Brain drugs can now cross the once impermeable blood-brain barrier

New technologies for transferring drugs to the brain show prospects for Alzheimer's disease, cancer and much more.

Daiza Gordon watched her two younger brothers die when they were teenagers. They had Hunter syndrome, a rare, incurable disease that mainly affects boys, in which the gene of an important enzyme is missing. The guilt aggravated her grief when her attempts to resuscitate her younger brother failed. She was only 19 years old.

Gordon continued to find out how ruthless genetics can be. All three of her own sons were born with this condition. When her two elders celebrated their second birthday, symptoms began to appear: thickening of facial features, loss of tongue, hearing and movement, as well as other consequences for mental and physical development.

But she sees hope for her sons, which was denied to her brothers. Her children are included in a clinical trial, testing a technology to transfer the replacement of the missing enzyme called iduronate-2-sulfatase (IDS) to the brain. Early results indicate an improvement in some cognitive and physical symptoms of the condition. Gordon's older sons are no longer deaf, and they started running. They meet milestones of development that she never dared to hope for. Her two-year-old child, who started therapy when he was only three months old, has no early symptoms. "When I look at them, I realize that they have a chance for a real future," says Gordon.

Regular IDS replacement infusions have been the standard of care for the past two decades, and it protects important organs such as the liver and kidneys from damage. But without help, a large enzyme cannot pass through the Protective Barrier, which separates blood from one of the most important organs - the brain.

For Gordon's children, this help comes from an innovative molecular transport system, a chemical tag attached to the IDS, which carries it through tightly bound cells that make up the blood-brain barrier. Several such shuttles are currently being developed that take advantage of natural transport systems in the brain. Due to the ability to move large biological drugs, including antibodies, proteins and viruses used in gene therapy, these shuttles promise to revolutionize neuropharmacology. And this is not only for rare diseases such as Hunter syndrome, but also for cancer, Alzheimer's disease and other common brain disorders.

This field is in its infancy, and much remains to be learned about how to target large therapeutic molecules at the exact places in the brain where they are needed, says James Gorman, chief researcher of the Weiss Institute's Brain Targeting Program at Harvard University in Boston, Massachusetts. Nevertheless, the excitement is palpable. "It seems that every large company in this space has a program to develop brain shuttles," he says.

Hit the wall

Floating in its protective bag in the sea of cerebrospinal fluid, the human brain is a very demanding organ. Its abundant metabolic and other needs are provided by approximately 650 kilometers of large and small blood vessels, which are lined with a layer of densely packed endothelial cells. This lining forms a blood-brain barrier that holds toxic molecules, while allowing them to pass to those that are necessary for the brain. Oxygen and other small, fat-soluble molecules simply dissipate. But some molecules, such as iron and glucose, require specialized transporters that are embedded in endothelial cells.

Pharmaceutical developers, as a rule, tried to keep brain drugs small and fat-soluble enough to pass unhindered through the blood-brain barrier. Some small synthetic drugs use transporters - for example, a drug for Parkinson's disease, levodopa, which drives on a conveyor, which usually provides access to an amino acid.

But large biological preparations require a different approach that offers new ways to interrupt disease processes, such as splitting protein splots, replacing missing enzymes and fixing or replacing faulty genes. These medicines do not cross easily.

Over the past four years, the U.S. Food and Drug Administration (FDA) has approved several antibodies targeting amyloid proteins that form brain plaques in Alzheimer's disease. These are the first methods of treatment that fight the underlying disease Pathology, but less than 0.1% of the intravenous dose passes through the blood-brain barrier.

"Since so few antibodies get into the brain, you have to give high doses - a waste of material and a probable source of side effects, which are sometimes serious," says neurobiologist Doug Selin from Uppsala University in Sweden.

How this small amount of antibodies penetrates the strength of the brain has been a mystery until the last year or so. Studies now show that its path is indirect, penetrating into the cerebrospinal fluid from the blood vessels in the brain sac, where the barrier is somewhat less dense1.

This route is far from optimal. When small molecules directly cross the blood-brain barrier, they enter the smallest capillaries that serve brain cells. When large molecules enter the cerebrospinal fluid, they tend to hang around the outside of the arterial blood vessels, which carried them where most of the brain's amyloid also settles. This creates two problems. Antibodies do not spread to deeper parts of the brain, and they can attack amyloid near blood vessels, causing inflammation and minor bleeding that can be life-threatening.

Scientists have been looking for the best, direct ways to the brain for more than 25 years, says Azad Bonnie, who heads research and development in the field of neurology at the pharmaceutical company Roche in Basel, Switzerland, "but only now everything is really taking off".

The most advanced approach tries to use a system involved in ensuring the supply of iron to the brain, which is necessary for many important enzymes and is transferred through the blood by protein transferrin. This large iron-bearing molecule is carried through the blood-brain barrier by transferrin receptors on endothelial cells.

With sufficient skills in the field of protein engineering, almost any therapeutic biological agent could be helped to pass through the barrier by attaching it to a molecular structure that targets the receptor in the same way as transferrin does, says Bonnie. The design usually includes a small part of the antibody created to bind to the receptor.

"It took many years of research to figure out how to make a safe brain shuttle," Bonnie says. The researchers had to make sure that it would not interfere with the normal function of the transferrin receptor; so that it did not get stuck inside endothelial cells; and that the therapeutic agent it transmits still works when it reaches its goal.

The brain room passes

The shuttle-based therapy is being actively developed for a number of brain diseases. "Now it is quite clear that we can get these drugs through the blood-brain barrier," says Gorman. "The big grain we face is how to effectively deliver them to where they need to get into the brain for different diseases and with different loads."

Some diseases are particularly well amenable to brain shuttles. Hunter syndrome was one of the first to benefit. It is part of a family of rare genetic diseases known as lysosomal diseases. Lysosomes are subcellular waste treatment centers that contain enzymes (including IDS) that break down cell waste products.

Cells treat foreign proteins, such as therapeutic IDS, as waste, and direct them directly into the lysosome, says Gorman, "which is ideal, because that's where the replacement enzyme should be."

In 2021, enzyme replacement therapy for Hunter syndrome, developed by JCR Pharmaceuticals in Asia, Japan, became the first and so far the only brain shuttle-based treatment that was allowed anywhere in the world. It is not yet available outside of Japan. Denali Therapeutics, a brain shuttle company based in San Francisco, California, which conducts trials involving Gordon's children, received accelerated designations from American and European drug regulatory agencies to speed up the approval process.

Alzheimer's disease is another disease for which pathology gives a logistical advantage of transfer technology. Amyloid plaques, which are targeted by preparations with antibodies, develop in the spaces between neurons. Thus, the shuttle should not enter the cells as soon as they pass through the blood-brain barrier. The first mobile antibody to go into clinical trials was trontinemab developed by Roche, and the intermediate results look encouraging. In April, Roche reported that in a small number of study participants, the drug purified the amyloid three times faster and by one fifth dose than the same antibody without a shuttle, and with much less brain edema. Early clinical trials continue.

Researchers working on transferrin-based shuttles are studying other possible target conditions, such as lysosomal diseases, neurodegenerative disorders, as well as some types of cancer for which therapeutic antibodies have become the standard of treatment. For example, researchers make shuttles to transfer the breast cancer drug herceptin and similar antibodies to the brain to treat tiny metastases that cannot be achieved in other ways.