chen, Roudabeh Vakil Monfared and Amal Alachkar, 2 November 2022, Molecular Neurobiology.
DOI: 10.1007/s12035-022-03095-9

The study was funded by the National Institutes of Health.

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70% of drugs advertised on TV are of “low therapeutic value,” study finds

January 17, 2023 Admin Leave a comment

Some new drugs sell themselves with impressive safety and efficacy data. For others, well, there are television commercials.

According to a new study, a little over 70 percent of prescription drugs advertised on television were rated as “low therapeutic value,” meaning they offer little benefit compared with drugs already on the market. The study, appearing in JAMA Open Network, aligns with longstanding skepticism that heavily promoted drugs have high therapeutic value.

“One explanation might be that drugs with substantial therapeutic value are likely to be recognized and prescribed without advertising, so manufacturers have greater incentive to promote drugs of lesser value,” said the authors, which include researchers at Harvard, Yale, and Dartmouth.

The US is one of only two countries that allow direct-to-consumer (DTC) drug advertisements, such as TV commercials. (The other is New Zealand.) Physicians, medical associations, and consumer advocates have long railed against the unusual practice. In 2006, consumer advocacy group Public Citizen summarized DTC advertising as “nothing less than an end-run around the doctor-patient relationship—an attempt to turn patients into the agents of pharmaceutical companies as they pressure physicians for medications they may not need.”

In 2015, the American Medical Association called for an all-out ban on DTC ads for prescription drugs and medical devices. AMA members said the ads were “driving demand for expensive treatments despite the clinical effectiveness of less costly alternatives.”

But DTC drug ads have continued, fueled by billions of dollars from the pharmaceutical industry.

Benefit not added

For the new study, researchers led by Aaron Kesselheim, who leads Harvard’s Program On Regulation, Therapeutics, And Law (PORTAL), looked at monthly lists of the top-advertised drugs on TV in the US between 2015 and 2021.

They also looked up therapeutic value ratings for those drugs from independent health assessment agencies in Canada, France, and Germany. The value ratings were based on drugs’ therapeutic benefit, safety profile, and strength of evidence, as compared with existing drugs. Any drug rating “moderate” or above was classified as a “high value” drug for the study. For drugs with multiple ratings, the study authors used the most favorable rating, which the authors note could overestimate the proportion of higher-benefit drugs.

Of the top advertised drugs, 73 had at least one value rating. Collectively, pharmaceutical companies spent $22.3 billion on advertising for those 73 drugs between 2015 and 2021. Even with the generous ratings, 53 of the 73 drugs (roughly 73 percent) were categorized as low-benefit. Collectively, these low-benefit drugs accounted for $15.9 billion of the ad spending. The top three low-benefit drugs by dollar amount were Dulaglutide (type 2 diabetes), Varenicline (smoking cessation), and Tofacitinib (rheumatoid arthritis).

The outlook for change is bleak, the authors note. “Policy makers and regulators could consider limiting direct-to-consumer advertising to drugs with high therapeutic or public health value or requiring standardized disclosure of comparative effectiveness and safety data,” Kesselheim and his colleagues concluded, “but policy changes would likely require industry cooperation or face constitutional challenge.”

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Alzheimer’s Breakthrough: New Therapeutic Target Found

January 8, 2023 Admin Leave a comment

Alzheimer’s disease is a progressive brain disorder that affects memory, thinking, and behavior. It is the most common cause of dementia among older adults and is characterized by the loss of brain cells and the shrinkage of brain tissue. According to the World Health Organization, Alzheimer’s disease affects about 50 million people worldwide, and this number is expected to triple by 2050.

Researchers from the German Center for Neurodegenerative Diseases (DZNE) have discovered that the protein medin co-aggregates with amyloid-β in the blood vessels of the brains of

The Hertie Institute for Clinical Brain Research in Tübingen, the University of Tübingen, and various international institutions and partners were also involved in this long-term project.

Medin belongs to the group of amyloids. Of these proteins, amyloid-β is best known because it clumps together in the brains of Alzheimer’s patients. These aggregates then deposit both as so-called plaques directly in the brain tissue, but also in its blood vessels, thereby damaging the nerve cells and the blood vessels, respectively. But while many studies have focused on amyloid-β, medin has not been a focus of interest. “There was little evidence of pathology, that is, of a clinically striking finding associated with medin – and that is often the prerequisite for a more in-depth study of an amyloid,” Jonas Neher explains.

