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Researchers developing new cancer treatments with high-intensity focused ultrasound
24-Aug-2021 4:15 PM EDT, by University of Waterloo
Newswise — Researchers are bringing the use of acoustic waves to target and destroy cancerous tumours closer to reality.
While doctors have used low-intensity ultrasound as a medical imaging tool since the 1950s, experts at the University of Waterloo are using and extending models that help capture how high-intensity focused ultrasound (HIFU) can work on a cellular level.
Led by Siv Sivaloganathan, an applied mathematician and researcher with the Centre for Math Medicine at the Fields Institute, the study found by running mathematical models in computer simulations that fundamental problems in the technology can be solved without any risk to actual patients.
Sivaloganathan, together with his graduate students June Murley, Kevin Jiang and postdoctoral fellow Maryam Ghasemi, creates the mathematical models used by engineers and doctors to put HIFU into practice. He said his colleagues in other fields are interested in the same problems, “but we’re coming at this from different directions”.
“My side of it is to use mathematics and computer simulations to develop a solid model that others can take and use in labs or clinical settings. And although the models are not nearly as complex as human organs and tissue, the simulations give a huge head start for clinical trials.”
One of the obstacles that Sivaloganathan is currently working to overcome is that in targeting cancers, HIFU also poses risks to healthy tissue. When HIFU is being used to destroy tumours or cancerous lesions, the hope is that good tissue won’t be destroyed. The same applies when focusing the intense acoustic waves on a tumour on the bone where lots of heat energy gets released. Sivaloganathan and his colleagues are working to understand how the heat dissipates and if it damages the bone marrow.
Other researchers working with Sivaloganathan include engineers, who are building the physical technology, and medical doctors, in particular, James Drake, chief surgeon at Hospital for Sick Children, looking at the practical application of HIFU in clinical settings.
Sivaloganathan believes HIFU will make significant changes in cancer treatments and other medical procedures and treatments. HIFU is already finding practical application in the treatment of some prostate cancers.
“It’s an area that I think is going to take center stage in clinical medicine,” he said. “It doesn’t have the negative side effects of radiation therapy or chemotherapy. There are no side effects other than the effect of heat, which we are working on right now. It also has applications as a new way to break up blood clots and even to administer drugs.”
Sivaloganathan’s new research paper on math modelling for HIFU, “Dimension estimate of uniform attractor for a model of high intensity focussed ultrasound-induced thermotherapy,” with co-authors Messoud Efendiyev and June Murley, was recently published in the Bulletin of Mathematical Biology.
Heat-Controllable CAR T Cells Destroy Tumors and Prevent Relapse in New Study
18-Aug-2021 1:40 PM EDT, by Georgia Institute of Technology
Newswise — A team of researchers led by bioengineers at the Georgia Institute of Technology is expanding the precision and ability of a revolutionary immunotherapy that is already transforming oncology. CAR T-Cell therapy has been hailed by patients, clinical-researchers, investors, and the media as a viable cure for some cancers.
CAR T-Cell therapy involves engineering a patient’s T-cells, a type of white blood cell, in a lab. Then a chimeric antigen receptor (CAR) is added, and these customized immune cells are returned to the patient’s body, where they seek and destroy cancer cells. That’s how it works, when it works.
It’s a new, evolving, and booming area of immunotherapy, with more than 500 clinical trials analyzing CAR T-cells for cancer treatment going on right now around the world.
“These therapies have proven to be remarkably effective for patients with liquid tumors – so, tumors that are circulating in the blood, such as leukemia,” said Gabe Kwong, associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. “Unfortunately, for solid tumors – sarcomas, carcinomas – they don’t work well. There are many different reasons why. One huge problem is that the CAR T-cells are immunosuppressed by the tumor microenvironment.”
Kwong and his collaborators are changing the environment and making some cell modifications of their own to enhance the way CAR T-cells fight cancer. They’ve added a genetic on-off switch to the cells and a developed a remote-control system that sends the modified T-cells on a precision invasion of the tumor microenvironment, where they kill the tumor and prevent a relapse. And they explain it all in a study published recently in the journal Nature Biomedical Engineering.
