What is the Blood-Brain Barrier?

The blood-brain barrier (BBB) is a protective layer of tightly joined cells that line the blood vessels of the brain. It is crucial to preventing disease and preserving health by keeping harmful substances (such as toxins and infectious agents) from entering the brain. Unfortunately, this barrier also prevents certain drugs from reaching adequate concentrations in their targets within the brain, and there are limited options to circumvent the BBB to deliver them.

Safely and temporarily opening the barrier in a well-defined area, to deliver drugs at therapeutic levels, is a long-sought goal for treatment of a wide variety of neurological conditions, including brain tumors, Alzheimer’s disease, Parkinson’s disease, and epilepsy.

How Focused Ultrasound Opens the BBB

The story began in 2001, when Drs. Kullervo Hynynen, Nathan McDannold, Ferenc Jolesz, and colleagues first described a controlled, temporary, and reproducible manner of opening the BBB using FUS. Since then, researchers found that the addition of microbubbles or contrast agents improved the phenomenon's efficiency and efficacy. When the FUS vibrates the microbubbles, the movement loosens the BBB’s tight junctions and allows molecules to move from the vasculature to the targeted region of the brain. This year, the group at Columbia University completed a long-term safety study of repeatedly opening the BBB with FUS and microbubbles, finding their parameters safe for up to 20 months without any long-term negative physiological or neurological effects. The goal of using FUS for opening the BBB is to allow medications or biologics (neurotrophic factors, antibodies, stem cells, or viral vectors) to reach the brain when they normally would not.

Can FUS Unlock Treatment Options for Other Neurological Diseases?

With the fundamental mechanism established for opening the BBB with FUS and microbubbles, scientists around the world are working to advance the potential of FUS to play an integral role—either alone or in combination with other therapies—in the treatment of several neurological diseases. For example, pre-clinical research has been evaluating the use of FUS to deliver therapies to treat:

• Brain tumors/brain metastases with chemotherapy or immunotherapy
• Alzheimer’s disease with antibodies or stem cells
• Parkinson’s disease with neurotrophic factors
• Epilepsy

Foundation-supported BBB Research

The Focused Ultrasound Foundation is committed to advancing the use of FUS to open the BBB and treat a range of neurological conditions. In addition to supporting research through our funding awards, we have organized several workshops exploring this topic, including a September 2013 BBB Workshop, a February 2015 Immunotherapy Workshop, and a September 2015 Alzheimer’s Workshop.

The Foundation funded Sunnybrook’s first-in-human clinical trial through the Cornelia Flagg Keller Memorial Fund for Brain Research. In addition, we have supported six major BBB studies since 2011, and our initial investment of $300,000 has yielded more than $3 million in follow-on funding.

A Packaged Deal

Scientists are working on various methods of packaging drugs and biologics to do two things:

• Help the therapeutic molecules travel through the BBB and brain tissue by reducing their “stickiness.”
• Use focused ultrasound to “open” the package only at the precise location where they are needed.

In this type of packaging, “carrier vehicles” may more effectively deliver the proper clinical dosage to the correct region of the brain. Drugs, proteins, and genes can be packaged in microbubbles, nanoparticles, or viral vectors.

Who is Packaging Medications and Biologics?

Johns Hopkins University has a molecular packaging plant, and so do other academic institutions and private companies. Some of the companies have spun out of the academic centers and continue to collaborate with them. From Colorado to Virginia, then north to Boston and Toronto, scientists have a broad range of ideas and products that will assist the process of delivering drugs and biologics across the BBB. 

BBB Research Teams

Scientists at leading institutions across the globe are continually working to define and refine the technological parameters that enable the opening of the BBB with focused ultrasound. Throughout the past year, we have profiled several of the institutions, engineers, and individual researchers who are advancing this important application of the field. Read more about the teams at:

• Sunnybrook Research Institute
• Columbia University
• Brigham and Women’s Hospital/Harvard University
• Johns Hopkins University
• The University of Virginia
• The Queensland Brain Institute
• The University of Maryland

BBB Bibliography

Many publications on the use of FUS to open the BBB are now available, and new findings are continually being published. We have compiled a brief, alphabetical bibliography that includes some of the more recent review papers and those that provide a broader overview of this exciting field.

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