Geneticists develop novel gene therapy for glaucoma

 Scientists at Trinity College Dublin today announced a significant development toward a new therapeutic treatment of glaucoma.

Approximately 80 million people globally are affected by glaucoma, with a projected increase to more than 110 million by 2040. While topical eye drops are critical in preventing disease progression, up to 10% of patients become treatment resistant, putting them at risk for permanent vision loss.

The main clinical risk factor for glaucoma is elevated intraocular pressure; dangerous increases in pressure in the globe of the eye can lead to serious damage to the optic nerve head, which transmits light signals to the brain to allow us to see. This elevated pressure is caused by a build-up of unwanted proteins causing a blockage in drainage channels that, over time, can cause fluid to accumulate and pressure to increase.

The team at the Smurfit Institute of Genetics, in collaboration with the biotechnology company Exhaura Ltd., have shown that a gene therapy–based approach can decrease intraocular pressure in pre-clinical models of glaucoma. Their research is published this week in the journal Science Advances.

A single injection of a viral vector—essentially a virus the scientists have hijacked with the purpose of using it to deliver specific instructions to cells in the body—can increase the flow of aqueous fluid from the front of the eye and thereby decrease pressure in the eye. The key instructions are for cells to produce an enzyme matrix (metalloproteinase-3, or MMP-3) that helps kick this process into gear.

"This exciting project allowed us to bridge the gap between academia and industry and work very closely with a gene therapy company to develop a cutting edge therapy that we believe holds immense promise for patients in the future," said Professor Matthew Campbell, Professor in Genetics at Trinity.

Importantly, the work used multiple models of disease as well as making use of donor human eyes to screen the therapeutic efficacy of the gene therapy approach. This makes the impressive results all the more promising.

From rare to common diseases

Gene therapies have seen a dramatic advance in recent years, with multiple drugs now approved by both the FDA and EMA. However, to date, all of the approved gene therapies are for the treatment of rare or ultra-rare conditions. As our understanding of the underlying mechanism of common diseases is now becoming more evolved, the concept of using gene therapy for common diseases is now possible.

Dr Jeffrey O'Callaghan talks about what it means to have made a contribution that may impact millions of people positively. Credit: Trinity College Dublin

Dr. Jeffrey O'Callaghan, Postdoctoral research fellow at Trinity and first author of the study, added, "Our novel approach to treating glaucoma using gene therapy is the culmination of over seven years of research. We are now hopeful that this therapy will pave the way to the development of treatments for other forms of blinding eye diseases."

A multidisciplinary team of geneticists, ophthalmologists and translational biologists undertook the study. The close collaboration with Exhaura Ltd also allowed the team to direct all experimental outputs towards the translation of the findings to a regulatory focused clinical program.

More information: Jeffrey O'Callaghan et al, Matrix metalloproteinase-3 (MMP-3) mediated gene therapy for glaucoma, Science Advances (2023). DOI: 10.1126/sciadv.adf6537. www.science.org/doi/10.1126/sciadv.adf6537

https://medicalxpress.com/news/2023-04-geneticists-gene-therapy-glaucoma.html

Chinese Lab Developed COVID-19 Virus, Senate Report Claims

 by Zachary Steiber via The Epoch Times (emphasis ours),

The COVID-19 virus originated in a Chinese laboratory and was leaked unintentionally, a new U.S. Senate report concludes.

The virus, SARS-CoV-2, leaked from the Wuhan Institute of Virology (WIV), which tests bat coronaviruses, twice in 2019, researchers conducting the report say.

“The preponderance of information supports the plausibility of an unintentional research-related incident that likely resulted from failures of biosafety containment during SARS-CoV-2 vaccine-related research,” the 301-page report, released on April 17, states.

Sen. Roger Marshall (R-Ky.), a member of the Senate Health Committee, released the report, which was produced by a team that included Dr. Robert Kadlec, a longtime former government health official who played a key role in developing the COVID-19 vaccines, and staffers on the U.S. Senate Committee on Health, Education, Labor, and Pensions, where Marshall chairs the Subcommittee on Primary Health and Retirement Security. The final report updates an interim report released in the fall of 2022.

