Experimental Drug Quickly Reduces Age-Related Mental Decline

The compound, known as ISRIB, holds potential for reversing numerous cognitive problems in humans. Mice are used in scientific studies due to having genes that are approximately 85 percent similar to the genes of humans.

Just a few doses of an experimental drug can reverse age-related declines in memory and mental flexibility in mice, according to a new study by UC San Francisco scientists. The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals.

In the new study, published December 1, 2020 in the open-access journal eLife, researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function.

“ISRIB’s extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological ‘blockage’ rather than more permanent degradation,” said Susanna Rosi, PhD, Lewis and Ruth Cozen Chair II and professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science.

“The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress,” added Peter Walter, PhD, a professor in the UCSF Department of Biochemistry and Biophysics and a Howard Hughes Medical Institute investigator. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.”

Could Rebooting Cellular Protein Production Hold the Key to Aging and Other Diseases?

Walter has won numerous scientific awards, including the Breakthrough, Lasker and Shaw prizes, for his decades-long studies of cellular stress responses. ISRIB, discovered in 2013 in Walter’s lab, works by rebooting cells’ protein production machinery after it gets throttled by one of these stress responses — a cellular quality control mechanism called the integrated stress response (ISR; ISRIB stands for ISR InhiBitor).

The ISR normally detects problems with protein production in a cell — a potential sign of viral infection or cancer-promoting gene mutations — and responds by putting the brakes on cell’s protein-synthesis machinery. This safety mechanism is critical for weeding out misbehaving cells, but if stuck in the on position in a tissue like the brain, it can lead to serious problems, as cells lose the ability to perform their normal activities, Walter and colleagues have found.

In particular, recent animal studies by Walter and Rosi, made possible by early philanthropic support from The Rogers Family Foundation, have implicated chronic ISR activation in the persistent cognitive and behavioral deficits seen in patients after TBI, by showing that, in mice, brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight.

The cognitive deficits in TBI patients are often likened to premature aging, which led Rosi and Walter to wonder if the ISR could also underlie purely age-related cognitive decline. Aging is well known to compromise cellular protein production across the body, as life’s many insults pile up and stressors like chronic inflammation wear away at cells, potentially leading to widespread activation of the ISR.

“We’ve seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline,” said Rosi, who is director of neurocognitive research in the UCSF Brain and Spinal Injury Center and a member of the UCSF Weill Institute for Neurosciences. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step.”

ISRIB Improves Cognition, Boosts Neuron and Immune Cell Function

In the new study, researchers led by Rosi lab postdoc Karen Krukowski, PhD, trained aged animals to escape from a watery maze by finding a hidden platform, a task that is typically hard for older animals to learn. But animals who received small daily doses of ISRIB during the three-day training process were able to accomplish the task as well as youthful mice, much better than animals of the same age who didn’t receive the drug.

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. Several weeks after the initial ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed daily — a test of mental flexibility for aged mice who, like humans, tend to get increasingly stuck in their ways. The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.

To understand how ISRIB might be improving brain function, the researchers studied the activity and anatomy of cells in the hippocampus, a brain region with a key role in learning and memory, just one day after giving animals a single dose of ISRIB. They found that common signatures of neuronal aging disappeared literally overnight: neurons’ electrical activity became more sprightly and responsive to stimulation, and cells showed more robust connectivity with cells around them while also showing an ability to form stable connections with one another usually only seen in younger mice.

The researchers are continuing to study exactly how the ISR disrupts cognition in aging and other conditions and to understand how long ISRIB’s cognitive benefits may last. Among other puzzles raised by the new findings is the discovery that ISRIB also alters the function of the immune system’s T cells, which also are prone to age-related dysfunction. The findings suggest another path by which the drug could be improving cognition in aged animals, and could have implications for diseases from Alzheimer’s to diabetes that have been linked to heightened inflammation caused by an aging immune system.

“This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus,” said Rosi. “At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.

