Healthcare analytics, AI solutions for biological big data, providing an AI platform for the biotech, life sciences, medical and pharmaceutical industries, as well as for related technological approaches, i.e., curation and text analysis with machine learning and other activities related to AI applications to these industries.
Article SELECTION from Collection of Aviva Lev-Ari, PhD, RN Scientific Articles on PULSE on LinkedIn.com for Training Small Language Models (SLMs) in Domain-aware Content of Medical, Pharmaceutical, Life Sciences and Healthcare by 15 Subjects Matter
Article selection: Aviva Lev-Ari, PhD, RN
#1 – February 20, 2016
Contributions to Personalized and Precision Medicine & Genomic Research
Cancer Surgery Rethought: Immunotherapy Takes the Lead
Curator: Dr. Sudipta Saha, Ph.D.
In a recent phase 2 study published in The New England Journal of Medicine, the efficacy of nonoperative management was assessed in patients with mismatch repair–deficient (dMMR) solid tumors. Instead of undergoing curative-intent surgery, patients with stage I to III dMMR tumors were administered immune checkpoint inhibitors.
The study was conducted across two cohorts involving 117 patients. After two years of follow-up, a recurrence-free survival rate of 92% (95% CI, 86 to 99) was achieved. It was found that complete clinical responses could be maintained without surgical intervention, and substantial preservation of organ function was observed.
The avoidance of surgery was associated with fewer treatment-related complications and a significant improvement in patients’ quality of life. It has been emphasized that dMMR tumors, being highly immunogenic, respond exceptionally well to immune checkpoint blockade, thereby offering a viable alternative to conventional surgery-based treatment plans.
While the study’s findings have been considered ground breaking, long-term data have been recommended to fully validate this approach. Future studies are expected to refine patient selection criteria and monitoring strategies to ensure sustained outcomes.
Overall, a potential shift in the standard of care for patients with early-stage dMMR tumors has been proposed, highlighting how personalized immunotherapy can redefine oncological practice.
Shaping the Future: The Rise of Structural Nanomedicine
Curator: Dr. Sudipta Saha, Ph.D.
In their 2025 review, Mirkin, Mrksich, and Artzi describe how the field of structural nanomedicine is being transformed to revolutionize biomedical science. Therapeutic materials are now being designed with precise nanoscale architectures to optimize biological interactions, improve efficacy, and reduce side effects.
It is explained that, unlike traditional drug delivery methods, structural nanomedicine is centered on the engineering of form and function at the molecular level. Advances in DNA and RNA nanotechnology, self-assembling peptide systems, and engineered nanoparticles have been utilized to create customizable platforms capable of navigating complex biological environments. These structures are being programmed to respond to specific physiological triggers, thereby enabling targeted delivery and controlled release.
A strong emphasis is placed on how rational design principles—borrowed from materials science, chemistry, and bioengineering—are driving innovation. Examples are presented where precisely constructed nanostructures have been shown to outperform conventional therapies in cancer treatment, immunomodulation, and regenerative medicine.
Attention is drawn to the challenges that must still be addressed, including the scalability of manufacturing, regulatory barriers, and the need for deeper insights into nano-bio interactions at the systems level. It is argued that interdisciplinary collaboration will be required for the successful translation of structural nanomedicine from laboratory research to clinical application.
Ultimately, structural nanomedicine is portrayed as a paradigm shift—where passive carrier systems are being replaced by dynamic, functional architectures that actively engage in therapeutic processes. Optimism is expressed that through continued technological convergence, a new generation of precision therapies tailored to individual patients will be realized.
This review is recommended for researchers, clinicians, and industry professionals seeking to remain informed about future directions in biomedical innovation.
Nobel Prize in Chemistry 2024 to David Baker, Demis Hassabis and John M. Jumper
Reporter: Aviva Lev-Ari, PhD, RN
UPDATED on 10/22/2024
ProteinMPNN, which is now available free on the open-source software repository GitHub, will give researchers the tools to make unlimited new designs. “The challenge, of course … is what are you going to design?” Baker says.
In a second Nobel win for AI, the Royal Swedish Academy of Sciences has awarded half the 2024 prize in chemistry to Demis Hassabis, the cofounder and CEO of Google DeepMind, and John M. Jumper, a director at the same company, for their work on using artificial intelligence to predict the structures of proteins. The other half goes to David Baker, a professor of biochemistry at the University of Washington, for his work on computational protein design. The winners will share a prize pot of 11 million Swedish kronor ($1 million).
The potential impact of this research is enormous. Proteins are fundamental to life, but understanding what they do involves figuring out their structure—a very hard puzzle that once took months or years to crack for each type of protein. By cutting down the time it takes to predict a protein’s structure, computational tools such as those developed by this year’s award winners are helping scientists gain a greater understanding of how proteins work and opening up new avenues of research and drug development. The technology could unlock more efficient vaccines, speed up research on cures for cancer, or lead to completely new materials.
Hassabis and Jumper created AlphaFold, which in 2020 solved a problem scientists have been wrestling with for decades: predicting the three-dimensional structure of a protein from a sequence of amino acids. The AI tool has since been used to predict the shapes of all proteins known to science.
