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Focused ultrasound reached millions on January 22 when it was featured in an episode of CNN’s Vital Signs, called “What Brain Surgery With No Scalpel Looks Like.” The 23-minute program is hosted by famed correspondent and neurosurgeon Dr. Sanjay Gupta. Viewers followed Brenda Hric, a patient with essential tremor, as she was treated in December at the University of Virginia by Dr. Jeff Elias, and the episode featured an in-depth interview with our Chairman and Founder, Neal F. Kassell, MD. Said Brenda after her treatment, “It was the first time I had been able to see my fingers ‘still’ in about 20 years. I think it’s definitely a miracle.” The episode aired originally on CNN International and is now available online. We encourage you to watch the program and share it broadly.  More CNN Coverage An article profiling focused ultrasound’s transformative use in treating brain conditions such as essential tremor, depression, OCD, and more recently received top billing on CNN’s homepage. The article was in conjunction with the Vital Signs episode. Dr. Kassell was interviewed for the piece and said, “My belief is that in 10 years, focused ultrasound will be a mainstream therapy that is affecting millions of patients every year around the world. It’ll be widely accepted.” Read: “A Sound You Can’t Hear But May One Day Change Your Life” Thank you for helping us spread the word about focused ultrasound and speed the time to widespread adoption of the technology – saving time, saving lives.

Key Points The Foundation’s Research Awards Program initiated nine preclinical studies from October through December 2022, the fourth quarter of last year. The funded projects address brain, bone, low back pain, and breast cancer applications of focused ultrasound. The Foundation’s Research Awards Program initiated nine new preclinical studies from October through December 2022, the fourth quarter of last year. The funded projects address brain, bone, low back pain, and breast cancer applications of focused ultrasound. “All of the preclinical brain projects are linked to an initiative that came out of the May 2021 glioblastoma workshop,” said Lauren Powlovich, MD, the Foundation’s Associate Chief Medical Officer. “The aim of this group of projects is to identify a method to better quantify the amount of drug delivered to brain tissue after blood-brain barrier opening (BBBO). We are meeting quarterly to discuss progress and new ideas.” Each newly initiated project is listed below. Brain Preclinical Probing the Abilities of Contrast-Enhanced MRI to Track Microbubble-Enhanced Focused Ultrasound Nano-Medicine Delivery in the Brain and Brain Tumors led by Costas Arvanitis, PhD, at the Georgia Institute of Technology For this project, researchers will determine how to confirm therapeutic delivery of nanoparticles to the brain during microbubble-enhanced focused ultrasound (MB-FUS) procedures. The goal is to improve the delivery of therapeutic nanoparticles to brain tumors by studying optimal nanoparticle properties and methods to confirm nanoparticle delivery in the brain and brain tumors. Mapping Drug Concentrations After Blood-Brain Barrier Disruption Using MALDI Mass Spectrometry Imaging led by Nathan McDannold, PhD, at Brigham and Women’s Hospital For this project, researchers will explore the use of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry to quantify the amount of therapeutic delivered to brain tissue after BBBO, then creating specific calibration curves to compare with the MRI images. The goal is to identify a method to better quantify the amount of drug delivered to the brain tissue following BBBO. PET-Labeling and Testing of Paclitaxel Nanoformulations with Microbubbles and Focused Ultrasound led by Graeme Woodworth, MD, at the University of Maryland School of Medicine For this project, researchers will determine whether PET-labeling of nanoparticle therapeutics could enable quantitative visualization of localized nanoparticle delivery during microbubble-enhanced blood-brain barrier opening with clinical focused ultrasound systems in advanced preclinical models of glioblastoma. Mapping of Antibody and Liposome Permeability into the Brain Following Focused Ultrasound Treatment Through T1/T2w Dynamic Contrast-Enhanced (DCE) Magnetic Resonance Imaging led by Antonios Pouliopoulos, PhD, at King’s College Hospital in London For this project, the research team will confirm focused ultrasound–mediated delivery of antibody- and liposome-based therapies by delivering two MR-labelled model drugs across the blood-brain barrier (BBB) and then conducting DCE MRI scans to determine the extent of drug delivery within the tissue. Evaluation of MRI Visualization of Focused Ultrasound–Induced Blood-Brain Barrier (BBB) Opening in White Matter led by Meghan O’Reilly, PhD, at Sunnybrook Health Sciences Centre For this project, researchers will determine how to improve drug delivery to white matter in the brain. Contrast-enhanced MRI is used to assess changes in BBB permeability following focused ultrasound