Key Points
- The Foundation’s Research Awards Program recently initiated nine preclinical projects that use focused ultrasound to treat neuropathic pain, pancreatic cancer, dementia, Alzheimer’s disease, and more.
- Review the Foundation’s Research Applicant Funding Guide and apply for funding.
The Foundation is pleased to announce that nine new preclinical studies were launched in the third quarter of 2024. These projects are studying the use of focused ultrasound for neuropathic pain, pancreatic cancer and other types of cancer, dementia, and Alzheimer’s disease. Technically, researchers are working to develop new strategies that use focused ultrasound for neuromodulation, cancer immunotherapy, gene therapy, and delivering drugs across the blood-brain barrier (BBB).
“This latest group of preclinical research projects covers a broad range of diseases and many mechanisms of action, demonstrating the breadth of therapeutic opportunities currently under investigation,” said Joe Kilroy, PhD, the Foundation’s associate director of research and education.
Each newly initiated project is listed below.
Pain (1)
Focused Ultrasound and Magnetic Spinal Cord Stimulation for Neuropathic Pain led by Julie Pilitsis, MD, PhD, at the University of Arizona
Low-intensity focused ultrasound (liFUS) stimulation can be limited in regions where bone affects energy delivery. In this project, researchers will test a novel device that combines micro transmagnetic stimulation with liFUS (μTMS/liFUS) and assess its feasibility and efficacy in modulating the most common spinal cord target, the thoracic dorsal columns, in a rat model of common peroneal injury. The theory is that the combination of μTMS/liFUS could be used to treat neuropathic pain by reducing pain responses.
“There is a clear unmet need to develop non-pharmacological pain treatments,” says Chrit Moonen, PhD, the Foundation’s project manager for this study. “TMS has shown some potential but lacks deep penetration and spatial precision. The combination of μTMS and liFUS is a novel and interesting approach.”
Gene Therapy Program (1)
Development of Viral Vectors Optimized for Noninvasive, Site-Specific Gene Delivery to the Brain led by Jerzy Szablowski, PhD, at Rice University
Systemically administered adeno-associated virus vectors can be engineered to reduce side effects and increase delivery to the brain, as well as transduction within it, when used in conjunction with focused ultrasound blood-brain barrier opening. Having previously shown a 12-fold improvement specific targeting in the brain, researchers will now develop a next-generation vector with the goal of achieving nearly 100% brain delivery efficiency of a tolerable dose. If successful, this type of gene therapy could be used to non-surgically treat disorders that affect specific brain regions, such Parkinson’s Disease, epilepsy, or psychiatric disorders.
Cancer Immunotherapy Program (3)
Quantitative Susceptibility Mapping MRI to Track Delivery and Spatial Distribution of Iron Oxide Nanoparticles (IONPs) led by Wilson Miller, PhD, and Rich Price, PhD, at the University of Virginia Health System*
Clinical trials are now using focused ultrasound plus microbubbles (FUS+MBs) to open the blood-brain barrier and deliver systemically administered therapeutics to brain tumors. To better understand how FUS+MBs impacts the delivered dose and spatial distribution of biologics within the diverse tumor microenvironment, researchers will attempt to quantify FUS-mediated delivery of IONPs of various sizes and analyze the concentration distribution properties of skewness and coefficient of variation. These data will enable optimization of systemic dosing by therapeutic size and FUS sonication placement, ensuring effective drug delivery and coverage of brain metastases in both pre-clinical and clinical settings.
Deploying MR-Guided Focused Ultrasound Blood-Brain Barrier Opening (BBBO) to Promote Dendritic Cell Activation in the Glioblastoma (GBM) Tumor Microenvironment led by Timothy Bullock, PhD, at the University of Virginia Health System*
To better understand the specific aspects of dendritic cell (DC) dysfunction within brain tumors, which can inform immunotherapeutic strategies, researchers will investigate the barriers to tumor antigen acquisition by DCs and optimize DC activation to improve T-cell activation. The theory is that BBBO-enhanced delivery of various immuno-oncology agents can enhance DC activity in preclinical models of GBM.
Investigating Focused Ultrasound Effect on Tumor-Associated Macrophages led by AeRyon Kim, PhD, and Timothy Bullock, PhD, at the University of Virginia health System*
For this project, researchers will investigate which types of macrophages are recruited to pre- or post- focused ultrasound–ablated tumor areas and their impact on T cell activation, particularly immunosuppressive TREM2+ macrophages. In the absence of immunosuppressive macrophages, focused ultrasound can promote a robust anti-tumor immune response. This work will be conducted in tissue taken from human breast cancer biopsies that are collected before and during treatment in a clinical trial that is combining focused ultrasound and gemcitabine. The researchers are interested in determining whether focused ultrasound treatment recruits immunosuppressive TREM2+ macrophages around the ablated tumor area.