“I’ve dedicated my career to advancing AI because of its unparalleled potential to improve the lives of billions of people,” said Demis Hassabis. “AlphaFold has already been used by more than two million researchers to advance critical work, from enzyme design to drug discovery. I hope we’ll look back on AlphaFold as the first proof point of AI’s incredible potential to accelerate scientific discovery,” he added.
Baker has created several AI tools for designing and predicting the structure of proteins, such as a family of programs called Rosetta. In 2022, his lab created an open-source AI tool called ProteinMPNN that could help researchers discover previously unknown proteins and design entirely new ones. It helps researchers who have an exact protein structure in mind find amino acid sequences that fold into that shape.
Most recently, in late September, Baker’s lab announced it had developed custom molecules that allow scientists to precisely target and eliminate proteins associated with diseases in living cells.
“[Proteins] evolved over the course of evolution to solve the problems that organisms faced during evolution. But we face new problems today, like covid. If we could design proteins that were as good at solving new problems as the ones that evolved during evolution are at solving old problems, it would be really, really powerful,” Baker told MIT Technology Review in 2022.
born 1962 in Seattle, WA, USA. PhD 1989 from University of California, Berkeley, CA, USA. Professor at University of Washington, Seattle, WA, USA and Investigator, Howard Hughes Medical Institute, USA.
University of Washington, Seattle, WA, USA
Howard Hughes Medical Institute, USA
Demis Hassabis “for protein structure prediction”
born 1976 in London, UK. PhD 2009 from University College London, UK. CEO of Google DeepMind, London, UK.
Google DeepMind, London, UK
John M. Jumper “for protein structure prediction”
born 1985 in Little Rock, AR, USA. PhD 2017 from University of Chicago, IL, USA. Senior Research Scientist at Google DeepMind, London, UK.
Google DeepMind, London, UK
The Nobel Prize in Chemistry 2024 is about proteins, life’s ingenious chemical tools. David Baker has succeeded with the almost impossible feat of building entirely new kinds of proteins. Demis Hassabis and John Jumper have developed an AI model to solve a 50-year-old problem: predicting proteins’ complex structures. These discoveries hold enormous potential.
“One of the discoveries being recognised this year concerns the construction of spectacular proteins. The other is about fulfilling a 50-year-old dream: predicting protein structures from their amino acid sequences. Both of these discoveries open up vast possibilities,” says Heiner Linke, Chair of the Nobel Committee for Chemistry.
Proteins generally consist of 20 different amino acids, which can be described as life’s building blocks. In 2003, David Baker succeeded in using these blocks to design a new protein that was unlike any other protein. Since then, his research group has produced one imaginative protein creation after another, including proteins that can be used as pharmaceuticals, vaccines, nanomaterials and tiny sensors.
The second discovery concerns the prediction of protein structures. In proteins, amino acids are linked together in long strings that fold up to make a three-dimensional structure, which is decisive for the protein’s function. Since the 1970s, researchers had tried to predict protein structures from amino acid sequences, but this was notoriously difficult. However, four years ago, there was a stunning breakthrough.
In 2020, Demis Hassabis and John Jumper presented an AI model called AlphaFold2. With its help, they have been able to predict the structure of virtually all the 200 million proteins that researchers have identified. Since their breakthrough, AlphaFold2 has been used by more than two million people from 190 countries. Among a myriad of scientific applications, researchers can now better understand antibiotic resistance and create images of enzymes that can decompose plastic.
Life could not exist without proteins. That we can now predict protein structures and design our own proteins confers the greatest benefit to humankind.
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This year’s Nobel Prize laureates in chemistry Demis Hassabis and John Jumper have developed an AI model to solve a 50-year-old problem: predicting proteins’ complex structures.
In 2020, Hassabis and Jumper presented an AI model called AlphaFold2. With its help, they have been able to predict the structure of virtually all the 200 million proteins that researchers have identified. Since their breakthrough, AlphaFold2 has been used by more than two million people from 190 countries. Among a myriad of scientific applications, researchers can now better understand antibiotic resistance and create images of enzymes that can decompose plastic.
Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use
In this curation we wish to present two breaking through goals:
Goal 1:
Exposition of a new direction of research leading to a more comprehensive understanding of Metabolic Dysfunctional Diseases that are implicated in effecting the emergence of the two leading causes of human mortality in the World in 2023: (a) Cardiovascular Diseases, and (b) Cancer
Goal 2:
Development of Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics for these eight subcellular causes of chronic metabolic diseases. It is anticipated that it will have a potential impact on the future of Pharmaceuticals to be used, a change from the present time current treatment protocols for Metabolic Dysfunctional Diseases.
According to Dr. Robert Lustig, M.D, an American pediatric endocrinologist. He is Professor emeritus of Pediatrics in the Division of Endocrinology at the University of California, San Francisco, where he specialized in neuroendocrinology and childhood obesity, there are eight subcellular pathologies that drive chronic metabolic diseases.