However, medin is actually found in the blood vessels of almost everybody over 50 years of age, making it the most common amyloid known. With his team, Jonas Neher originally found that medin even develops in aging mice, and reported this discovery two years ago in the scientific journal PNAS. The older the mice get, the more medin accumulates in the blood vessels of their brains, was the finding at the time. What’s more, when the brain becomes active and triggers an increase in blood supply, vessels with medin deposits expand more slowly than those without medin. This ability of blood vessels to expand, however, is important to optimally supply the brain with oxygen and nutrients.

For their latest results, the researchers built on this foundation and looked specifically at Alzheimer’s disease. First, they were able to show in Alzheimer’s mouse models that medin accumulates even more strongly in the brain’s blood vessels if amyloid-β deposits are also present. Importantly, these findings were confirmed when brain tissue from organ donors with Alzheimer’s dementia was analyzed. However, when mice were genetically modified to prevent medin formation, significantly fewer amyloid-β deposits developed, and as a result, less damage to blood vessels occurred.

“There are only a handful of research groups worldwide working on medin at all,” says Jonas Neher. Most recently, a study from the U.S. reported that medin levels may increase in Alzheimer’s patients. However, it remained unclear whether this increase is merely a consequence of the disease or whether it is one of the causes.

“We have now been able to show through many experiments that medin actually promotes vascular pathology in Alzheimer’s models,” Neher said. So medin deposits are indeed a cause of blood vessel damage. “And this indicates that medin is one of the causes of the disease,” Neher said.

In their studies, the researchers stained tissue sections from both mice and Alzheimer’s patients in such a way that specific proteins become visible. This allowed them to show that medin and amyloid-β are deposited together in blood vessels of the brain – co-localization is the technical term for this. In the next step, they were able to prove that these two amyloids also co-aggregate – that is, form mixed deposits.

“Amazingly, medin interacts directly with amyloid-β and promotes its aggregation – this was completely unknown,” Jonas Neher summarizes the results.

It is precisely from this insight that the researchers draw hope for the development of a new treatment. “Medin could be a therapeutic target to prevent vascular damage and cognitive decline resulting from amyloid accumulation in the blood vessels of the brain,” they conclude. It is undisputed among experts that in addition to amyloid-β aggregates in brain tissue, the development of Alzheimer’s disease is also promoted by vascular alterations – that is, reduced function or damage to blood vessels. Therefore, treatments that target not only plaques but also affected blood vessels could help patients.

Next, it will now be necessary to determine if medin aggregates can be removed therapeutically and whether this intervention actually has an effect on cognitive performance. The scientists first want to test this in mouse models, because these reflect the pathological changes in Alzheimer’s patients very well.

Reference: “Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease” by Jessica Wagner, Karoline Degenhardt, Marleen Veit, Nikolaos Louros, Katerina Konstantoulea, Angelos Skodras, Katleen Wild, Ping Liu, Ulrike Obermüller, Vikas Bansal, Anupriya Dalmia, Lisa M. Häsler, Marius Lambert, Matthias De Vleeschouwer, Hannah A. Davies, Jillian Madine, Deborah Kronenberg-Versteeg, Regina Feederle, Domenico Del Turco, K. Peter R. Nilsson, Tammaryn Lashley, Thomas Deller, Marla Gearing, Lary C. Walker, Peter Heutink, Frederic Rousseau, Joost Schymkowitz, Mathias Jucker and Jonas J. Neher, 16 November 2022, Nature.
DOI: 10.1038/s41586-022-05440-3

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New COVID Subvariant Resistant to All Therapeutic Antibodies

December 20, 2022 Admin Leave a comment

Researchers discovered that neither individual antibodies nor antibody cocktails were able to neutralize the Omicron subvariant BQ.1.1.

The findings indicate that new antibody therapies must be developed.