The latest study builds on the lab’s body of work exploring remotely controlled cell therapies, in which the researchers can precisely target tumors, wherever they are in the body, with a local deposition of heat. “And this heat basically activates the CAR T-cells inside the tumors, overcoming the problems of immunosuppression,” said Kwong.
In the earlier study, the researchers did not clinically treat tumors, but they are doing that now with the new work. To generate heat in a mouse’s tumor, they shone laser pulses from outside the animal’s body, onto the spot where a tumor is located. Gold nanorods delivered to the tumor turn the light waves into localized, mild heat, raising the temperature to 40-42 Celsius (104-107.6 F), just enough to activate the T-Cells’ on-switch, but not so hot that it would damage healthy tissue, or the T-cells. Once turned on, the cells go to work, increasing the expression of cancer-fighting proteins.
The real novelty, Kwong said, was in genetically engineering clinical-grade CAR T-Cells, something the team worked on for the past three years. Now, in addition to a switch that responds to heat, the researchers have added a few upgrades to the T-cells, rewiring them to produce molecules to stimulate the immune system.
Localized production of these potent, engineered proteins (cytokines and Bispecific T-cell Engagers) has to be controlled precisely.
“These cancer-fighting proteins are really good at stimulating CAR T-cells, but they are too toxic to be used outside of tumors,” said Kwong. “They are too toxic to be delivered systemically. But with our approach we can localize these proteins safely. We get all the benefits without the drawbacks.”
The latest study shows the system cured cancer in mice, and the team’s approach not only shrunk tumors but prevented relapse – critical for long-term survival. Further studies will delve into additional tailoring of T-cells, as well as how heat will be deposited at the tumor site. A gentle laser was used to heat the tumor site. That won’t be the case when the technology moves on to human studies.
“We’ll use focused ultrasound, which is completely non-invasive and can target any site in the body,” Kwong said. “One of the limitations with laser is that it doesn’t penetrate very far in the body. So, if you have a deep-seated malignant tumor, that would be a problem. We want to eliminate problems.”
The research was funded by the NIH Director’s New Innovator Award (DP2HD091793), the National Center for Advancing Translational Sciences (UL1TR000454), and the Shurl and Kay Curci Foundation.
CITATION: Ian C. Miller, Ali Zamat, Lee-Kai Sun, Hathaichanok Phuengkham, Adrian M. Harris, Lena Gamboa1, Jason Yang7, John P. Murad7, Saul J. Priceman, Gabriel A. Kwong. “Enhanced intratumoural activity of CAR T cells engineered to produce immunomodulators under photothermal control.” (Nature Biomedical Engineering, August 2021)
About Georgia Tech
The Georgia Institute of Technology, or Georgia Tech, is a top 10 public research university developing leaders who advance technology and improve the human condition. The Institute offers business, computing, design, engineering, liberal arts, and sciences degrees. Its nearly 40,000 students representing 50 states and 149 countries, study at the main campus in Atlanta, at campuses in France and China, and through distance and online learning. As a leading technological university, Georgia Tech is an engine of economic development for Georgia, the Southeast, and the nation, conducting more than $1 billion in research annually for government, industry, and society.
Ultrasound Remotely Triggers Immune Cells to Attack Tumors in Mice Without Toxic Side Effects
12-Aug-2021 3:05 AM EDT, by University of California San Diego
Newswise — Bioengineers at the University of California San Diego have developed a cancer immunotherapy that pairs ultrasound with cancer-killing immune cells to destroy malignant tumors while sparing normal tissue.
The new experimental therapy significantly slowed down the growth of solid cancerous tumors in mice.
The team, led by the labs of UC San Diego bioengineering professor Peter Yingxiao Wang and bioengineering professor emeritus Shu Chien, detailed their work in a paper published Aug. 12 in Nature Biomedical Engineering.
The work addresses a longstanding problem in the field of cancer immunotherapy: how to make chimeric antigen receptor (CAR) T-cell therapy safe and effective at treating solid tumors.
CAR T-cell therapy is a promising new approach to treat cancer. It involves collecting a patient’s T cells and genetically engineering them to express special receptors, called CAR, on their surface that recognize specific antigens on cancer cells. The resulting CAR T cells are then infused back into the patient to find and attack cells that have the cancer antigens on their surface.