ISRIB May Have Wide-Ranging Implications for Neurological Disease

It turns out that chronic ISR activation and resulting blockage of cellular protein production may play a role in a surprisingly wide array of neurological conditions. Below is a partial list of these conditions, based on a recent review by Walter and colleague Mauro Costa-Mattioli of Baylor College of Medicine, which could potentially be treated with an ISR-resetting agent like ISRIB:

  • Frontotemporal Dementia
  • Alzheimer’s Disease
  • Amyotrophic Lateral Sclerosis (ALS)
  • Age-related Cognitive Decline
  • Multiple Sclerosis
  • Traumatic Brain Injury
  • Parkinson’s Disease
  • Down Syndrome
  • Vanishing White Matter Disorder
  • Prion Disease

ISRIB has been licensed by Calico, a South San Francisco, Calif. company exploring the biology of aging, and the idea of targeting the ISR to treat disease has been picked up by other pharmaceutical companies, Walter says.

One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects, but so far in all their studies, the researchers have observed none. This is likely due to two factors, Walter says. First, it takes just a few doses of ISRIB to reset unhealthy, chronic ISR activation back to a healthier state, after which it can still respond normally to problems in individual cells. Second, ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form — against an aggressive viral infection, for example.

Naturally, both of these factors make the molecule much less likely to have negative side effects — and more attractive as a potential therapeutic. According to Walter: “It almost seems too good to be true, but with ISRIB we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window.

New Materials for Wound and Skin Healing

Good research into healing — it leverages the body’s own natural resources.

Materials are widely used to help heal wounds: Collagen sponges help treat burns and pressure sores, and scaffold-like implants are used to repair bones. However, the process of tissue repair changes over time, so scientists are developing biomaterials that interact with tissues as healing takes place.

Now, Dr Ben Almquist and his team at Imperial College London have created a new molecule that could change the way traditional materials work with the body. Known as traction force-activated payloads (TrAPs), their method lets materials talk to the body’s natural repair systems to drive healing.

The researchers say incorporating TrAPs into existing medical materials could revolutionise the way injuries are treated. Dr Almquist, from Imperial’s Department of Bioengineering, said: “Our technology could help launch a new generation of materials that actively work with tissues to drive healing.”

The findings are published today in Advanced Materials.

Cellular call to action

After an injury, cells ‘crawl’ through the collagen ‘scaffolds’ found in wounds, like spiders navigating webs. As they move, they pull on the scaffold, which activates hidden healing proteins that begin to repair injured tissue.

The researchers designed TrAPs as a way to recreate this natural healing method. They folded the DNA segments into three-dimensional shapes known as aptamers that cling tightly to proteins. Then, they attached a customisable ‘handle’ that cells can grab onto on one end, before attaching the opposite end to a scaffold such as collagen.

During laboratory testing of their technique, they found that cells pulled on the TrAPs as they crawled through the collagen scaffolds. The pulling made the TrAPs unravel like shoelaces to reveal and activate the healing proteins. These proteins instruct the healing cells to grow and multiply.

The researchers also found that by changing the cellular ‘handle’, they can change which type of cell can grab hold and pull, letting them tailor TrAPs to release specific therapeutic proteins based on which cells are present at a given point in time. In doing so, the TrAPs produce materials that can smartly interact with the correct type of cell at the correct time during wound repair.

This is the first time scientists have activated healing proteins using different types of cells in human-made materials. The technique mimics healing methods found in nature. Dr Almquist said: “Using cell movement to activate healing is found in creatures ranging from sea sponges to humans. Our approach mimics them and actively works with the different varieties of cells that arrive in our damaged tissue over time to promote healing.”

From lab to humans

This approach is adaptable to different cell types, so could be used in a variety of injuries such as fractured bones, scar tissue after heart attacks, and damaged nerves. New techniques are also desperately needed for patients whose wounds won’t heal despite current interventions, like diabetic foot ulcers, which are the leading cause of non-traumatic lower leg amputations.

TrAPs are relatively straightforward to create and are fully human-made, meaning they are easily recreated in different labs and can be scaled up to industrial quantities. Their adaptability also means they could help scientists create new methods for laboratory studies of diseases, stem cells, and tissue development.