These eight subcellular pathologies can’t be measured at present time.
In this curation we will attempt to explore methods of measurement for each of these eight pathologies by harnessing the promise of the emerging field known as Bioelectronics.
Unmeasurable eight subcellular pathologies that drive chronic metabolic diseases
Glycation
Oxidative Stress
Mitochondrial dysfunction [beta-oxidation Ac CoA malonyl fatty acid]
Insulin resistance/sensitive [more important than BMI], known as a driver to cancer development
Membrane instability
Inflammation in the gut [mucin layer and tight junctions]
Epigenetics/Methylation
Autophagy [AMPKbeta1 improvement in health span]
Diseases that are not Diseases: no drugs for them, only diet modification will help
Image source
Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease
These eight Subcellular Pathologies driving Chronic Metabolic Diseases are becoming our focus for exploration of the promise of Bioelectronics for two pursuits:
Will Bioelectronics be deemed helpful in measurement of each of the eight pathological processes that underlie and that drive the chronic metabolic syndrome(s) and disease(s)?
IF we will be able to suggest new measurements to currently unmeasurable health harming processes THEN we will attempt to conceptualize new therapeutic targets and new modalities for therapeutics delivery – WE ARE HOPEFUL
In the Bioelecronics domain we are inspired by the work of the following three research sources:
Michael Levin is an American developmental and synthetic biologist at Tufts University, where he is the Vannevar Bush Distinguished Professor. Levin is a director of the Allen Discovery Center at Tufts University and Tufts Center for Regenerative and Developmental Biology. Wikipedia
THE VOICE of Dr. Justin D. Pearlman, MD, PhD, FACC
PENDING
THE VOICE of Stephen J. Williams, PhD
Ten TakeAway Points of Dr. Lustig’s talk on role of diet on the incidence of Type II Diabetes
25% of US children have fatty liver
Type II diabetes can be manifested from fatty live with 151 million people worldwide affected moving up to 568 million in 7 years
A common myth is diabetes due to overweight condition driving the metabolic disease
There is a trend of ‘lean’ diabetes or diabetes in lean people, therefore body mass index not a reliable biomarker for risk for diabetes
Thirty percent of ‘obese’ people just have high subcutaneous fat. the visceral fat is more problematic
there are people who are ‘fat’ but insulin sensitive while have growth hormone receptor defects. Points to other issues related to metabolic state other than insulin and potentially the insulin like growth factors
At any BMI some patients are insulin sensitive while some resistant
Visceral fat accumulation may be more due to chronic stress condition
Fructose can decrease liver mitochondrial function
A methionine and choline deficient diet can lead to rapid NASH development
Mimicking vaginal cells and microbiome interactions on chip microfluidic culture
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Scientists at Harvard University’s Wyss Institute for Biologically Inspired Engineering have developed the world’s first “vagina-on-a-chip,” which uses living cells and bacteria to mimic the microbial environment of the human vagina. It could help to test drugs against bacterial vaginosis, a common microbial imbalance that makes millions of people more susceptible to sexually transmitted diseases and puts them at risk of preterm delivery when pregnant. Vaginal health is difficult to study in a laboratory setting partly because laboratory animals have “totally different microbiomes” than humans. To address this, scientists have created an unique chip, which is an inch-long, rectangular polymer case containing live human vaginal tissue from a donor and a flow of estrogen-carrying material to simulate vaginal mucus.
The organs-on-a-chip mimic real bodily function, making it easier to study diseases and test drugs. Previous examples include models of the lungs and the intestines. In this case, the tissue acts like that of a real vagina in some important ways. It even responds to changes in estrogen by adjusting the expression of certain genes. And it can grow a humanlike microbiome dominated by “good” or “bad” bacteria. The researchers have demonstrated that Lactobacilli growing on the chip’s tissue help to maintain a low pH by producing lactic acid. Conversely, if the researchers introduce Gardnerella, the chip develops a higher pH, cell damage and increased inflammation: classic bacterial vaginosis signs. So, the chip can demonstrate how a healthy / unhealthy microbiome affects the vagina.
The next step is personalization or subject specific culture from individuals. The chip is a real leap forward, it has the prospect of testing how typical antibiotic treatments against bacterial vaginosis affect the different bacterial strains. Critics of organ-on-a-chip technology often raise the point that it models organs in isolation from the rest of the body. There are limitations such as many researchers are interested in vaginal microbiome changes that occur during pregnancy because of the link between bacterial vaginosis and labor complications. Although the chip’s tissue responds to estrogen, but it does not fully mimic pregnancy without feedback loops from other organs. The researchers are already working on connecting the vagina chip to a cervix chip, which could better represent the larger reproductive system.
All these information indicate that the human vagina chip offers a new model to study host-vaginal microbiome interactions in both optimal and non-optimal states, as well as providing a human relevant preclinical model for development and testing of reproductive therapeutics, including live bio-therapeutics products for bacterial vaginosis. This microfluidic human vagina chip that enables flow through an open epithelial lumen also offers a unique advantage for studies on the effect of cervicovaginal mucus on vaginal health as clinical mucus samples or commercially available mucins can be flowed through this channel. The role of resident and circulating immune cells in host-microbiome interactions also can be explored by incorporating these cells into the vagina chip in the future, as this has been successfully done in various other organ chip models.