This therapy has worked well for the treatment of some blood cancers and lymphoma, but not against solid tumors. That’s because many of the target antigens on these tumors are also expressed on normal tissues and organs. This can cause toxic side effects that can kills cells—these effects are known as on-target, off-tumor toxicity.
“CAR T cells are so potent that they may also attack normal tissues that are expressing the target antigens at low levels,” said first author Yiqian (Shirley) Wu, a project scientist in Wang’s lab.
“The problem with standard CAR T cells is that they are always on—they are always expressing the CAR protein, so you cannot control their activation,” explained Wu.
To combat this issue, the team took standard CAR T cells and re-engineered them so that they only express the CAR protein when ultrasound energy is applied. This allowed the researchers to choose where and when the genes of CAR T cells get switched on.
“We use ultrasound to successfully control CAR T cells directly in vivo for cancer immunotherapy,” said Wang, who is a faculty member of the Institute of Engineering in Medicine and the Center for Nano-ImmunoEngineering, both at UC San Diego. What’s exciting about the use of ultrasound, noted Wang, is that it can penetrate tens of centimeters beneath the skin, so this type of therapy has the potential to non-invasively treat tumors that are buried deep inside the body.
The team’s approach involves injecting the re-engineered CAR T cells into tumors in mice and then placing a small ultrasound transducer on an area of the skin that’s on top of the tumor to activate the CAR T cells. The transducer uses what’s called focused ultrasound beams to focus or concentrate short pulses of ultrasound energy at the tumor. This causes the tumor to heat up moderately—in this case, to a temperature of 43 degrees Celsius (109 degrees Fahrenheit)—without affecting the surrounding tissue. The CAR T cells in this study are equipped with a gene that produces the CAR protein only when exposed to heat. As a result, the CAR T cells only switch on where ultrasound is applied.
The researchers put their CAR T cells to the test against standard CAR T cells. In mice that were treated with the new CAR T cells, only the tumors that were exposed to ultrasound were attacked, while other tissues in the body were left alone. But in mice that were treated with the standard CAR T cells, all tumors and tissue expressing the target antigen were attacked.
“This shows our CAR T-cell therapy is not only effective, but also safer,” said Wu. “It has minimal on-target, off-tumor side effects.”
###
The work is still in the early stages. The team will be performing more preclinical tests and toxicity studies before it can reach clinical trials.
Paper: “Control of the activity of CAR-T cells within tumours via focused ultrasound.” Co-authors include Yahan Liu, Ziliang Huang, Xin Wang, Jiayi Li, Linshan Zhu, Molly Allen, Yijia Pan, Robert Bussell, Aaron Jacobson, Thomas Liu and Shu Chien, UC San Diego; Zhen Jin, Shanghai Jiao Tong University, China; and Praopim Limsakul, Prince of Songkla University, Thailand.
This work was supported in part by the National Institutes of Health (grants HL121365, GM125379, GM126016, CA204704 and CA209629).
Disclosure: Peter Yingxiao Wang is scientific co-founder of and has financial interest in Cell E&G Inc. and in Acoustic Cell Therapy Inc., a company that aims to license the technology for further development. These financial interests do not affect the design, conduct or reporting of this research.
NIBIB-Funded Bioengineers Hit Neurons with Targeted Ultrasound in Approach to Inhibit Pain
Acoustic method could offer non-invasive, non-addictive remedy
11-Aug-2021 11:35 AM EDT, by National Institute of Biomedical Imaging and Bioengineering
Newswise — Neuromodulation comprises a range of therapeutic approaches to relieving symptoms, such as pain or tremors, or to restore movement or function. Therapeutic stimulation of neurons with electrical energy or chemicals—and potentially with acoustic waves—can amplify or dampen neuronal impulses in the brain or body. Acoustic signals in the form of ultrasound offer a promising class of neuromodulation which would be an especially valuable approach because it is non-invasive—no surgical procedure to implant electrodes for stimulation is required. Ultrasound offers a temporary modulation that can be tuned for a desired effect. Now researchers have demonstrated that it has the potential to be targeted at neurons with specific functions.
A team led by Bin He, Ph.D., professor of biomedical engineering at Carnegie Mellon University, and funded in part by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), has demonstrated the potential of a neuromodulation approach that uses low-intensity ultrasound energy, called transcranial focused ultrasound—or tFUS. In a paper published in the May 4, 2021, issue of Nature Communications, the authors describe tFUS in experiments with rodents that demonstrate the non-invasive neuromodulation alternative.