Researchers started with two hypotheses, Marshall told reporters in a briefing. One was that the virus started in animals before spilling over to humans, known as a natural origin. The other was a leak from the Wuhan lab, located in the same city where the first COVID-19 cases were detected in late 2019.

“They exhausted every piece of evidence that they could find, every resource witness that they could talk to, to come up with conclusions,” Marshall said.

Kadlec’s team of consultants spent approximately 18 months probing the COVID-19 origins and concluded that the available evidence supports a lab leak.

More specifically, there was likely an aerosol leak that caused an infection of lab personnel or the virus may have been released to the outside environment due to biocontainment failures. One theory revolves around cleaning agents causing corrosion of welded seams in the lab, a possibility mentioned in multiple 2019 documents on upgrading the lab.

“Patents addressed biocontainment faults with animal transfer cabinets, biosafety autoclaves, leaky airtight doors, and excessive corrosive disinfectants affecting stainless steel laboratory equipment and biocontainment structures,” the report states.

Sen. Roger Marshall gives a briefing in Washington on April 16, 2023. (Zachary Stieber/The Epoch Times)

Both domestic and foreign bodies have for years raised concerns about biosafety at the WIV. A 2018 U.S. State Department cable, for instance, (pdf) reported that the then-newly opened biosafety level four lab at the facility had a “serious shortage” of trained technicians to safely operate the lab.

Researchers at the lab, before the pandemic, reported experimenting on mice, bats, and palm civets to find coronaviruses that were more capable of infecting humans, and sometimes experimented at sub-biosafety level four conditions. A more recent summary showed scientists conducted experiments that increased the function of a bat coronavirus. WIV’s refusal to reveal the full results of their experiments resulted in U.S. officials ending a subgrant after the pandemic started.

Research-related lab biosafety issues can unfold in a number of ways, while most infections acquired in laboratories due to lapses are never conclusively determined, researchers have said previously.

Chinese reports, communications, and notices were offered as support for the lab leak theory, including an attempt in November 2019 to procure an air incinerator at the lab. That suggested “some concern about the risk of an infectious aerosol escape,” researchers say in the new report. They also noted that WIV staffers underwent a remedial biosafety training course that same month.

Characteristics of SARS-CoV-2 suggest the virus was manmade, including the presence of a furin cleavage site at the same location that was proposed in a grant proposal by EcoHealth Alliance, the report concludes. EcoHealth funneled U.S. taxpayer money to scientists in Wuhan.

https://www.zerohedge.com/political/chinese-lab-developed-covid-19-virus-senate-report-claims

New study challenges the idea that early Parkinson's disease causes cognitive dysfunction

 Like many neurodegenerative diseases, Parkinson's disease (PD) is a thief that hacks into human operating systems and corrupts their cognitive hard drives until they can no longer control their movements or perform activities of daily living.

Often, in its later stages, Parkinson's disease steals data too, leading to memory loss, confusion and dementia.

Both the cause and cure of Parkinson's disease remain elusive, but research has helped afflicted individuals manage their symptoms and lead healthier post-diagnosis lives. Individuals diagnosed with Parkinson's disease tend to have higher education than the general population and are often in their prime earning years, and the reasons for these two quirks are not well understood.

Large data sets

A recent study led by an MUSC neuropsychologist will help researchers in the field better evaluate whether their clinical trials are producing valuable outcomes in reducing the symptoms of individuals with PD.

Along with a team of collaborators, Travis Turner, Ph.D., assistant professor and director of the Neuropsychology Division at MUSC, dug deep into an existing treasure trove of data to clarify the cognitive impact of the early stages of PD. What he found initially seemed counter-intuitive and challenges the notion of cognitive deficits in individuals experiencing PD for less than five years.

Turner and his colleagues determined that the disease generally does not reduce cognitive function during the first five years of the disease, at least not as measured by standardized tests on patients. This finding applies as well to those who were already experiencing mild cognitive impairment.

Specifically, Turner's team examined cognitive test results from the Parkinson's Progression Markers Initiative (PPMI) on nearly 400 individuals, including 253 newly diagnosed PD patients and 134 healthy controls. Within the cohort, 84 of the individuals were identified as having pre-existing mild cognitive impairment. PPMI conducted a battery of tests on memory, visuospatial functions, processing speed, working memory and verbal fluency.