Are the currently approved antibody therapies used to treat patients who have a higher risk of developing severe

The Omicron subvariants BA.1, BA.4, BA.5 as well as Q.1.1 have a high number of mutations in the spike protein. Some of these mutations are escape mutations that allow the virus to escape neutralization by antibodies. In addition, resistance to biotechnologically produced antibodies, which are administered to high-risk patients as a preventive measure or as therapy for a diagnosed SARS-CoV-2 infection, is also developing. Omicron sub-lineage BQ.1.1 is the first variant resistant to all antibody therapies currently approved by the EMA (European Medicines Agency) and/or FDA (US Food and Drug Administration). Credit: Markus Hoffmann, Deutsches Primatenzentrum

However, certain SARS-CoV-2 variants, notably the Omicron variant, avoid neutralizing antibodies and cause symptomatic infections even in vaccinated or convalescent individuals due to mutations in the spike protein. This is known as immune evasion, and it poses a hazard to high-risk populations including the elderly and people with weakened immune systems, for example, due to illness or medication.

They often fail to develop an immune response sufficient for protection from severe disease, even after full vaccination. To protect high-risk patients, biotechnologically produced antibodies are administered as a preventive measure or as an early therapy upon confirmed SARS-CoV-2 infection. Mutations in the spike protein of different SARS-CoV-2 variants confer resistance to individual antibody therapies. Therefore, it is important to regularly monitor whether therapeutic antibodies continue to be effective against currently circulating viral variants.

A team of researchers from the Infection Biology Unit at the German Primate Center – Leibniz Institute for Primate Research and the Division of Molecular Immunology at the Friedrich-Alexander-University Erlangen-Nürnberg has investigated how efficiently approved antibody therapies inhibit the currently circulating Omicron subvariants. The researchers found that the Omicron subvariant BQ.1.1, which is on the rise worldwide, is resistant to all available antibody therapies.

“For our studies, we mixed non-propagating viral particles carrying the spike protein of selected viral variants with different dilutions of the antibodies to be tested and subsequently measured the amount of antibody needed to inhibit infection of cell cultures. In total, we tested twelve individual antibodies, six of which are approved for clinical use in Europe, and four antibody cocktails” explains Prerna Arora, lead author of the study.

The researchers found that the Omicron subvariant BQ.1.1 could not be neutralized by either individual antibodies or antibody cocktails. In contrast, the currently predominant Omicron subvariant BA.5 was still neutralized by one approved antibody and two approved antibody cocktails.

“With high-risk patients in mind, we are very concerned about the Omicron subvariant BQ.1.1 being resistant to all approved antibody therapies. Particularly in regions where BQ.1.1 is widespread, physicians should not rely on antibody therapies alone when treating infected high-risk patients, but should also consider administering other drugs such as paxlovid or molnupiravir,” comments study leader Markus Hoffmann on the results of the study.

The finding that the Omicron subvariant BQ.1.1 is already resistant to a new antibody therapy that is about to be approved in the U.S. highlights the importance of developing new antibody therapies against COVID-19.

“The ever-increasing development of antibody resistance of SARS-CoV-2 variants calls for the development of new antibody therapies that are specifically targeted to currently circulating and future viral variants. Ideally, they should target regions in the spike protein that have little potential for escape mutations,” concludes Stefan Pöhlmann, head of the Infection Biology Unit at the German Primate Center – Leibniz Institute for Primate Research.

Reference: “Omicron sublineage BQ.1.1 resistance to monoclonal antibodies” by Prerna Arora, Amy Kempf, Inga Nehlmeier, Sebastian R Schulz, Hans-Martin Jäck, Stefan Pöhlmann and Markus Hoffmann, 18 November 2022,

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New Study To Evaluate Psilocybin’s Therapeutic Potential On Autistic Adults

June 4, 2022 Admin Leave a comment

Summary: A new study will explore how psilocybin affects different networks and serotonin function in the brains of autistic adults.

Source: King’s College London

The study will explore how psilocybin affects specific brain pathways in autistic adults, and is the first ever mechanistic study of psilocybin in autistic adults.

It will investigate whether there is a difference in the function of serotonin brain networks in autistic and non-autistic adults.

The researchers will use a range of imaging techniques and behavioural tasks to examine how the serotonin system is modulated by COMP360 psilocybin. It is an investigator-initiated exploratory study that will take place at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London.

The study is co-sponsored by King’s IoPPN and South London and Maudsley NHS Foundation Trust. It will enrol 70 adult participants, including 40 autistic people and 30 non-autistic people.