Aptamers are currently used as drugs, meaning they are already proven safe and optimised for clinical use. Because TrAPs take advantage of aptamers that are currently optimised for use in humans, they may be able to take a shorter path to the clinic than methods that start from ground zero.

Dr Almquist said: “The TrAP technology provides a flexible method to create materials that actively communicate with the wound and provide key instructions when and where they are needed. This sort of intelligent, dynamic healing is useful during every phase of the healing process, has the potential to increase the body’s chance to recover, and has far-reaching uses on many different types of wounds. This technology has the potential to serve as a conductor of wound repair, orchestrating different cells over time to work together to heal damaged tissues.”

New Bandage Speeds Skin Healing By Using Electric Stimulation

It’s cool that the bandage worked well on rats (which are used in scientific experiments due to having some important similarities to humans) by using electric stimulation created by an electric field.

Skin has a remarkable ability to heal itself. But in some cases, wounds heal very slowly or not at all, putting a person at risk for chronic pain, infection and scarring. Now, researchers have developed a self-powered bandage that generates an electric field over an injury, dramatically reducing the healing time for skin wounds in rats. They report their results in ACS Nano.

Chronic skin wounds include diabetic foot ulcers, venous ulcers and non-healing surgical wounds. Doctors have tried various approaches to help chronic wounds heal, including bandaging, dressing, exposure to oxygen and growth-factor therapy, but they often show limited effectiveness. As early as the 1960s, researchers observed that electrical stimulation could help skin wounds heal. However, the equipment for generating the electric field is often large and may require patient hospitalization. Weibo Cai, Xudong Wang and colleagues wanted to develop a flexible, self-powered bandage that could convert skin movements into a therapeutic electric field.

To power their electric bandage, or e-bandage, the researchers made a wearable nanogenerator by overlapping sheets of polytetrafluoroethylene (PTFE), copper foil and polyethylene terephthalate (PET). The nanogenerator converted skin movements, which occur during normal activity or even breathing, into small electrical pulses. This current flowed to two working electrodes that were placed on either side of the skin wound to produce a weak electric field. The team tested the device by placing it over wounds on rats’ backs. Wounds covered by e-bandages closed within 3 days, compared with 12 days for a control bandage with no electric field. The researchers attribute the faster wound healing to enhanced fibroblast migration, proliferation and differentiation induced by the electric field.

Regenerative Bandage Hydrogel Boosts Internal Self-Healing for Wounds

A very notable advance that should become a promising part of healing in the future.

A simple scrape or sore might not cause alarm for most people. But for diabetic patients, an untreated scratch can turn into an open wound that could potentially lead to a limb amputation or even death.

A Northwestern University team has developed a new device, called a regenerative bandage, that quickly heals these painful, hard-to-treat sores without using drugs. During head-to-head tests, Northwestern’s bandage healed diabetic wounds 33 percent faster than one of the most popular bandages currently on the market.

“The novelty is that we identified a segment of a protein in skin that is important to wound healing, made the segment and incorporated it into an antioxidant molecule that self-aggregates at body temperature to create a scaffold that facilitates the body’s ability to regenerate tissue at the wound site,” said Northwestern’s Guillermo Ameer, who led the study. “With this newer approach, we’re not releasing drugs or outside factors to accelerate healing. And it works very well.”

Because the bandage leverages the body’s own healing power without releasing drugs or biologics, it faces fewer regulatory hurdles. This means patients could see it on the market much sooner.

The research was published today, June 11, in the Proceedings of the National Academy of Sciences. Although Ameer’s laboratory is specifically interested in diabetes applications, the bandage can be used to heal all types of open wounds.

[…]

The difference between a sore in a physically healthy person versus a diabetic patient? Diabetes can cause nerve damage that leads to numbness in the extremities. People with diabetes, therefore, might experience something as simple as a blister or small scratch that goes unnoticed and untreated because they cannot feel it to know it’s there. As high glucose levels also thicken capillary walls, blood circulation slows, making it more difficult for these wounds to heal. It’s a perfect storm for a small nick to become a limb-threatening — or life-threatening — wound.