treatment but the contrast enhancement in white matter is lower than in grey matter, so research is needed to be able to use MRI visualization for both applications. MRI Compatible Optical-Driven Focus Ultrasound for Neuromodulation led by Chen Yang, PhD, at Boston University Ultrasound neural modulation is an emerging noninvasive neuromodulation tool. The goal of this project is to develop a compact, MRI-compatible, optically driven focused ultrasound source for ultrasound neural modulation with a broader accessibility than standard focused ultrasound systems. Its application in noninvasive brain modulation and its efficacy in treating epilepsy in a mouse model will be demonstrated. Body Ultrasound-Triggered Gelation to Treat Discogenic Lower Back Pain led by Constantin Coussios, PhD, at the University of Oxford This one-year collaborative study will combine the materials engineering expertise at Imperial College with the biomedical ultrasound expertise at the University of Oxford to optimize material formulations and focused ultrasound exposure parameters with the objective of translating these techniques for percutaneous nucleus pulposus replacement. Doing so would offer a new minimally invasive day case procedure to treat discogenic lower back pain and restore spinal function. Patterning of Mesenchymal Stem Cell Differentiation for Bone Regeneration Using Focused Ultrasound–Mediated Hydrogel Stiffening led by Mario Fabiilli, PhD, at the University of Michigan For this project, researchers will use focused ultrasound to alter the stiffness of a custom acoustic responsive scaffold (ARS) and stimulate bone regeneration. The ARS contains mesenchymal stem cells encapsulated within hydrogels The hydrogel acts as a surrogate for the native extracellular matrix. The studies seek to demonstrate a proof-of-concept for implanting ARS at the site of bone loss. Preclinical High-Intensity Focused Ultrasound (HIFU) Treatment of Breast Adenocarcinoma Using a Noninvasive Toroidal Transducer led by David Melodelima, PhD, at Inserm LabTAU For this project, researchers will determine whether HIFU ablation of breast adenocarcinoma is feasible and effective with a toroidal transducer. The group will use a clinical device that has previously been effective for liver metastases and pancreatic tumors. Learn How to Apply for a Research Award >

Key Points Ethan Miller has been a principal in his family-run Cassiopeia Foundation for more than 20 years. The Cassiopeia Foundation has supported focused ultrasound research for Alzheimer’s disease and other neurodegenerative disorders. The Cassiopeia constellation Ethan Miller has been a principal in his family-run Cassiopeia Foundation for more than 20 years. He grew up in Radnor Township, Pennsylvania, outside of Philadelphia. After graduating from Haverford College with a BA in Economics in 1976, Ethan earned his law degree from the University of Pennsylvania Law School in 1979, and then practiced business law for over 25 years in St. Louis, Baltimore, and Charlottesville, VA. Today, he owns and operates an upstream oil and gas company based in Lafourche Parish, Louisiana. What was the reason for your support of the Focused Ultrasound Foundation?Cassiopeia’s first grant to the Focused Ultrasound Foundation was to support its work in the treatment of Alzheimer’s disease. Our giving honors Cassiopeia’s founder, Patricia Jones Edgerton, who was afflicted with Alzheimer’s for over a decade before her death. We were, and continue to be, excited about the potential for focused ultrasound to transform the treatment of Alzheimer’s and other neurodegenerative diseases including ALS, Parkinson’s, Huntington’s disease, dystonia, and essential tremor. We first heard Dr. Neal Kassell speak about the potential benefits of focused ultrasound treatment at a gathering of potential funders in 2006 or so. Neal and the Focused Ultrasound Foundation team have been in the forefront of developing and popularizing ultrasound treatment in the United States and elsewhere in the world.  How does the Focused Ultrasound Foundation fit within your approach to philanthropy?Our approach to philanthropy is to find and support the best people. I first met Neal Kassell when he came to the University of Virginia Department of Neurosurgery in 1984, nearly 40 years ago, and have followed his career. Neal is not only brilliant but a visionary as well. Our approach is to identify people like Neal, provide them with necessary resources, and then stand back and watch. A lot of traditional philanthropy is risk averse. We recognize that risk-taking is required to achieve breakthroughs in medicine (and elsewhere). We are not afraid of risk and believe that the potential benefits of focused ultrasound treatments are worth taking risks for. The Cassiopeia Foundation has made hundreds of grants totaling many hundreds of millions of dollars in its 20 plus year history. I am personally proudest of the two grants we have made to the Focused Ultrasound Foundation. We are honored to support Neal Kassell and the Focused Ultrasound Foundation in their mission.