The study is led by Professor Grainne McAlonan, Professor of Translational Neuroscience at King’s IoPPN, and conducted by Tobias Whelan, PhD student at King’s and Research Scientist at COMPASS Pathways.

Tobias is also supervised by Professor Declan Murphy and Dr Nicolaas Puts from King’s IoPPN, who are investigators in the study. Professor Sir Simon Baron-Cohen and Dr Carrie Allison at the Autism Research Centre at the University of Cambridge are collaborators and external advisors.

“I am delighted that COMPASS Pathways is supporting our investigations into the brain science of neurodiversity.

“Our long-term goal is to provide more and better tailored choices for autistic people and those with related conditions. Before embarking on clinical trials, we need to really understand brain mechanisms in autistic people,” said professor Grainne McAlonan, King’s IoPPN

About this psychopharmacology and ASD research news

Author: Patrick O’Brien
Source: King’s College London
Contact: Patrick O’Brien – King’s College London
Image: The image is in the public domain

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Changing our DNA: ‘The age of human therapeutic gene editing is here’

May 31, 2022 Admin Leave a comment

While Rose spent her short life helping to break down the stigma attached to a devastating illness, geneticist David Liu has dedicated his career to developing ways to alter the genetic code that took her life at such a tender age.

“That a single misspelling in her DNA ended Adalia’s life so early is a loss for all of us,” said Liu, a professor of chemistry and chemical biology and director of the Merkin Institute of Transformative Technologies in Healthcare at Harvard University.

“I did not get the chance to meet Adelia before she passed away in January. But every progeria patient I have met has been warm, charming, articulate and profoundly inspiring,” Liu told CNN.

In his Harvard lab, Liu and his team have invented new ways to repair mutated genes that are less damaging to DNA than prior technologies. One of his lab’s innovations is called a base editor, which he used last year to cure progeria in mice. There are four bases in DNA: adenine (A), cytosine (C), guanine (G) and thymine (T). These form specific pairs: A with T, and G with C.

Liu is hopeful the tool will soon be used in human clinical trials to reverse progeria in people.

“The base editor goes into the cells of the animal, looks for the mistake, which in progeria is a C to a T and changes the T back into a C,” Liu said in advance of his presentation on the topic to the Life Itself conference, a health and wellness event presented in partnership with CNN.

“And that’s it. We never come back into the patient — it’s a one-time treatment that permanently fixes the mutation that causes the disease,” said Liu, who is also vice-chair of faculty at the Broad Institute of MIT and Harvard, a biomedical and genomic research center in Cambridge, Massachusetts.

Six months after announcing success with progeria, Liu and scientists at St. Jude Children’s Research Hospital announced they had used base editors to reverse sickle cell disease in mice.

“The age of human therapeutic gene editing isn’t just coming. It’s already here,” Liu said.

The benefit of a ‘nick’

Scientists edit genes by using enzymes that have been engineered to target a specific sequence in DNA, cut out the offending genetic material and insert replacement DNA. For decades, however, known methods of modifying our genetic code were clumsy, often missing their target or cutting too much or too little genetic material.

The arrival of CRISPR systems in the 1990s and specifically CRISPR-Cas-9 in 2013 heralded a new, more elegant way to edit genes. CRISPR uses what is called guide RNA to get the Cas-9 enzyme to a more precise spot on the DNA strand to make the cut.

After years of vetting, the US Food and Drug Administration approved CRISPR-Cas-9 in 2021 for use in human clinical trials for sickle cell disease. Clinical trials are also underway to test the safety of gene editing in a blood disorder called beta thalassemia, leber congenital amaurosis, which is a form of inherited childhood blindness, blood cancers leukemia and lymphoma, Type 1 diabetes, and HIV/AIDS, to name a few.

In 2021, researchers reported they had successfully edited a rare, painful condition called transthyretin amyloidosis in six people with a single treatment. The fatal disease causes a protein called TTR to fold into clumps and attack the heart and nerves. The study, published in August, reported levels of TTR in some people declined by an average of 87% after treatment.

Like older editing technologies, however, CRISPR-Cas-9 cuts both strands of DNA, which has some disadvantages, Liu said. For one, some cells reversed the changes after they were made, he said, “so the overall efficiency of the editing was very low.”

Liu’s team discovered that if you cut only one strand of the DNA double helix with CRISPR-based technology and “nick” the other, the cell was more likely to implement the corresponding change on the second strand without complaint — and with fewer mistakes.