2022 FDA Drug Approval List, 2022 Biological Approvals and Approved Cellular and Gene Therapy Products
Reporter: Aviva Lev-Ari, PhD, RN
SOURCE
Tal Bahar’s post on LinkedIn on 1/17/2023
Novel Drug Approvals for 2022
FDA’s Center for Drug Evaluation and Research (CDER)
New Molecular Entities (“NMEs”)
Some of these products have never been used in clinical practice. Below is a listing of new molecular entities and new therapeutic biological products that CDER approved in 2022. This listing does not contain vaccines, allergenic products, blood and blood products, plasma derivatives, cellular and gene therapy products, or other products that the Center for Biologics Evaluation and Research approved in 2022.
Others are the same as, or related to, previously approved products, and they will compete with those products in the marketplace. See Drugs@FDA for information about all of CDER’s approved drugs and biological products.
Certain drugs are classified as new molecular entities (“NMEs”) for purposes of FDA review. Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient drug or as part of a combination product. These products frequently provide important new therapies for patients. Some drugs are characterized as NMEs for administrative purposes, but nonetheless contain active moieties that are closely related to active moieties in products that FDA has previously approved. FDA’s classification of a drug as an “NME” for review purposes is distinct from FDA’s determination of whether a drug product is a “new chemical entity” or “NCE” within the meaning of the Federal Food, Drug, and Cosmetic Act.
To treat adults with HIV whose HIV infections cannot be successfully treated with other available treatments due to resistance, intolerance, or safety considerations Press Release
To decrease the incidence of infection in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia
The Center for Biologics Evaluation and Research (CBER) regulates products under a variety of regulatory authorities. See the Development & Approval Process page for a description of what products are approved as Biologics License Applications (BLAs), Premarket Approvals (PMAs), New Drug Applications (NDAs) or 510Ks.
Biologics License Applications and Supplements
New BLAs (except those for blood banking), and BLA supplements that are expected to significantly enhance the public health (e.g., for new/expanded indications, new routes of administration, new dosage formulations and improved safety).
Other Applications Approved or Cleared by the Center for Biologics Evaluation and Research (CBER)
Medical devices involved in the collection, processing, testing, manufacture and administration of licensed blood, blood components and cellular products.
There are five FDA-approved CAR-T treatments for blood cancers and two gene therapies to treat rare diseases now on the market in the U.S. The late-stage pipeline could produce several more cancer CAR-Ts and gene therapies to treat a range of diseases.
One of the biggest races to watch in the cell therapy space will be that between Gilead Sciences’ Yescarta and Bristol Myers Squibb’s Breyanzi, both of which are gunning to move their CAR-Ts into earlier lines of treatment in large B-cell lymphoma (LBCL). At ASH, both companies rolled out impressive data from their trials in the second-line setting, but Gilead could have the upper hand by virtue of its three-year head start in the market, analysts said. Gilead expects to hear from the FDA on a label expansion in the second-line setting in April.
New avenues for research in membrane biology reveals the mobility of protein at work
Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc
Membrane proteins(MPs) are proteins that exist in the plasma membrane and conduct a variety of biological functions such as ion transport, substrate transport, and signal transduction. MPs undergo function-related conformational changes on time intervals spanning from nanoseconds to seconds. Many MP structures have been solved thanks to recent developments in structural biology, particularly in single-particle cryo-Electron Microscopy (cryo-EM). Obtaining time-resolved dynamic information on MPs in their membrane surroundings, on the other hand, remains a significant difficulty.
OmpG (Open state) in a fully hydrated dimyristoylphosphatidylcholine (DMPC) bilayer. The protein is shown in light green cartoon. Lipids units are depicted in yellow, while their phosphate and choline groups are illustrated as orange and green van der Waals spheres, respectively. Potassium and chloride counterions are shown in green and purple, respectively. A continuous and semi-transparent cyan representation is used for water. https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-021-24660-1/MediaObjects/41467_2021_24660_MOESM1_ESM.pdf
Weill Cornell Medicine (WCM) researchers have found that they can record high-speed protein movements while linking them to function. The accomplishment should allow scientists to examine proteins in more depth than ever before, and in theory, it should allow for the development of drugs that work better by hitting their protein targets much more effectively.
The researchers utilized High-Speed Atomic Force Microscopy (HS-AFM) to record the rapid motions of a channel protein and published in a report in Nature Communications on July 16. Such proteins generally create channel or tube-like structures in cell membranes, which open to allow molecules to flow under particular conditions. The researchers were able to record the channel protein’s rapid openings and closings with the same temporal resolution as single channel recordings, a typical technique for recording the intermittent passage of charged molecules through the channel.
Senior author Simon Scheuring, professor of physiology and biophysics in anesthesiology at WCM, said,
There has been a significant need for a tool like this that achieves such a high bandwidth that it can ‘see’ the structural variations of molecules as they work.
