Over the last three decades, focused ultrasound (FUS) technology research at the Brigham has integrated physics and math into medical research, created scalpel-free surgical alternates for patients with uterine fibroids, bone metastases, prostate cancer and essential tremors and Parkinson’s tremors. Researchers and clinicians are now wielding the tool to deliver gene therapies straight to the brain, bypassing the protective blood-brain barrier.
“We’ve known that the blood-brain barrier (BBB), characterized by tight junctions between cells, hinders drugs from entering the brain,” said Nicholas Todd, PhD, of the Department of Radiology. “There’s been all kinds of ideas for how to circumvent that, but nothing that has been particularly successful until focused ultrasound technologies.”
FUS technology delivers high-power ultrasound energy to a small target within the brain. Microbubbles, or tiny gas filled particles, are injected into the bloodstream simultaneously. When the microbubbles pass through the area where the ultrasound is focused, they physically oscillate. This pushing and pulling of the blood vessel walls disrupts the tight connections between endothelial cells that make up the BBB. Then, drugs that might not normally penetrate the BBB are able to reach the brain. The BBB openings close shortly thereafter, ensuring there is no long lasting (or potentially damaging) alterations.
Focused on the Future of FUS
The BWH Focused Ultrasound Laboratory, currently led by Nathan McDannold, PhD, of the Department of Radiology, pioneered the FUS system in the 1990s. Since then, they have focused on progressing clinical translation. The most successful application has been treating patients with tremor, led by neurosurgeons Reese Cosgrove and John Rolston.
“It has been rewarding to see how this field has grown and to personally see it impact patients’ lives every week,” said McDannold “To be able to work on a technology from the idea stage, and see it advance from preclinical models to clinical trials and ultimately reimbursement is a privilege and a rarity in science.”
Current FUS technology is integrated with an MRI scanner, which helps target the ultrasound waves to specific areas of the brain. The scans also help researchers track their progress, ensuring that the blood-brain barrier is open and for safety monitoring as the treatment is delivered.
In the future, the team hopes to run the ultrasound system using more basic optical tools like neuronavigation, eliminating the need for advanced MRI technologies and trained personnel to operate them. Such advances would allow focused ultrasounds to serve more patients.
“Once the technology is validated to use more widely, we might not need an MRI anymore,” Todd explained. “If we understand the treatment and safety parameters better, we may not need MRI to achieve an effective treatment.”
New Disease Targets
Currently, researchers in the Brigham FUS lab are testing whether their early-stage, non-invasive, incision-free technology can be used to improve how gene therapies are delivered directly to the brain.
“One thing that’s unique about gene therapies is a clear target gene of interest that you want to either silence or enhance to treat the disease,” Todd said. “Other labs have developed RNA, DNA or CRISPR therapies to target genes, but they just can’t get them to the brain without direct injection. This is where we come in.”Todd is working with Kimberly Kegel-Gleason, PhD, of the Department of Neurology at the Mass General Hospital, to use the technology suppress a gene responsible for Huntington’s disease. Specifically, FUS is used to deliver RNA treatment with a viral vector to carry it. Other researchers at the Brigham, including Fengfeng Bei, PhD, of the Department of Neurosurgery, are studying variants of the viral vector that might be able to cross the blood-brain barrier.
“We have collaborators with all different kinds of drug and disease expertise,” Todd said. “Getting drugs to the brain is a real problem, and we want our applications to ultimately solve this problem and reach patients.”
Other genetic disorders the team is working on include Niemann-Pick Disease Type C, a rare lysosomal storage disorder caused by a single gene, and Pompe disease, which is treated by an enzyme replacement therapy. Combined with the transformative power of new and emerging gene therapies, FUS also has the potential to deliver drugs for the treatment of diseases such as glioblastoma and neurodegenerative conditions.
Brigham Clinical Trial Begins to Help Patients with Advanced Brain Tumors
Nascent clinical trials across the United States and Canada have applied the technology to deliver treatments for Alzheimer’s disease, ALS and other neurodegenerative conditions. The Brigham is part of multicenter phase 1 trial focused on delivering chemotherapies to patients with glioblastomas — aggressive and almost always fatal brain tumors.
“We turned to FUS because it’s very difficult to get many drugs into the brain,” said Alexandra J. Golby, MD, of the Department of Neurosurgery and the Department of Radiology. “Patients with glioblastoma have so few treatment options, so they really have the potential to benefit from this technology.”
After their primary tumor is removed surgically and treated with radiation, patients return for chemotherapy. At this time, FUS is used to target the tumor’s margins to prevent further spread. The team has completed their initial study and expects to publish results focused on treatment safety and feasibility.
“We identified radiographic evidence of blood-brain barrier opening and demonstrated that patients could safely have repeated treatments,” said Golby, whose clinical focus is on image-guided neurosurgery with a special interest in surgery for patients with brain tumors – as part of the Dana-Farber Brigham Cancer Center. “Next, we need to establish not only that the blood-brain barrier can be opened but also that use of this technique can impact clinical outcomes for these patients.”
Together, Todd, McDannold and Golby are making important advances with the goal of providing lifesaving gene therapies to patients with a range of neurological conditions.
“Our collaborations with clinicians are critical at every stage of technology development, from the idea stage to clinical trials,” said McDannold. “They keep us on track and provide a reality check when our ideas or expectations are unrealistic. They also have firsthand experience on how terrible these conditions are for their patients and inspire us to keep working.”