Editing larger sequences of DNA

Liu and his team also invented another type of CRISPR-based tool called a prime editor, which could make larger, more complex edits to DNA that base editors could not.

In tests using human cells grown in the lab, Liu’s team used prime editing to correct the genes responsible for Tay-Sachs disease, a fatal neurological disorder that attacks in the first few months of life. Children with Tay-Sachs typically die within a few years after symptoms begin.

“An analogy I like to use is that the original CRISPR-Cas_9 is like scissors that cut DNA. Base editors are like pencils that precisely correct letters by changing them to one of four different letters,” Liu explained. “And prime editors are like molecular word processors that do a true search and replace of larger sequences.”

Only a third of the 75,000 known “misspellings” that cause genetic disease can be corrected by base editors, Liu said. “But add in our prime editor, and between the two they can finally liberate us from being beholden to the vast majority of misspellings in our DNA,” he said.

“We have to make sure all of these different technologies go through clinical trials very carefully,” Liu added. “But if they prove to be safe and efficacious, then one could imagine treating not just rare misspellings that cause grievous genetic diseases, but perhaps even treating gene variants we know contribute to terrible diseases like Alzheimer’s disease or high cholesterol.”

In a 2019 blog post, former National Institutes of Health director Dr. Francis Collins called prime editing “revolutionary,” saying Liu and his team had “used their new system to insert new DNA segments up to 44 letters long and to remove segments at least 80 letters long.”

However, Collins added, “It’s unclear if prime editing can insert or remove DNA that’s the size of full-length genes — which may contain up to 2.4 million letters.”

Genetic editing will not be a solution for all of life’s illness, Liu cautioned. For example, infections and cancer cells are two areas that are not well matched for gene editing, because you would need to touch each cell to stop the illness.

“But with many genetic diseases, we often only need to edit 20% or 30% of tissue to rescue the genetic disease,” Liu said. “That’s what we saw with progeria and sickle cell disease in mice. A little bit of editing can go a long way to rescue these diseases in animals, and we think in people as well.”

Correction: An earlier version of this story incorrectly attributed comments by Liu as made during the Life Itself conference. They were from an interview.

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Changing our DNA: ‘The age of human therapeutic gene editing is here’

May 31, 2022 Admin Leave a comment

“I did not get the chance to meet Adelia before she passed away in January. But every progeria patient I have met has been warm, charming, articulate and profoundly inspiring,” Liu told CNN.

Liu is hopeful the tool will soon be used in human clinical trials to reverse progeria in people.

“The base editor goes into the cells of the animal, looks for the mistake, which in progeria is a C to a T and changes the T back into a C,” Liu told an audience Tuesday at the Life Itself conference, a health and wellness event presented in partnership with CNN.

Six months after announcing success with progeria, Liu and scientists at St. Jude Children’s Research Hospital announced they had used base editors to reverse sickle cell disease in mice.

“The age of human therapeutic gene editing isn’t just coming. It’s already here,” Liu told the Life Itself audience.

The benefit of a ‘nick’

Editing larger sequences of DNA

Liu and his team also invented another type of CRISPR-based tool called a prime editor, which could make larger, more complex edits to DNA that base editors could not.

However, Collins added, “It’s unclear if prime editing can insert or remove DNA that’s the size of full-length genes — which may contain up to 2.4 million letters.”

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Tag Archives: therapeutic

Scientists Reveal New Potential Therapeutic Targets for Mental and Neurological Disorders

UCI researchers have discovered the crucial role of cilia in the striatum of the brain in time perception.

70% of drugs advertised on TV are of “low therapeutic value,” study finds

Benefit not added

Alzheimer’s Breakthrough: New Therapeutic Target Found

New COVID Subvariant Resistant to All Therapeutic Antibodies

The findings indicate that new antibody therapies must be developed.

New Study To Evaluate Psilocybin’s Therapeutic Potential On Autistic Adults

About this psychopharmacology and ASD research news

Changing our DNA: ‘The age of human therapeutic gene editing is here’

The benefit of a ‘nick’

Editing larger sequences of DNA

Changing our DNA: ‘The age of human therapeutic gene editing is here’

The benefit of a ‘nick’

Editing larger sequences of DNA

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