Researchers can now produce incredibly detailed photographs of molecules using techniques like X-ray crystallography and electron microscopy, showing their structures down to the atomic scale. The average or dominant structural positionings, or conformations, of the molecules, are depicted in these “images,” which are often calculated from thousands of individual photos. In that way, they’re similar to the long-exposure still photos from the dawn of photography.
Many molecules, on the other hand, are flexible and always-moving machinery rather than fixed structures. Scientists need to generate videos, not still photos, to reveal how such molecules move as they work, to see how their motion translates to function to catch their critical functional conformations, which may only exist for a brief moment. Current techniques for dynamic structural imaging, on the other hand, have several drawbacks, one of which being the requirement for fluorescent tags to be inserted on the molecules being photographed in many cases.
Scheuring and his lab were early adopters of the tag-free HS-AFM approach for studying molecular dynamics. The technology, which can photograph molecules in a liquid solution similar to a genuine cellular environment, employs an extremely sensitive probe, similar to a record player’s stylus, to feel its way over a molecule and therefore build up a picture of its structure. Standard HS-AFM isn’t quick enough to capture the high-speed dynamics of many proteins, but Scheuring and colleagues have developed a modified version, HS-AFM height spectroscopy(HS-AFM-HS), that works much faster by collecting dynamic changes in only one dimension: height.
The researchers used HS-AFM-HS to record the opening and closing of a relatively simple channel protein, OmpG, found in bacteria and widely studied as a model channel protein in the new study, led by the first author Raghavendar Reddy Sanganna Gari, a postdoctoral research associate in Scheuring’s laboratory. They were able to monitor OmpG gating at an effective rate of roughly 20,000 data points per second, seeing how it transitioned from open to closed states or vice versa as the acidity of the surrounding fluid varied.
More significantly, they were able to correlate structural dynamics with functional dynamics in a membrane protein of this size for the first time in a partnership with Crina Nimigean, professor of physiology and biophysics in anesthesiology, and her group at WCM.
The demonstration opens the door for a wider application of this method in basic biology and drug development.
Sanganna Gari stated,
We’re now in an exciting period of HS-AFM technology, for example using this technique to study how some drugs modulate the structural dynamics of the channel proteins they target.
Main Source
Technique reveals proteins moving as they work. By Jim Schnabel in Cornell Chronicle, August 16, 2021.
Despite heated discussion over whether it works, the FDA has approved Aduhelm, bringing a new ray of hope to the Alzheimer’s patients.
Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc
Despite heated discussion over whether it works, the FDA has approved Aduhelm, bringing a new ray of hope to the Alzheimer’s patients.
On Monday, 7th June 2021, a controversial new Alzheimer’sDisease treatment was licensed in the United States for the first time in nearly 20 years, sparking calls for it to be made available worldwide despite conflicting evidence about its usefulness. The drug was designed for people with mild cognitive impairment, not severe dementia, and it was designed to delay the progression of Alzheimer’s disease rather than only alleviate symptoms.
The route to FDA clearance for Aducanumab has been bumpy – and contentious.
Though doctors, patients, and the organizations that assist them are in desperate need of therapies that can delay mental decline, scientists question the efficacy of the new medicine, Aducanumab or Aduhelm. In March 2019, two trials were halted because the medications looked to be ineffective. “The futility analysis revealed that the studies were most likely to fail,” said Isaacson of Weill Cornell Medicine and NewYork-Presbyterian. Biogen, the drug’s manufacturer revealed several months later that a fresh analysis with more participants found that individuals who got high doses of Aducanumab exhibited a reduction in clinical decline in one experiment. Patients treated with high-dose Aducanumab had 22% reduced clinical impairment in their cognitive health at 18 months, indicating that the advancement of their early Alzheimer’s disease was halted, according to FDA briefing documents from last year.
When the FDA’s members were split on the merits of the application in November, it was rejected. Three of its advisers went public, claiming that there was insufficient evidence that it worked in a scientific journal. They were concerned that if the medicine was approved, it might reduce the threshold for future approvals, owing to the scarcity of Alzheimer’s treatments.
Dr. Caleb Alexander, a drug safety and effectiveness expert at the Johns Hopkins Bloomberg School of Public Health, was one of the FDA advisers who was concerned that the data presented to the agency was a reanalysis after the experiment was stopped. It was “like the Texas sharpshooter fallacy,” he told the New York Times, “where the sharpshooter blows up a barn and then goes and paints a bullseye around the cluster of holes he loves.”
Some organizations, such as the non-profit Public Citizen’s Health Research Group, claimed that the FDA should not approve Aducanumab for the treatment of Alzheimer’s disease because there is insufficient proof of its efficacy.
The drug is a monoclonal antibody that inhibits the formation of amyloid protein plaques in the brain, which are thought to be the cause of Alzheimer’s disease. The majority of Alzheimer’s medications have attempted to erase these plaques.
Aducanumab appears to do this in some patients, but only when the disease is in its early stages. This means that people must be checked to see if they have the disease. Many persons with memory loss are hesitant to undergo testing because there is now no treatment available.