“Transcranial focused ultrasound is a promising approach that could be used to treat forms of chronic pain, among other applications,” said Moria Bittmann, Ph.D., director of the NIBIB program in Biorobotic Systems. “In conditions where symptoms include debilitating pain, externally generated impulses of ultrasound at controlled frequencies and intensity could inhibit pain signals.”
For their studies, He and his team designed an assembly that included an ultrasound transducer and a device that records data from neuron signals, called a multi-electrode array. During experiments with anesthetized rodents, the researchers penetrated the skull and brain with various brief pulses of acoustic waves, targeting specific neurons in the brain cortex. They simultaneously recorded the change in electrophysiological signals from different neuron types with the multi-electrode array.
When a signal is sent from one neuron to another, whether engaging the senses or controlling movement, the firing of that signal across the synapse, or junction, between neurons is called a spike. Two types of neurons observed by the researchers are excitatory and inhibitory neurons. When the researchers used tFUS to emit repeated bursts of ultrasound stimulation directly at excitatory neurons, they observed an elevated impulse rate, or spike. They observed that inhibitory neurons subjected to the same tFUS energy did not display a significant spike rate disturbance. The study demonstrated that the ultrasound signal can be transmitted through the skull to selectively activate specific neuron sub-populations, in effect targeting neurons with different functions.
“Our research addresses an unmet need to develop non-toxic, non-addictive, non-pharmacologic therapies for human use,” said He. “We hope to further develop the tFUS approach with variation in ultrasound frequencies and to pursue insights into neuronal activity so that this technology has the optimal chance for benefiting brain health.”
The application of this research has broad implications; it’s not just limited to one disease. For many people suffering from pain, depression and addiction, He believes non-invasive tFUS neuromodulation could be used to facilitate treatment. “If we can localize and target areas of the brain using acoustic, ultrasound energy, I believe we can potentially treat a myriad of neurological and psychiatric diseases and conditions,” He said.
The editors at Nature Communications selected the paper for a special feature, called “From brain to behaviour [sic],” which comprises some of the most exciting work on the brain published this year by the journal.
This work was supported, in part, by NIH grants from NIBIB (EB029354, EB021027), the National Institute of Mental Health (MH114233), the National Center for Advancing Translational Sciences (AT009263), and the National Institute of Neurological Disorders and Stroke (NS096761).
22-Jul-2021 3:50 PM EDT, by Hackensack Meridian Health
Newswise — HACKENSACK, NJ – On June 14, 2021, Hackensack Meridian Hackensack University Medical Center became the first and only center in New Jersey — and one of only a few in the country — to offer noninvasive MRI-guided focused ultrasound to treat hand tremors, or involuntary and rhythmic shaking that affects people with certain neurological conditions.
The treatment is performed with the Exablate® Neuro platform, developed by medical technology company Insightec and is approved by the U.S. Food and Drug Administration (FDA) for essential tremor and tremor-dominant Parkinson’s disease that has not responded to medications.
Focused ultrasound uses sound waves that travel through the skin and skull, which means that the procedure can be performed without any incisions. Under MRI guidance, the sound waves are precisely focused on a targeted area deep in the brain. The sound waves converge to heat the target tissue, which disrupts the abnormal signals that cause tremor.
The focused ultrasound system together with the MRI includes safety features that measure temperature changes in the skull and reduce the risk of damage to surrounding brain tissue.
“Essential tremor affects 10 million Americans, and Parkinson’s disease affects approximately one million Americans,” said Hooman Azmi, M.D., director, Division of Functional and Restorative Neurosurgery at the Hackensack University Medical Center Neuroscience Institute and associate professor of neurosurgery at Hackensack Meridian School of Medicine who will treat patients using focused ultrasound technology. “MR-guided focused ultrasound is an amazing development because it has the potential to instantaneously decrease or eliminate tremors and improve quality of life for millions of patients who are living with a movement disorder.”
And because the focused ultrasound procedure is noninvasive, requires no incisions and is performed while the patient is awake, treatment often can be done on an outpatient basis.