A small step back

Parkinson's disease patients performed normally on all but two tests, a measure of working memory and a processing speed test. Further examination of the results determined that the latter difference was entirely a function of motor decline: PD patients could not physically respond as quickly because of motor symptoms like tremor and rigidity. Employing a test to account for that variable eliminated the difference between PD patients and the control group.

For the memory test, individuals with PD experienced a mild dip, perhaps the source of what some who are diagnosed describe as brain fog. "Mild means some degree of subjective decline with more complicated tasks: doing bills, taxes, personal scheduling, non-routine work," said Turner. The difference, he says, would not generally be noticeable by anyone but the individual themselves.

The results were contrary to the team's expectations, particularly with regard to PD patients who were already experiencing mild impairment, Turner said. The data suggested that even those already affected suffered little-to-no further cognitive decline during the first five years after diagnosis.

Another surprise: that no other researchers had mined the repository of information and analyzed the results previously.

"Early cognitive decline is commonly reported by PD patients. There have been a lot of neuro-protective trials that look at non-motor symptoms like anxiety, depression and cognition, but no one had looked at this robust data set before," he said.

Earlier research

Previous tests on Parkinson's disease patients have produced a variety of results, some even somewhat contradictory according to Turner, but they lacked the controls or the sample size that his study included.

For example, one study that investigated mild cognitive impairment in PD patients did find more diminished ability, but it included individuals regardless of their time with the PD diagnosis. Individuals in later stages of PD often do exhibit cognitive impairment and even dementia, and their inclusion may have been clouding the results.

Another review employing the MOCA screening test produced similar findings as Turner's study, but with a single measure that offered a more global view of the disease's impact rather than his team's more specific findings.

Turner says the result of his analysis could have a far-reaching effect on future PD research. It suggests that researchers developing disease-modifying or neuroprotective interventions for PD should not use these neuropsychological tests as outcomes in clinical trials, as their paper suggests that they are not sensitive to the early subjective changes often reported by patients.

The impact

Turner is optimistic that he and his colleagues have unearthed something important. "I feel like it is big news," he said. "I am hoping it can be used for industry trials that I really want to succeed. I'm a PD researcher, so if a drug comes along that slows or stops its progression, I want reliable outcome measures that are sensitive to that effect."

Turner has dedicated his career to studying Parkinson's disease and foresees a continuation of symptomatic therapies emerging in the next 5-10 years that can sustain and enhance the quality of life for individuals suffering with the disease and provide fewer and less-severe side effects. Therapies that modify some subtypes of this complex disease will be the next step towards a cure, something Turner believes researchers are moving closer to all the time.

More information: Travis H. Turner et al, Are Standardized Tests Sensitive to Early Cognitive Change in Parkinson's Disease? (2023)

https://medicalxpress.com/news/2023-04-idea-early-parkinson-disease-cognitive.html

Neuroscientists identify cells especially vulnerable to Alzheimer's disease

 Neurodegeneration, or the gradual loss of neuron function, is one of the key features of Alzheimer's disease. However, it doesn't affect all parts of the brain equally.

One of the first brain regions to show neurodegeneration in Alzheimer's disease is a part of the hypothalamus called the mammillary body. In a new study, MIT researchers have identified a subset of neurons within this body that are most susceptible to neurodegeneration and hyperactivity. They also found that this damage leads to memory impairments.

The findings suggest that this region may contribute to some of the earliest symptoms of Alzheimer's disease, making it a good target for potential new drugs to treat the disease, the researchers say.

"It is fascinating that only the lateral mammillary body neurons, not those in the medial mammillary body, become hyperactive and undergo neurodegeneration in Alzheimer's disease," says Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory and the senior author of the study.

In a study of mice, the researchers showed that they could reverse memory impairments caused by hyperactivity and neurodegeneration in mammillary body neurons by treating them with a drug that is now used to treat epilepsy.