The few Alzheimer’s medications available appear to have limited effectiveness. When Aricept, also known as Donepezil, was approved more than 20 years ago, there was a major battle to get it. It was heralded as a breakthrough at the time – partly due to the lack of anything else. It has become obvious that it slows mental decline for a few months but makes little effect in the long run.
The findings of another trial for some patients backed up those conclusions.
Biogen submitted a Biologics License Application to the FDA in July 2020, requesting approval of the medicine.
The FDA’s decision has been awaited by Alzheimer’s disease researchers, clinicians, and patients since then.
Support for approval of the drug
Other groups, such as the Alzheimer’s Association, have supported the drug’s approval.
The Alzheimer’s Association‘s website stated on Friday, “This is a critical time, regardless of the FDA’s final judgment. We’ve never been this close to approving an Alzheimer’s drug that could affect the disease’s development rather than just the symptoms. We can keep working together to achieve our goal of a world free of Alzheimer’s disease and other dementias.”
The drug has gotten so much attention that the Knight Alzheimer Disease Research Center at Washington University in St. Louis issued a statement on Friday stating that even if it is approved, “it will still likely take several months for the medication to pass other regulatory steps and become available to patients.”
Biogen officials told KGO-TV on Monday that the medicine will be ready to ship in about two weeks and that they have identified more than 900 facilities across the United States that they feel will be medically and commercially suitable.
Officials stated the corporation will also provide financial support to qualifying patients so that their out-of-pocket payments are as low as possible. Biogen has also pledged not to raise the price for at least the next four years.
Most Medicare customers with supplemental plans, according to the firm, will have a limited or capped co-pay.
Case studies connected to the Drug Approval
Case 1
Ann Lange, one of several Chicago-area clinical trial volunteers who received the breakthrough Alzheimer’s treatment, said,
It really offers us so much hope for a long, healthy life.
Lange, 60, has Alzheimer’s disease, which she was diagnosed with five years ago. Her memory has improved as a result of the monthly infusions, she claims.
She said,
I’d forget what I’d done in the shower, so I’d scribble ‘shampoo, conditioner, face, body’ on the door. Otherwise, I’d lose track of what I’m doing “Lange remarked. “I’m not required to do that any longer.
Case 2
Jenny Knap, 69, has been receiving infusions of the Aducanumab medication for about a year as part of two six-month research trials. She told CNN that she had been receiving treatment for roughly six months before the trial was halted in 2019, and that she had recently resumed treatment.
Knap said,
I can’t say I noticed it on a daily basis, but I do think I’m doing a lot better in terms of checking for where my glasses are and stuff like that.
When Knap was diagnosed with mild cognitive impairment, a clinical precursor to Alzheimer’s disease, in 2015, the symptoms were slight but there.
Her glasses were frequently misplaced, and she would repeat herself, forgetting previous talks, according to her husband, Joe Knap.
Joe added,
We were aware that things were starting to fall between the cracks as these instances got more often
Jenny went to the Lou Ruvo Center for Brain Health at the Cleveland Clinic in Ohio for testing and obtained her diagnosis. Jenny found she was qualified to join in clinical trials for the Biogen medicine Aducanumab at the Cleveland Clinic a few years later, in early 2017. She volunteered and has been a part of the trial ever since.
It turns out that Jenny was in the placebo category for the first year and a half, Joe explained, meaning she didn’t get the treatment.
They didn’t realize she was in the placebo group until lately because the trial was blind. Joe stated she was given the medicine around August 2018 and continued until February 2019 as the trial progressed. The trial was halted by Biogen in March 2019, but it was restarted last October, when Jenny resumed getting infusions.
Jenny now receives Aducanumab infusions every four weeks at the Cleveland Clinic, which is roughly a half-hour drive from their house, with Joe by her side. Jenny added that, despite the fact that she has only recently begun therapy, she believes it is benefiting her, combined with a balanced diet and regular exercise (she runs four miles).
The hope of Aducanumab is to halt the progression of the disease rather than to improve cognition. We didn’t appreciate any significant reduction in her condition, Jenny’s doctor, Dr. Babak Tousi, who headed Aducanumab clinical studies at the Cleveland Clinic, wrote to CNN in an email.
This treatment is unlike anything we’ve ever received before. There has never been a drug that has slowed the growth of Alzheimer’s disease, he stated, Right now, existing medications like donepezil and memantine aid with symptoms but do not slow the disease’s progression.
Jenny claims that the medicine has had no significant negative effects on her.
There was signs of some very minor bleeding in the brain at one point, which was quite some time ago. It was at very low levels, in fact, Joe expressed concern about Jenny, but added that the physicians were unconcerned.
According to Tousi, with repeated therapy, “blood vessels may become leaky, allowing fluid and red blood cells to flow out to the surrounding area,” and “micro hemorrhages have been documented in 19.1% of trial participants who got” the maximal dose of therapy”.
Jenny and Joe’s attitude on the future has improved as a result of the infusions and keeping a healthy lifestyle, according to Joe. They were also delighted to take part in the trial, which they saw as an opportunity to make a positive influence in other people’s lives.