“Patients who undergo focused ultrasound treatment experience immediate improvement and don’t need to stay overnight in the hospital,” said Dr. Azmi. “That means patients require little downtime after the procedure and can return to everyday activities sooner.”
The benefits of MR-guided focused ultrasound include:
- No surgical incisions
- Little to no risk of infection
- A return to everyday activities in a few days
- Performed as an outpatient procedure — no overnight hospital stay required
- Immediate reduction in tremors
- Strong safety and clinical efficacy data
- Minimal side effects
“Hackensack University Medical Center is the only center in New Jersey to offer this groundbreaking procedure, so we can offer our patients a treatment for tremors that isn’t available elsewhere in the state,” said Mark Sparta, FACHE, president and chief hospital executive, Hackensack University Medical Center and executive vice president of Population Health, Hackensack Meridian Health. “Without the need for invasive brain surgery, our neurosurgery experts will be able to provide leading-edge, life-changing treatment for patients with tremor-dominant movement disorders.”
“Many patients experience immediate improvement with minimal complications,” said Patrick Roth, M.D., chair, Department of Neurosurgery, Hackensack University Medical Center. “By expanding their access to this treatment, we can help restore confidence and independence for people suffering from debilitating tremors.”
“With the addition of focused ultrasound technology at Hackensack University Medical Center, patients in New Jersey no longer have to travel to access this incredible treatment option,” said Randy Thomas, director, Orthopedics, Neuroscience, Hackensack University Medical Center. “Our neurosurgery team can now offer this treatment option close to home without the need for an overnight hospital stay or lengthy recovery time, making the treatment more convenient for patients and caregivers.”
“The Hackensack University Medical Center Neuroscience Institute is at the forefront of movement disorder treatment, and we are proud to be one of only a few centers in the country to offer MR-guided focused ultrasound treatment to our patients,” said Florian Thomas, M.D., Ph.D., professor and chair of the Department of Neurology at Hackensack University Medical Center and at Hackensack Meridian School of Medicine. “This treatment provides hope for patients whose tremor symptoms have not responded to other therapies and offers a noninvasive option that can deliver immediate and outstanding results.”
Watch this video that captures our first patient’s procedure and for more information, contact Mary McGeever at 551-795-1675 or [email protected]. Photos of our first patient also attached.
ABOUT HACKENSACK MERIDIAN HEALTH HACKENSACK UNIVERSITY MEDICAL CENTER
Hackensack Meridian Health Hackensack University Medical Center, a 771-bed nonprofit teaching and research hospital located in Bergen County, NJ, is the largest provider of inpatient and outpatient services in the state. Founded in 1888 as the county’s first hospital, it is now part of the largest, most comprehensive, and truly integrated health care network in New Jersey, offering a complete range of medical services, innovative research, and life-enhancing care, which comprises 35,000 team members and more than 7,000 physicians. Hackensack University Medical Center is ranked #2 in New Jersey and #59 in the country in U.S. News & World Report’s 2019-20 Best Hospital rankings and is ranked high-performing in the U.S. in colon cancer surgery, lung cancer surgery, COPD, heart failure, heart bypass surgery, aortic valve surgery, abdominal aortic aneurysm repair, knee replacement and hip replacement. Out of 4,500 hospitals evaluated, Hackensack is one of only 57 that received a top rating in all nine procedures and conditions. Hackensack University Medical Center is one of only five major academic medical centers in the nation to receive Healthgrades America’s 50 Best Hospitals Award for five or more years in a row. Becker’s Hospital Review recognized Hackensack University Medical Center as one of the 100 Great Hospitals in America 2018. The medical center is one of the top 25 green hospitals in the country according to Practice Greenhealth, and received 26 Gold Seals of Approval™ by The Joint Commission – more than any other hospital in the country. It was the first hospital in New Jersey and second in the nation to become a Magnet® recognized hospital for nursing excellence; receiving its sixth consecutive designation in 2019. Hackensack University Medical Center has created an entire campus of award-winning care, including: John Theurer Cancer Center, a consortium member of the NCI-designated Georgetown Lombardi Comprehensive Cancer Center; the Heart & Vascular Hospital; and the Sarkis and Siran Gabrellian Women’s and Children’s Pavilion, which houses the Joseph M. Sanzari Children’s Hospital and Donna A. Sanzari Women’s Hospital, which was designed with The Deirdre Imus Environmental Health Center® and listed on the Green Guide’s list of Top 10 Green Hospitals in the U.S. Hackensack University Medical Center is the Hometown Hospital of the New York Giants and the New York Red Bulls and is Official Medical Services Provider to THE NORTHERN TRUST PGA Golf Tournament. It remains committed to its community through fundraising and community events, especially the Tackle Kids Cancer Campaign providing much needed research at the Children’s Cancer Institute housed at the Joseph M. Sanzari Children’s Hospital. To learn more, visit www.HackensackUMC.org.
