A new inlet to treating neurological disease

Image of brains showing red tracer dye, indicating passage of molecules through the blood-brain barrier
These brain images tell a story about the blood-brain barrier: At left, the brain before injection of red tracer dye. At center, an injection of tracer dye shows only a small amount of molecules can infiltrate the blood brain barrier. At right, a new approach for crossing the blood-brain barrier increases the tracer’s penetration into brain tissue.

The blood-brain barrier was designed by nature to protect the brain and central nervous system (CNS) from toxins and other would-be invaders in the body’s circulating blood. Made up of tightly-packed cells, the barrier allows nutrients to pass into the CNS and waste products from the brain to be flushed out, while blocking entry of harmful substances.

A dysfunctional blood-brain barrier can contribute to CNS diseases including Alzheimer’s and multiple sclerosis (MS). But, ironically, the same blood-brain barrier can keep out drugs intended to treat CNS disease. Scientists have long been seeking ways to overcome this obstacle.

Now, Timothy Hla, PhD, and members of his laboratory in the Boston Children’s Hospital Vascular Biology Program have found a way to selectively control openings in the blood brain barrier to allow passage of small drug molecules. Their findings were recently published in Proceedings of the National Academy of Sciences.

“We believe this discovery could lead to a safe way of delivering therapeutics into the CNS for treatment of neurodegenerative and neuroinflammatory diseases, as well as neurological cancers,” says Hla, who also is chair and professor of surgery at Harvard Medical School.

Opening portholes in the blood-brain barrier

Hla’s lab had previously done work that paved the way for development of a drug called fingolimod, which blocks a receptor known as S1P1 that regulates cell migration, adhesion, survival and proliferation. S1P1, which was discovered by Hla’s lab, is essential for the development of blood vessels and prevents “leaky” vessel walls. It has been implicated in MS, Alzheimer’s and stroke. In fact, the drug fingolimod is already FDA-approved for use in the treatment of MS.

But the role of S1P1 in regulating the blood-brain barrier was still unknown.

So, Hla’s team looked at mice that were missing the gene for S1P1 in their blood vessel cells. Using fluorescent tracers of different atomic sizes, they looked for signs of leakage. In normal mice, only a small fraction of these tracers would be able to make it into the brain. But in the mice without S1P1 in blood vessels, they saw that some tracers were much better able to pass through the mice’s blood-brain barriers and enter their brain tissue. Tracers with the mass of 1,000 to 3,000 atoms permeated freely across the barrier, but, interestingly, tracers with a mass between 7,000 and 10,000 atoms could not as a result of their size.

“Our observations revealed that S1P1 does play a key role in regulating passage across the blood-brain barrier in a size-selective manner,” says Hla.

A drug to enhance treatment of neurological diseases?

Next, the team asked if fingolimod could be administered — reversibly — to open the blood-brain barrier on demand.

Just as in the mice missing S1P1, fluorescent tracers of 1,000-3,000 atoms (but not 7,000-10,000 atoms) in size could permeate the blood-brain barrier in healthy mice that were given fingolimod for three days. After coming off fingolimod for a week, the mice’s blood-brain barriers returned to normal and no longer allowed  tracers to easily pass.

“Our findings give us reason to believe that S1P1 inhibitors could potentially be used in combination with small-molecule drugs to boost treatment of various CNS diseases,” says Hla.

Building on this concept, Hla and his team plan to see if they can further manipulate the blood-brain barrier pharmacologically to gain even more precise control over which molecules permeate into the brain and CNS.

Keisuke Yanagida (Boston Children’s/Harvard Medical School) and Catherine Liu (Weill Cornell Medicine) were co-first authors on the paper. Other authors listed here. This work was supported by the National Institutes of Health (HL89934, HL117798, HL135821, NS89323, NS95441, NS100447, HL094465), a Fondation Leducq Transatlantic Network Grant, the American Heart Association (GIA12GRNT12050110 and 15SDG227600007) and the Japan Society for the Promotion of Science.