The secret behind Ameer’s regenerative bandage is laminin, a protein found in most of the body’s tissues including the skin. Laminin sends signals to cells, encouraging them to differentiate, migrate and adhere to one another. Ameer’s team identified a segment of laminin — 12 amino acids in length — called A5G81 that is critical for the wound-healing process.

[…]

The bandage’s antioxidant nature counters inflammation. And the hydrogel is thermally responsive: It is a liquid when applied to the wound bed, then rapidly solidifies into a gel when exposed to body temperature. This phase change allows it to conform to the exact shape of the wound — a property that helped it out-perform other bandages on the market.

“Wounds have irregular shapes and depths. Our liquid can fill any shape and then stay in place,” Ameer said. “Other bandages are mostly based on collagen films or sponges that can move around and shift away from the wound site.”

Patients also must change bandages often, which can rip off the healing tissue and re-injure the site. Ameer’s bandage, however, can be rinsed off with cool saline, so the regenerating tissue remains undisturbed.

Not only will the lack of drugs or biologics make the bandage move to market faster, it also increases the bandage’s safety. So far, Ameer’s team has not noticed any adverse side effects in animal models. This is a stark difference from another product on the market, which contains a growth factor linked to cancer.

“It is not acceptable for patients who are trying to heal an open sore to have to deal with an increased risk of cancer,” Ameer said.

Next, Ameer’s team will continue to investigate the bandage in a larger pre-clinical model.

Peptide-Based Dental Product May Rebuild Cavities

It’s amazing that the drill method is still prevalent in 2018. New approaches that use substances such as peptides and lasers are the innovations of the future.

Researchers at the University of Washington have designed a convenient and natural product that uses proteins to rebuild tooth enamel and treat dental cavities.

The research finding was first published in ACS Biomaterials Science and Engineering.

“Remineralization guided by peptides is a healthy alternative to current dental health care,” said lead author Mehmet Sarikaya, professor of materials science and engineering and adjunct professor in the Department of Chemical Engineering and Department of Oral Health Sciences.

The new biogenic dental products can — in theory — rebuild teeth and cure cavities without today’s costly and uncomfortable treatments.

“Peptide-enabled formulations will be simple and would be implemented in over-the-counter or clinical products,” Sarikaya said.

Cavities are more than just a nuisance. According to the World Health Organization, dental cavities affect nearly every age group and they are accompanied by serious health concerns. Additionally, direct and indirect costs of treating dental cavities and related diseases have been a huge economic burden for individuals and health care systems.

[…]

Taking inspiration from the body’s own natural tooth-forming proteins, the UW team has come up with a way to repair the tooth enamel. The researchers accomplished this by capturing the essence of amelogenin — a protein crucial to forming the hard crown enamel — to design amelogenin-derived peptides that biomineralize and are the key active ingredient in the new technology. The bioinspired repair process restores the mineral structure found in native tooth enamel.

“These peptides are proven to bind onto tooth surfaces and recruit calcium and phosphate ions,” said Deniz Yucesoy, a co-author and a doctoral student at the UW.

The peptide-enabled technology allows the deposition of 10 to 50 micrometers of new enamel on the teeth after each use. Once fully developed, the technology can be used in both private and public health settings, in biomimetic toothpaste, gels, solutions and composites as a safe alternative to existing dental procedures and treatments. The technology enables people to rebuild and strengthen tooth enamel on a daily basis as part of a preventive dental care routine. It is expected to be safe for use by adults and children.

Injectable Bandage Developed, Could Stop Internal Bleeding in Mere Minutes

Likely enough to be part of the new frontier in physical healing. There has long been a need for bandage-type medical applications that can heal both internally and externally.

Scientists have invented an injectable ‘bandage’ made out of a common food ingredient and nanoparticles. And not only does this material staunch bleeding stunningly fast, it also helps wounds heal more quickly.

When a person is wounded, they don’t necessarily just bleed on the outside – gunshots and other injuries often cause internal bleeding as well, which needs to be dealt with as quickly as possible.

In recent years, scientists have been coming up with new kinds of materials that can quickly plug a wound – such as this incredible sponge-filled syringe – but getting that same effect deeper in the body has remained a challenge.