Former MIT postdoc Wen-Chin (Brian) Huang and MIT graduate students Zhuyu (Verna) Peng and Mitchell Murdock are the lead authors of the paper, which appears today in Science Translational Medicine.

Predisposed to degeneration

As Alzheimer's disease progresses, neurodegeneration occurs along with the buildup of amyloid beta plaques and misfolded Tau proteins, which form tangles in the brain. One question that remains unresolved is whether this neurodegeneration strikes indiscriminately, or if certain types of neurons are more susceptible.

"If we could identify specific molecular properties of classes of neurons that are predisposed to dysfunction and degeneration, then we would have a better understanding of neurodegeneration," Murdock says. "This is clinically important because we could find ways to therapeutically target these vulnerable populations and potentially delay the onset of cognitive decline."

In a 2019 study using a mouse model of Alzheimer's disease, Tsai, Huang, and others found that the mammillary bodies—a pair of structures found on the left and right underside of the hypothalamus—had the highest density of amyloid beta. These bodies are known to be involved in memory, but their exact role in normal memory and in Alzheimer's disease is unknown.

To learn more about the mammillary body's function, the researchers used single-cell RNA-sequencing, which can reveal the genes that are active within different types of cells in a tissue sample. Using this approach, the researchers identified two major populations of neurons: one in the medial mammillary body and the other in the lateral mammillary body. In the lateral neurons, genes related to synaptic activity were very highly expressed, and the researchers also found that these neurons had higher spiking rates than medial mammillary body neurons.

Based on those differences, the researchers wondered if the lateral neurons might be more susceptible to Alzheimer's disease. To explore that question, they studied a mouse model with five genetic mutations linked to early-onset Alzheimer's in humans. The researchers found that these mice showed much more hyperactivity in lateral mammillary body neurons than healthy mice. However, the medial mammillary body neurons in healthy mice and the Alzheimer's model did not show any such differences.

The researchers found that this hyperactivity emerged very early—around two months of age (the equivalent of a young human adult), before amyloid plaques begin to develop. The lateral neurons became even more hyperactive as the mice aged, and these neurons were also more susceptible to neurodegeneration than the medial neurons.

"We think the hyperactivity is related to dysfunction in memory circuits and is also related to a cellular progression that might lead to neuronal death," Murdock says.

The Alzheimer's mouse model showed impairments in forming new memories, but when the researchers treated the mice with a drug that reduces neuronal hyperactivity, their performance on memory tasks was significantly improved. This drug, known as levetiracetam, is used to treat epileptic seizures and is also in clinical trials to treat epileptiform activity—hyperexcitability in the cortex, which increases the risk of seizures—in Alzheimer's patients.

The researchers also studied human brain tissue from the Religious Orders Study/Memory and Aging Project (ROSMAP), a longitudinal study that has tracked memory, motor, and other age-related issues in older people since 1994. Using single-cell RNA-sequencing of mammillary body tissue from people with and without Alzheimer's disease, the researchers found two clusters of neurons that correspond to the lateral and medial mammillary body neurons they found in mice.

Similar to the mouse studies, the researchers also found signatures of hyperactivity in the lateral mammillary bodies from Alzheimer's tissue samples, including overexpression of genes that encode potassium and sodium channels. In those samples, they also found higher levels of neurodegeneration in the lateral neuron cluster, compared to the medial cluster.

Other studies of Alzheimer's patients have found a loss of volume of the mammillary body early in the disease, along with deposition of plaques and altered synaptic structure. All of these findings suggest that the mammillary body could make a good target for potential drugs that could slow down the progression of Alzheimer's disease, the researchers say.

Tsai's lab is now working on further defining how the lateral neurons of the mammillary body are connected to other parts of the brain, to figure out how it forms memory circuits. The researchers also hope to learn more about what properties of the lateral neurons of the mammillary body make them more vulnerable to neurodegeneration and amyloid deposition.