Key Points Researchers at Sunnybrook Health Sciences Centre and The Hospital for Sick Children are collaborating on a clinical trial using focused ultrasound in patients with diffuse intrinsic pontine glioma (DIPG). DIPGs are highly aggressive and devastating brain tumors that affect young children. In this trial, physicians are exploring focused ultrasound-induced blood-brain barrier opening to enhance delivery of chemotherapy to the tumor. Researchers at Sunnybrook Health Sciences Centre and The Hospital for Sick Children (SickKids) have begun a collaborative clinical trial using focused ultrasound to open the blood-brain barrier (BBB) and deliver chemotherapy in patients with diffuse intrinsic pontine glioma (DIPG). DIPGs are highly aggressive and devastating brain tumors that affect young children, typically aged 5–9. They affect a region of the brainstem that regulates the body’s involuntary activities such as breathing, heart rate, and swallowing. Only 10 percent of children survive past the two-year mark after diagnosis because current therapies are highly ineffective. One reason that brain tumors – including DIPG – are challenging to treat is the BBB. This protective layer of tightly joined cells that lines the blood vessels in the brain prevents harmful substances, such as toxins and infectious agents, from diffusing into the surrounding brain tissue. However, it can also prevent therapeutic agents – like chemotherapy – from getting into the brain. Focused ultrasound has been shown to temporarily disrupt the BBB in a noninvasive, safe, and targeted manner. The ultrasound waves interact with microbubbles in the vessels, causing them to vibrate rapidly and create openings that can enable therapies to pass through. In this trial, researchers are investigating the safety and feasibility of using Insightec’s Exablate Neuro device to open the BBB in 10 participants between the ages of 5 and 18. Participants will undergo focused ultrasound therapy in conjunction with chemotherapy during three treatment cycles, about four to six weeks apart. The first patient underwent the initial procedure earlier this month. The trial is being led by Nir Lipsman, MD, PhD, neurosurgeon and director of Sunnybrook’s Harquail Centre for Neuromodulation, and James Rutka, MD, PhD, director of the Arthur and Sonia Labatt Brain Tumour Research Centre at SickKids.  “DIPG is a devastating pediatric brain tumor which is inoperable due to its location in the brainstem,” says Dr. Lipsman. “Focused ultrasound is an innovative and noninvasive approach to more effectively delivering chemotherapy directly to the tumor. Our hope is that this continued research will bring us closer to enhancing treatments to help change the course of the disease.” Sunnybrook Health Sciences Centre is a Focused Ultrasound Foundation Center of Excellence, and the Foundation is funding a portion of this clinical trial. For PatientsIf you are interested in learning more about this clinical trial, please contact James Rutka, MD, (416-813-6425, james.rutka@sickkids.ca) or Maheleth Llinas (416-480-6100 ext 2476, maheleth.llinas@sunnybrook.ca). Read Sunnybrook’s Announcement >See Coverage by CTV > Additional DIPG Trials in the USFocused ultrasound is being investigated to address DIPG at other sites in the US. At Children’s National Hospital (CNH) in Washington, DC, a team of researchers is conducting two clinical trials. One approach is similar to the Sunnybrook trial, where focused ultrasound will be used to open the BBB in an effort to deliver chemotherapy to the tumor. The other trial at CNH is testing sonodynamic therapy as a way to destroy the tumor. Both clinical trials are currently recruiting patients. CNH became the Foundation’s first pediatric Center of Excellence in 2020. Another DIPG clinical trial investigating focused ultrasound-induced BBB opening to deliver chemotherapy began in July 2021 at Columbia University.