Now a team of biomedical engineers at Texas A&M University has invented a totally new ‘injectable bandage’. It’s comprised of a seaweed-derived gelling agent and two-dimensional clay nanoparticles.

Together, these unlikely ingredients form what’s known as a hydrogel – highly absorbent, jelly-like substance with a super-high water content that can work remarkably well as wound dressing.

[…]

“An ideal injectable bandage should solidify after injection in the wound area and promote a natural clotting cascade,” explains biomedical engineer Akhilesh K. Gaharwar from Texas A&M.

On top of that, the team also noticed significantly improved tissue regeneration and wound healing in their treated lab samples. And, best of all, the nanoparticles used to make this hydrogel could also deliver medication to the wound site, slowly releasing it into the body as needed.

So far, the team’s hydrogel hasn’t been tested in human wounds, but its highly promising performance means it could only be a matter of time until doctors can add this injectable bandage to their arsenal.

New Nanofiber Dressings Significantly Accelerate Wound Healing

Quite cool, and being nature-based is a plus, but it remains to be seen how soon this research (knowing the corrupted U.S. medical system) will actually help people who need it.

Researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and the Wyss Institute for Biologically Inspired Engineering have developed new wound dressings that dramatically accelerate healing and improve tissue regeneration. The two different types of nanofiber dressings, described in separate papers, use naturally-occurring proteins in plants and animals to promote healing and regrow tissue.

“Our fiber manufacturing system was developed specifically for the purpose of developing therapeutics for the wounds of war,” said Kit Parker, the Tarr Family Professor of Bioengineering and Applied Physics at SEAS and senior author of the research. “As a soldier in Afghanistan, I witnessed horrible wounds and, at times, the healing process for those wounds was a horror unto itself. This research is a years-long effort by many people on my team to help with these problems.”

[…]

The researchers made fibrous fibronectin using a fiber manufacturing platform called Rotary Jet-Spinning (RJS), developed by Parker’s Disease Biophysics Group. RJS works likes a cotton candy machine — a liquid polymer solution, in this case globular fibronectin dissolved in a solvent, is loaded into a reservoir and pushed out through a tiny opening by centrifugal force as the device spins. As the solution leaves the reservoir, the solvent evaporates and the polymers solidify. The centrifugal force unfolds the globular protein into small, thin fibers. These fibers — less than one micrometer in diameter — can be collected to form a large-scale wound dressing or bandage.

“The dressing integrates into the wound and acts like an instructive scaffold, recruiting different stem cells that are relevant for regeneration and assisting in the healing process before being absorbed into the body,” said Christophe Chantre, a graduate student in the Disease Biophysics Group and first author of the paper.

In in vivo testing, the researchers found that wounds treated with the fibronectin dressing showed 84 percent tissue restoration within 20 days, compared to 55.6 percent restoration in wounds treated with a standard dressing.

The researchers also demonstrated that wounds treated with the fibronectin dressing have close to normal epidermal thickness and dermal architecture, and even regrew hair follicles — often considered one of the biggest challenges in the field of wound healing.

“This is an important step forward,” said Chantre. “Most work done on skin regeneration to date involves complex treatments combining scaffolds, cells and even growth factors. Here we were able to demonstrate tissue repair and hair follicle regeneration using an entirely material approach. This has clear advantages for clinical translation.”

[…]

In a similar way to fibronectin fibers, the research team used RJS to spin ultra-thin soy fibers into wound dressings. In experiments, the soy and cellulose-based dressing demonstrated a 72-percent increase in healing over wounds with no dressing and a 21-percent increase in healing over wounds dressed without soy protein.

“These findings show the great promise of soy-based nanofibers for wound healing,” said Seungkuk Ahn, a graduate student in the Disease Biophysics Group and first author of the paper. “These one-step, cost-effective scaffolds could be the next generation of regenerative dressings and push the envelope of nanofiber technology and the wound care market.”

At the end of the article it says that Harvard has “protected the intellectual property relating to these projects and is exploring commercialization opportunities,” meaning that it shouldn’t be much of a surprise if the consumer products based on this research take too long to go to market and/or are too expensive.