ABOUT HACKENSACK MERIDIAN HEALTH
Hackensack Meridian Health is a leading not-for-profit health care organization that is the largest, most comprehensive, and truly integrated health care network in New Jersey, offering a complete range of medical services, innovative research, and life-enhancing care.
Hackensack Meridian Health comprises 17 hospitals from Bergen to Ocean counties, which includes three academic medical centers – Hackensack University Medical Center in Hackensack, Jersey Shore University Medical Center in Neptune, JFK Medical Center in Edison; two children’s hospitals – Joseph M. Sanzari Children’s Hospital in Hackensack, K. Hovnanian Children’s Hospital in Neptune; nine community hospitals – Bayshore Medical Center in Holmdel, Mountainside Medical Center in Montclair, Ocean Medical Center in Brick, Palisades Medical Center in North Bergen, Pascack Valley Medical Center in Westwood, Raritan Bay Medical Center in Old Bridge, Raritan Bay Medical Center in Perth Amboy, Riverview Medical Center in Red Bank, and Southern Ocean Medical Center in Manahawkin; a behavioral health hospital – Carrier Clinic in Belle Mead; and two rehabilitation hospitals – JFK Johnson Rehabilitation Institute in Edison and Shore Rehabilitation Institute in Brick.
Additionally, the network has more than 500 patient care locations throughout the state which include ambulatory care centers, surgery centers, home health services, long-term care and assisted living communities, ambulance services, lifesaving air medical transportation, fitness and wellness centers, rehabilitation centers, urgent care centers and physician practice locations. Hackensack Meridian Health has more than 36,000 team members, and 7,000 physicians and is a distinguished leader in health care philanthropy, committed to the health and well-being of the communities it serves.
The network’s notable distinctions include having four of its hospitals are among the top hospitals in New Jersey for 2020-21, according to U.S. News & World Report. Additionally, the health system has more top-ranked hospitals than any system in New Jersey. Children’s Health is again ranked a top provider of pediatric health care in the United States and earned top 50 rankings in the annual U.S. News’ 2020-21 Best Children’s Hospitals report. Other honors include consistently achieving Magnet® recognition for nursing excellence from the American Nurses Credentialing Center and being named to Becker’s Healthcare’s “150 Top Places to Work in Healthcare/2019” list.
The Hackensack Meridian School of Medicine, the first private medical school in New Jersey in more than 50 years, welcomed its first class of students in 2018 to its On3 campus in Nutley and Clifton. The Hackensack Meridian Center for Discovery and Innovation (CDI), housed in a fully renovated state-of-the-art facility, seeks to translate current innovations in science to improve clinical outcomes for patients with cancer, infectious diseases and other life-threatening and disabling conditions.
Additionally, the network partnered with Memorial Sloan Kettering Cancer Center to find more cures for cancer faster while ensuring that patients have access to the highest quality, most individualized cancer care when and where they need it.
Hackensack Meridian Health is a member of AllSpire Health Partners, an interstate consortium of leading health systems, to focus on the sharing of best practices in clinical care and achieving efficiencies.
To learn more, visit www.hackensackmeridianhealth.org.
About INSIGHTEC
INSIGHTEC is a fast-growing global medical technology innovator transforming patient lives through incisionless surgery. The company’s award-winning Exablate® Neuro is the first and only focused ultrasound platform approved by the FDA to treat essential tremor and tremor-dominant Parkinson’s disease that has not responded to medications.
MRI’s Magnetic Field Affects Focused Ultrasound Technology
12-Jul-2021 1:50 PM EDT, by Washington University in St. Louis
Newswise — MRI-guided focused ultrasound combined with microbubbles can open the blood-brain barrier and allow therapeutic drugs to reach the diseased brain location under the guidance of MRI. It is a promising technique that has been shown safe in patients with various brain diseases, such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS) and glioblastoma.