There was this apprehension of what was ahead before we went into the clinical trial, Joe recalled. “The medical aspect of the infusion gives us reason to be optimistic. However, doing the activity on a daily basis provides us with immediate benefits.”
The drug’s final commercialization announcement
Aducanumab, which will be marketed as Aduhelm, is a monthly intravenous infusion that is designed to halt cognitive decline in patients with mild memory and thinking issues. It is the first FDA-approved medication for Alzheimer’s disease that targets the disease process rather than just the symptoms.
The manufacturer, Biogen, stated Monday afternoon that the annual list price will be $56,000. In addition, diagnostic tests and brain imaging will very certainly cost tens of thousands of dollars.
The FDA approved approval for the medicine to be used but ordered Biogen to conduct a new clinical trial, recognizing that prior trials of the medicine had offered insufficient evidence to indicate effectiveness.
Biogen Inc said on Tuesday that it expects to start shipping Aduhelm, a newly licensed Alzheimer’s medicine, in approximately two weeks and that it has prepared over 900 healthcare facilities for the intravenous infusion treatment.
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Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development
Reporter:Amandeep Kaur, B.Sc., M.Sc.
In early February, Prof. Eran Segal updated in one of his tweets and mentioned that “We say with caution, the magic has started.”
The article reported that this statement by Prof. Segal was due to decreasing cases of COVID-19, severe infection cases and hospitalization of patients by rapid vaccination process throughout Israel. Prof. Segal emphasizes in another tweet to remain cautious over the country and informed that there is a long way to cover and searching for scientific solutions.
A daylong webinar entitled “COVID-19: The epidemic that rattles the world” was a great initiative by Weizmann Institute to share their scientific knowledge about the infection among the Israeli institutions and scientists. Prof. Gideon Schreiber and Dr. Ron Diskin organized the event with the support of the Weizmann Coronavirus Response Fund and Israel Society for Biochemistry and Molecular Biology. The speakers were invited from the Hebrew University of Jerusalem, Tel-Aviv University, the Israel Institute for Biological Research (IIBR), and Kaplan Medical Center who addressed the molecular structure and infection biology of the virus, treatments and medications for COVID-19, and the positive and negative effect of the pandemic.
The article reported that with the emergence of pandemic, the scientists at Weizmann started more than 60 projects to explore the virus from different range of perspectives. With the help of funds raised by communities worldwide for the Weizmann Coronavirus Response Fund supported scientists and investigators to elucidate the chemistry, physics and biology behind SARS-CoV-2 infection.
Prof. Avi Levy, the coordinator of the Weizmann Institute’s coronavirus research efforts, mentioned “The vaccines are here, and they will drastically reduce infection rates. But the coronavirus can mutate, and there are many similar infectious diseases out there to be dealt with. All of this research is critical to understanding all sorts of viruses and to preempting any future pandemics.”
The following are few important projects with recent updates reported in the article.
Mapping a hijacker’s methods
Dr. Noam Stern-Ginossar studied the virus invading strategies into the healthy cells and hijack the cell’s systems to divide and reproduce. The article reported that viruses take over the genetic translation system and mainly the ribosomes to produce viral proteins. Dr. Noam used a novel approach known as ‘ribosome profiling’ as her research objective and create a map to locate the translational events taking place inside the viral genome, which further maps the full repertoire of viral proteins produced inside the host.
She and her team members grouped together with the Weizmann’s de Botton Institute and researchers at IIBR for Protein Profiling and understanding the hijacking instructions of coronavirus and developing tools for treatment and therapies. Scientists generated a high-resolution map of the coding regions in the SARS-CoV-2 genome using ribosome-profiling techniques, which allowed researchers to quantify the expression of vital zones along the virus genome that regulates the translation of viral proteins. The study published in Nature in January, explains the hijacking process and reported that virus produces more instruction in the form of viral mRNA than the host and thus dominates the translation process of the host cell. Researchers also clarified that it is the misconception that virus forced the host cell to translate its viral mRNA more efficiently than the host’s own translation, rather high level of viral translation instructions causes hijacking. This study provides valuable insights for the development of effective vaccines and drugs against the COVID-19 infection.
Like chutzpah, some things don’t translate
Prof. Igor Ulitsky and his team worked on untranslated region of viral genome. The article reported that “Not all the parts of viral transcript is translated into protein- rather play some important role in protein production and infection which is unknown.” This region may affect the molecular environment of the translated zones. The Ulitsky group researched to characterize that how the genetic sequence of regions that do not translate into proteins directly or indirectly affect the stability and efficiency of the translating sequences.
Initially, scientists created the library of about 6,000 regions of untranslated sequences to further study their functions. In collaboration with Dr. Noam Stern-Ginossar’s lab, the researchers of Ulitsky’s team worked on Nsp1 protein and focused on the mechanism that how such regions affect the Nsp1 protein production which in turn enhances the virulence. The researchers generated a new alternative and more authentic protocol after solving some technical difficulties which included infecting cells with variants from initial library. Within few months, the researchers are expecting to obtain a more detailed map of how the stability of Nsp1 protein production is getting affected by specific sequences of the untranslated regions.