Brain Program (3)
Focused Ultrasound and Microbubbles (FUS-MB) Targeting α-Synuclein (α-syn) Pathology-Related Dementia led by Andreas Nørgaard Glud, MD, PhD, at Aarhus University Hospital
Over half of patients with Parkinson’s disease develop dementia. FUS-MB has been shown to increase neurotrophic factor levels, acetylcholine signaling, and synapse marker levels, and inhibit age-related changes in dendritic branching. To determine whether FUS-MB treatments can ameliorate cognitive dysfunction, researchers will conduct preclinical studies on the effect of FUS-MB on microglial-mediated α-syn clearance and progressive cortical synapse loss. They will also investigate the underlying pathways of these effects. The group will then determine whether noninvasive imaging of microglia activity and synapse density might serve as biomarkers of FUS-MB treatment effects and measure any biochemical changes induced by FUS-MB.
“α-syn build-up has been identified as a major factor in progression of Parkinson’s disease,” said Dr. Moonen, who is managing this project for the Foundation. “The glymphatic system may be essential for removal of α-syn. The project by Dr. Glud and coworkers will investigate if and how the glymphatic system can be stimulated by FUS-MB.”
Ultrasound-Targeted Microbubble Cavitation to Increase Delivery of Drugs for Alzheimer’s Disease Across the BBB led by Flordeliza S. Villaneuva, MD, at the University of Pittsburgh
Ultrasound-targeted microbubble cavitation (UTMC) can transiently open the BBB to increase therapeutic delivery to the brain. Clinical translation depends on the determination of how UTMC affects dosing for therapeutic efficacy. Researchers will use a murine model of Alzheimer’s Disease to measure brain amyloid-beta levels as a biomarker of pharmacodynamic efficacy after administering a monoclonal antibody against amyloid beta. The hope is that BBB opening with UTMC can help achieve therapeutic efficacy at lower doses, with fewer adverse effects.
Quantitative, Noninvasive, Longitudinal Measurement of Drug Concentration after MR-Guided Focused Ultrasound–Mediated Blood-Brain Barrier Disruption Using PET/MRI in a Porcine Model led by Kazim H. Narsinh, MD, at the University of California San Francisco
MR-guided focused ultrasound (MRgFUS) plus microbubbles can be used to enhance the delivery of therapeutic agents to the brain by transiently opening the BBB. Although gadolinium chelates (i.e., MR contrast agents) can be used to assess BBB opening, their passage across the BBB does not accurately recapitulate the pharmacokinetics of the therapeutic molecules under investigation. Therefore, researchers will develop a large animal (porcine) model for MRgFUS-mediated BBB opening that enables longitudinal, quantitative assessment of the biodistribution of 18F-fluorobenzoyl-doxorubicin, a radioactive analog of the chemotherapeutic doxorubicin, to allow whole-body positron emission tomography (PET) imaging of drug biodistribution after MRgFUS. This project is part of the Foundation’s efforts to develop ways to quantify drug delivery across the BBB.
Pancreatic Cancer (1)
Enhancing Post-Histotripsy Anti-Tumor Immune Responses and Drug Delivery via Tumor Vascular Normalization in Pancreatic Adenocarcinoma led by Anutosh Ganguly, MSc, MBA, PhD, at the University of Michigan
Cancer cell growth creates irregular blood vessels that favor tumor progression by decreasing oxygen and preventing immune cell and chemotherapy uptake. Histotripsy has been shown to abrogate tumor hypoxia, promote anti-tumor immune responses, and enhance intratumoral chemotherapy delivery. In this project, researchers are seeking to determine whether these effects are mediated by vascular normalization and can be leveraged to enhance chemotherapy drug delivery in a preclinical model of pancreatic cancer.
*This project was funded by the Commonwealth of Virginia as a result of the Foundation’s advocacy efforts. It will be conducted at the University of Virginia’s Focused Ultrasound Cancer Immunotherapy Center.
New! Foundation staff recently completed a guide for researchers seeking grant funding. The “Research Funding Applicant Guide” is a robust document that describes the Focused Ultrasound Foundation, our research priorities, the two-part application process, and what happens after a funding decision is made. “We hope that the applicant guide will help investigators to better understand the FUS Foundation proposal process and requirements,” said Dr. Kilroy.