More information: Wen-Chin Huang et al, Lateral mammillary body neurons in mouse brain are disproportionately vulnerable in Alzheimer's disease, Science Translational Medicine (2023). DOI: 10.1126/scitranslmed.abq1019. www.science.org/doi/10.1126/scitranslmed.abq1019

https://medicalxpress.com/news/2023-04-neuroscientists-cells-vulnerable-alzheimer-disease.html

Newfound link between Alzheimer's and iron could lead to new medical interventions

 There is a growing body of evidence that iron in the brain may play a role in Alzheimer's disease. Lending weight to that idea, a new imaging probe has for the first time shown that in the same regions of the brain where the amyloid beta plaques associated with Alzheimer's occur, there is also an increase in iron redox, meaning the iron in these regions is more reactive in the presence of oxygen. Their imaging probe could yield even more details about the causes of Alzheimer's and help in the search for new drugs to treat it.

A team from The University of Texas at Austin and the University of Illinois at Urbana-Champaign has published a study today on the new imaging technique and findings in Science Advances.

"The link between iron redox and Alzheimer's disease has been a black box," said Yi Lu, corresponding author and professor of chemistry at UT Austin. "The most exciting part to me is that we now have a way to shine light into this black box so that we can begin to understand this whole process in much more detail."

About a decade ago, scientists discovered ferroptosis, a process in the body that is dependent on elevated iron levels, leads to cell death and plays a key role in neurodegenerative diseases, such as Alzheimer's. Using magnetic resonance imaging on living Alzheimer's patients, scientists have observed that these patients tend to have elevated iron levels in the brain, although that method doesn't differentiate between different forms of iron. Together, these findings suggested that iron might play a role in destroying brain cells in Alzheimer's patients.

For the new study, the researchers developed DNA-based fluorescent sensors that can detect two different forms of iron (Fe2+ and Fe3+) at the same time in cell cultures and in brain slices from mice genetically modified to mimic Alzheimer's. One sensor glows green for Fe2+ and the other glows red for Fe3+. This is the first imaging technique that can simultaneously detect both forms of iron in cells and tissue while also indicating their quantity and spatial distribution.

Schematic of a novel iron sensor. When a short strand of DNA called a DNAzyme (green) binds to a specific form of iron (e.g., Fe3+ or Fe2+), the DNAzyme cuts a second strand of DNA (red) and releases a fluorescent signal (yellow) that indicates visually the presence of the specific form of iron. Credit: David Steadman/University of Texas at Austin

"The best part about our sensor is that we can now visualize the changes of Fe2+ and Fe3+ and their ratios in each location," said Yuting Wu, a co-first author of the study and a postdoctoral researcher in Lu's lab at UT Austin. "We can change one parameter at a time to see if it changes the plaques or the oxidative states of iron."

That ability could help them better understand why there is an increased ratio of Fe3+ to Fe2+ in the location of amyloid beta plaques and whether increased iron redox is involved in forming the plaques.

Another key question is whether the iron redox is directly involved in cell death in Alzheimer's, or simply a byproduct. The researchers plan to explore this question in Alzheimer's mice. If further research determines that iron and its redox changes indeed cause cell death in Alzheimer's patients, that information could provide a potential new strategy for drug development. In other words, perhaps a drug that change the ratio of Fe3+ to Fe2+ could help protect brain cells. The new imaging probe could be used to test how well drug candidates work at changing the ratio.

To develop the sensors, the scientists first hired a commercial lab to produce a library of 100 trillion short DNA strands, through a chemical process called oligonucleotide synthesis. They then conducted a screening process to find those strands that recognize—or in chemistry parlance "bind tightly to and conduct a catalytic reaction with"—a specific form of iron and not any other forms. To complete the sensors, other components were added including molecules called fluorophores that glow in a specific color when the probe recognizes the specific form of iron.

Lu, who moved his lab to UT Austin from the University of Illinois at Urbana-Champaign in the summer of 2021, collaborated with researchers there including professor of chemistry Liviu Mirica.

More information: Yuting Wu et al, Simultaneous Fe2+/Fe3+ imaging shows Fe3+ over Fe2+ enrichment in Alzheimer's disease mouse brain, Science Advances (2023). DOI: 10.1126/sciadv.ade7622. www.science.org/doi/10.1126/sciadv.ade7622

https://medicalxpress.com/news/2023-04-newfound-link-alzheimer-iron-medical.html

Study: Milder autism far outpacing 'profound' diagnoses

 As autism diagnoses become increasingly common, health officials have wondered how many U.S. kids have relatively mild symptoms and how many have more serious symptoms, such as very low IQ and inability to speak.

A first-of-its-kind study released Wednesday shows the rate of such "profound" autism is rising, though far slower than milder autism cases.

"It's very important to know how many people have profound autism so that we can properly prepare for their needs," including more health and education services, said Alison Singer, executive director of the advocacy and research group Autism Science Foundation.

Singer—the mother of a 25-year-old woman with profound autism—was a co-author of the paper, which was published by the journal Public Health Reports. Scientists at the Centers for Disease Control and Prevention led the research.

Though autism has been diagnosed for at least 80 years, the new study is the first to put a number on the share of U.S. children who have the most severe version of it. It comes less than two years after an international commission of autism experts established a definition of profound autism: children with an IQ of 50 or less, and/or kids who can't communicate through speaking.

Under that definition, about a quarter of U.S. children identified as having autism by age 8 fall into the profound category, the new study found. It means more than 110,000 elementary school-age children in the U.S. have profound autism.

There are no blood or biological tests for autism. It's identified by making judgments about a child's behavior. Traditionally, it was diagnosed only in kids with severe language difficulties, social impairments and unusual repetitious behaviors. But the definition gradually expanded, and autism is now shorthand for a group of milder, related conditions, too.

The researchers looked at school and medical records from 2000 to 2016 for more than 20,000 8-year-olds identified as having autism spectrum disorders.

They found that the rate of profound diagnoses grew from about 3 cases per 1,000 children in 2000 to about 5 cases per 1,000 in 2016. But the rate of kids diagnosed with milder forms of autism grew from 4 per 1,000 to 14 per 1,000 over those years.

Milder forms of autism were more common in boys and white kids, the researchers found. Profound autism was more common in girls than boys.

A CDC study published last month found that autism overall is being diagnosed more frequently in Black and Hispanic children than in white kids in the U.S., a change from previous years when white children were more likely to be diagnosed. Experts cite improved screening and services, and increased awareness and advocacy. Among 8-year-olds, 1 in 36 had autism in 2020, the CDC estimates.

The new research found a large racial gap in profound autism. Among Black children with autism, 37% had profound autism. The same was true for about one-third of Hispanic kids with autism and about one-fifth of white children with autism.

More research is needed to understand the reasons for those differences, said the CDC's Michelle Hughes, the study's lead author.

Singer said the study's publication marks a recognition by the CDC that "autism spectrum disorder diagnoses is overly broad and that people who are diagnosed with (it) have very different needs." The data should help identify schooling and residential needs, she said.

Jan Blacher, an autism researcher at the University of California at Riverside, voiced mixed feelings about the report.

Using an IQ of 50 as a definition of profound autism can be problematic, she said. She has observed children with an IQ above 70 who had the kind of symptoms associated with profound autism, like spinning or a seemingly meaningless repeating of words.

"It's the symptoms of autism that make a difference," she said.

She worries that children who don't make the cut-off might not get the same attention and help as those who do.

"We have work to do at all levels of the continuum," she said.

More information: Michelle M. Hughes et al, The Prevalence and Characteristics of Children With Profound Autism, 15 Sites, United States, 2000-2016, Public Health Reports (2023). DOI: 10.1177/00333549231163551

https://medicalxpress.com/news/2023-04-milder-autism-outpacing-profound.html

Wearable patch can painlessly deliver drugs through the skin

 The skin is an appealing route for drug delivery because it allows drugs to go directly to the site where they're needed, which could be useful for wound healing, pain relief, or other medical and cosmetic applications. However, delivering drugs through the skin is difficult because the tough outer layer of the skin prevents most small molecules from passing through it.

In hopes of making it easier to deliver drugs through the skin, MIT researchers have developed a wearable patch that applies painless ultrasonic waves to the skin, creating tiny channels that drugs can pass through. This approach could lend itself to delivery of treatments for a variety of skin conditions, and could also be adapted to deliver hormones, muscle relaxants, and other drugs, the researchers say.

"The ease-of-use and high-repeatability offered by this system provides a game-changing alternative to patients and consumers suffering from skin conditions and premature skin aging," says Canan Dagdeviren, an associate professor in MIT's Media Lab and the senior author of the study. "Delivering drugs this way could offer less systemic toxicity and is more local, comfortable, and controllable."

MIT research assistants Chia-Chen Yu and Aastha Shah are the lead authors of the paper, which appears in Advanced Materials, as part of the journal's "Rising Stars" series, which showcases the outstanding work of researchers in the early stages of their independent careers. Other MIT authors include Research Assistant Colin Marcus and postdoc Md Osman Goni Nayeem. Nikta Amiri, Amit Kumar Bhayadia, and Amin Karami of the University of Buffalo are also authors of the paper.

A boost from sound waves

The researchers began this project as an exploration of alternative ways to deliver drugs. Most drugs are delivered orally or intravenously, but the skin is a route that could offer much more targeted drug delivery for certain applications.

"The main benefit with skin is that you bypass the whole gastrointestinal tract. With oral delivery, you have to deliver a much larger dose in order to account for the loss that you would have in the gastric system," Shah says. "This is a much more targeted, focused modality of drug delivery."

Ultrasound exposure has been shown to enhance the skin's permeability to small-molecule drugs, but most of the existing techniques for performing this kind of drug delivery require bulky equipment. The MIT team wanted to come up with a way to perform this kind of transdermal drug delivery with a lightweight, wearable patch, which could make it easier to use for a variety of applications.

The device that they designed consists of a patch embedded with several disc-shaped piezoelectric transducers, which can convert electric currents into mechanical energy. Each disc is embedded in a polymeric cavity that contains the drug molecules dissolved in a liquid solution. When an electric current is applied to the piezoelectric elements, they generate pressure waves in the fluid, creating bubbles that burst against the skin. These bursting bubbles produce microjets of fluid that can penetrate through the skin's tough outer layer, the stratum corneum.

"This works open the door to using vibrations to enhance drug delivery. There are several parameters that result in generation of different kinds of waveform patterns. Both mechanical and biological aspects of drug delivery can be improved by this new toolset," Karami says.

The patch is made of PDMS, a silicone-based polymer that can adhere to the skin without tape. In this study, the researchers tested the device by delivering a B vitamin called niacinamide, an ingredient in many sunscreens and moisturizers.

In tests using pig skin, the researchers showed that when they delivered niacinamide using the ultrasound patch, the amount of drug that penetrated the skin was 26 times greater than the amount that could pass through the skin without ultrasonic assistance.

The researchers also compared the results from their new device to microneedling, a technique sometimes used for transdermal drug delivery, which involves puncturing the skin with miniature needles. The researchers found that their patch was able to deliver the same amount of niacinamide in 30 minutes that could be delivered with microneedles over a six-hour period.

Local delivery

With the current version of the device, drugs can penetrate a few millimeters into the skin, making this approach potentially useful for drugs that act locally within the skin. These could include niacinamide or vitamin C, which is used to treat age spots or other dark spots on the skin, or topical drugs used to heal burns.

With further modifications to increase the penetration depth, this technique could also be used for drugs that need to reach the bloodstream, such as caffeine, fentanyl, or lidocaine. Dagdeviren also envisions that this kind of patch could be useful for delivering hormones such as progesterone. In addition, the researchers are now exploring the possibility of implanting similar devices inside the body to deliver drugs to treat cancer or other diseases.

The researchers are also working on further optimizing the wearable patch, in hopes of testing it soon on human volunteers. They also plan to repeat the lab experiments they did in this study, with larger drug molecules.

"After we characterize the drug penetration profiles for much larger drugs, we would then see which candidates, like hormones or insulin, can be delivered using this technology, to provide a painless alternative for those who are currently bound to self-administer injections on a daily basis," Shah says.

More information: Chia‐Chen Yu et al, A Conformable Ultrasound Patch for Cavitation‐Enhanced Transdermal Cosmeceutical Delivery, Advanced Materials (2023). DOI: 10.1002/adma.202300066

https://medicalxpress.com/news/2023-04-wearable-patch-painlessly-drugs-skin.html