The landscape of elimination
The article reported that the body’s immune system consists of two main factors- HLA (Human Leukocyte antigen) molecules and T cells for identifying and fighting infections. HLA molecules are protein molecules present on the cell surface and bring fragments of peptide to the surface from inside the infected cell. These peptide fragments are recognized and destroyed by the T cells of the immune system. Samuels’ group tried to find out the answer to the question that how does the body’s surveillance system recognizes the appropriate peptide derived from virus and destroy it. They isolated and analyzed the ‘HLA peptidome’- the complete set of peptides bound to the HLA proteins from inside the SARS-CoV-2 infected cells.
After the analysis of infected cells, they found 26 class-I and 36 class-II HLA peptides, which are present in 99% of the population around the world. Two peptides from HLA class-I were commonly present on the cell surface and two other peptides were derived from coronavirus rare proteins- which mean that these specific coronavirus peptides were marked for easy detection. Among the identified peptides, two peptides were novel discoveries and seven others were shown to induce an immune response earlier. These results from the study will help to develop new vaccines against new coronavirus mutation variants.
Gearing up ‘chain terminators’ to battle the coronavirus
Prof. Rotem Sorek and his lab discovered a family of enzymes within bacteria that produce novel antiviral molecules. These small molecules manufactured by bacteria act as ‘chain terminators’ to fight against the virus invading the bacteria. The study published in Nature in January which reported that these molecules cause a chemical reaction that halts the virus’s replication ability. These new molecules are modified derivates of nucleotide which integrates at the molecular level in the virus and obstruct the works.
Prof. Sorek and his group hypothesize that these new particles could serve as a potential antiviral drug based on the mechanism of chain termination utilized in antiviral drugs used recently in the clinical treatments. Yeda Research and Development has certified these small novel molecules to a company for testing its antiviral mechanism against SARS-CoV-2 infection. Such novel discoveries provide evidences that bacterial immune system is a potential repository of many natural antiviral particles.
Resolving borderline diagnoses
Currently, Real-time Polymerase chain reaction (RT-PCR) is the only choice and extensively used for diagnosis of COVID-19 patients around the globe. Beside its benefits, there are problems associated with RT-PCR, false negative and false positive results and its limitation in detecting new mutations in the virus and emerging variants in the population worldwide. Prof. Eran Elinavs’ lab and Prof. Ido Amits’ lab are working collaboratively to develop a massively parallel, next-generation sequencing technique that tests more effectively and precisely as compared to RT-PCR. This technique can characterize the emerging mutations in SARS-CoV-2, co-occurring viral, bacterial and fungal infections and response patterns in human.
The scientists identified viral variants and distinctive host signatures that help to differentiate infected individuals from non-infected individuals and patients with mild symptoms and severe symptoms.
In Hadassah-Hebrew University Medical Center, Profs. Elinav and Amit are performing trails of the pipeline to test the accuracy in borderline cases, where RT-PCR shows ambiguous or incorrect results. For proper diagnosis and patient stratification, researchers calibrated their severity-prediction matrix. Collectively, scientists are putting efforts to develop a reliable system that resolves borderline cases of RT-PCR and identify new virus variants with known and new mutations, and uses data from human host to classify patients who are needed of close observation and extensive treatment from those who have mild complications and can be managed conservatively.
Moon shot consortium refining drug options
The ‘Moon shot’ consortium was launched almost a year ago with an initiative to develop a novel antiviral drug against SARS-CoV-2 and was led by Dr. Nir London of the Department of Chemical and Structural Biology at Weizmann, Prof. Frank von Delft of Oxford University and the UK’s Diamond Light Source synchroton facility.
To advance the series of novel molecules from conception to evidence of antiviral activity, the scientists have gathered support, guidance, expertise and resources from researchers around the world within a year. The article reported that researchers have built an alternative template for drug-discovery, full transparency process, which avoids the hindrance of intellectual property and red tape.
The new molecules discovered by scientists inhibit a protease, a SARS-CoV-2 protein playing important role in virus replication. The team collaborated with the Israel Institute of Biological Research and other several labs across the globe to demonstrate the efficacy of molecules not only in-vitro as well as in analysis against live virus.
Further research is performed including assaying of safety and efficacy of these potential drugs in living models. The first trial on mice has been started in March. Beside this, additional drugs are optimized and nominated for preclinical testing as candidate drug.
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This year’s Nobel Prize laureates in chemistry Demis Hassabis and John Jumper have developed an AI model to solve a 50-year-old problem: predicting proteins’ complex structures.
In 2020, Hassabis and Jumper presented an AI model called AlphaFold2. With its help, they have been able to predict the structure of virtually all the 200 million proteins that researchers have identified. Since their breakthrough, AlphaFold2 has been used by more than two million people from 190 countries. Among a myriad of scientific applications, researchers can now better understand antibiotic resistance and create images of enzymes that can decompose plastic.
Read more about their story: https://bit.ly/4diKiJ2