While MRI has been commonly used for treatment guidance and assessment in preclinical research and clinical studies, until now, researchers did not know the impact of the static magnetic field generated by the MRI scanner on the blood-brain barrier opening size and drug delivery efficiency.
In new research published July 6 in Radiology, Hong Chen and her lab at Washington University in St. Louis have found for the first time that the magnetic field of the MRI scanner decreased the barrier’s opening volume by 3.3-fold to 11.7-fold, depending on the strength of the magnetic field, in a mouse model.
“Findings from this study suggest that the impact of the magnetic field needs to be considered in the clinical applications of focused ultrasound in brain drug delivery,” Chen said.
Read more on the engineering website.
Multi-Disciplinary Approach to Eradicate All Traces of HIV from Body, and Treat Co-existing Substance Use Disorders/Addiction
6-Jul-2021 7:05 AM EDT, by University of Maryland School of Medicine
Newswise — University of Maryland School of Medicine (UMSOM) Professor of Diagnostic Radiology & Nuclear Medicine, Linda Chang, MD, MS, received the National Institute on Drug Abuse (NIDA) 2021 Avant Garde Award (DP1) for HIV/AIDS and Substance Use Disorder Research — a National Institutes of Health (NIH) Director’s Pioneer Award. This prestigious award supports researchers with exceptional creativity, who propose high-impact research with the potential to be transformative to the field. Her proposed project will involve a team of experts in brain imaging, infectious diseases, addiction, animal research, and gene-editing technology with the goal to essentially eradicate all traces of HIV from the body, and treat commonly co-existing substance use disorders. 2021 Avant Garde Awardees are expected to receive more than $5 million over five years.
“I am extremely pleased, and feel very fortunate to have received this award,” says Dr. Chang, who has a secondary appointment in the Department of Neurology at UMSOM. “This project takes my work in a new direction. I believe my track record of being able to work across multiple disciplines with various researchers to initiate new areas of research and getting good results, along with the outstanding collaborators and resources at UMB, gave the proposal reviewers confidence that my team and I can significantly advance this new project.”
About 38 million people around the world live with HIV, according to the Centers for Disease Control and Prevention. Although antiretroviral therapies can treat HIV to the point of undetectable viral levels and lead to long, healthy lifespans, these medications must be taken for life to prevent a resurgence, as HIV can hide from these drugs by integrating copies of itself into a person’s genome. Once the drugs are stopped, the virus can reemerge.
From start to finish, Dr. Chang’s plan is to remove HIV from the genome, even in tough to reach spots like the brain, get more of the antiretroviral therapies into the brain, and stimulate the reward system in the brain to reduce drug cravings. The work will start out in mice before it can be tested in people.
Dr. Chang plans to use the gene-editing technology known as CRISPR to cut out copies of the hidden HIV genes in the genomes of mice, so they can be eradicated by antiretroviral drugs.
However, getting the CRISPR therapy into the brain can be difficult because of the blood-brain barrier, which protects the brain from infectious bacteria and foreign substances. The blood-brain barrier also prevents antiretroviral drugs from reaching high enough concentrations in the brain and central nervous system to effectively destroy HIV.
To seek out HIV in the brain, Dr. Chang and her team will temporarily disrupt the blood-brain barrier to allow more of the antiretroviral drugs or the CRISPR compounds to cross over the blood-brain barrier using an unique resource at the University of Maryland—the MRI-guided focused ultrasound system. This technique uses the MRI scan to help guide 2,000 pinpointed beams of high energy sound waves, along with microscopic bubbles, to non-invasively and temporarily open an area of the brain with the goal of eliminating the hidden reservoirs of virus in the brain’s immune cells.
About half of the people with HIV use substances, like drugs or alcohol, or have substance use disorders. Even tobacco or cannabis use in people with HIV is at 2-3 times that of the general population. Together with Victor Frenkel, PhD, an Associate Professor in the Department of Radiology and the Director of Translational Focused Ultrasound, and Donna Calu, PhD, Assistant Professor in the Department of Anatomy and Neurobiology, Dr. Chang will use low energy MR-guided focused ultrasound to suppress brain activity in the reward center of the brain, the nucleus accumbens. They hope this approach will suppress drug cravings in people with HIV who have substance use disorders.
The different components of this project will first be tested in mouse or rat models before moving onto clinical studies. As HIV does not normally infect mice, researchers use “humanized” mice that have weak immune systems, which are replaced with human blood stem cells that become human immune cells that can be infected with HIV. Although these humanized mice make lots of T cells— a main cell for HIV infection—they don’t make the immune cells that HIV uses to hide in the brain, known as microglia. Recently, Dr. Chang’s collaborator Howard E. Gendelman, MD, Margaret R. Larson Professor of Internal Medicine and Infectious Diseases Chair at University of Nebraska Medical Center, and his lab created a modified humanized mouse that has an extra human gene that allows the human blood stem cells to now make microglia.
“These new mice mean that these experiments can be done in a fraction of the time and cost and without the other hurdles that come along with using non-human primates, which are the only other animal that a special strain of HIV can infect,” says collaborator Alonso Heredia, PhD, Associate Professor of Medicine and scientist at UMSOM’s Institute of Human Virology.
He adds, “There have been many attempts to eradicate HIV in the body, and it is thought they have not been successful, in part because we cannot get to the HIV reservoirs in the brain. If this works, we will be much closer to a practical cure for HIV.” Dr. Heredia will be collaborating with Dr. Chang on this project using HIV-infected humanized mice that he has developed for his other ongoing projects.
For the addiction studies, Dr. Chang’s team will use the expertise and rodent models of addiction developed and optimized by Mary Kay Lobo, PhD, Professor of Anatomy and Neurobiology, and Dr. Calu. The mice will self-administer fentanyl, a powerful, synthetic opioid.
Dr. Frenkel and Dheeraj Gandhi, MBBS, Professor of Diagnostic Radiology and Nuclear Medicine and Clinical Director of Center of Metabolic Imaging and Therapeutics at UMSOM, are the team’s MRI-guided focused ultrasound and clinical research experts.
“My hearty congratulations to Dr. Chang and her colleagues and collaborators. If anything is called ‘cutting edge’ this work surely qualifies for that praise. We wish this group all the success possible,” said Robert C. Gallo, MD, The Homer & Martha Gudelsky Distinguished Professor in Medicine, Co-Founder and Director, Institute of Human Virology (IHV), University of Maryland School of Medicine, a Global Virus Network (GVN) Center of Excellence, and GVN Co-Founder and International Scientific Advisor.
Dr. Chang is an expert in using brain imaging to study how HIV or drug use affect the brain in adults and during adolescence, and how exposure to drugs in the womb affects childhood development. She has also conducted clinical trials for treating HIV-associated cognitive disorders and substance use disorders.
Dr. Chang joined UMSOM in 2017 through the Dean’s initiative Special Trans-Disciplinary Recruitment Award Program (STRAP). The STRAP Initiative was part of UMSOM’s multi-year research strategy ACCEL-Med (Accelerating Innovation and Discovery in Medicine) to increase the quality and reputation of clinical and basic science research bringing UMSOM among other top-tier medical research schools.
“Dr. Chang’s arrival to UMSOM spurred the exact kind of collaborative efforts we had hoped to foster through our recruitment program in order to accelerate discoveries, treatments and cures for the world’s most pressing diseases,” says E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, UMSOM. “I look forward to following her team’s progress on this ambitious project in the hope that one day we can eradicate HIV.”
Dr. Chang served on the National Advisory Council on Drug Abuse for NIDA and is a current member on the Council of Councils at the NIH.
About the University of Maryland School of Medicine
Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest-growing, top-tier biomedical research enterprises in the world — with 45 academic departments, centers, institutes, and programs; and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research.
With an operating budget of more than $1.2 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic and clinically-based care for nearly 2 million patients each year. The School of Medicine has more than $563 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 student trainees, residents, and fellows.
The combined School of Medicine and Medical System (“University of Maryland Medicine”) has an annual budget of nearly $6 billion and an economic impact of more than $15 billion on the state and local community. The School of Medicine, which ranks as the 8th highest among public medical schools in research productivity, is an innovator in translational medicine, with 600 active patents and 24 start-up companies. The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu
