30-31 The Brain

The blood-brain barrier (BBB) is the brain’s self-defence mechanism, keeping out bacteria and viruses but allowing in vital nutrients; unfortunately, it also blocks a very high per cent of drugs designed to treat neurological conditions.

Neurological diseases affect the central and peripheral nervous system, which includes the brain, spinal cord and nerves.

Here, we discuss current approaches to delivering drugs into the central nervous system (CNS), focusing on the specific challenges for key therapies like gene-silencing drugs that aim to treat rare neurological diseases. Almost half of the 8,000-10,000 known rare conditions are neurological.

The language surrounding novel approaches to CNS drug delivery can sometimes seem dramatic; there is talk of smuggling, piggybacking and Trojan horses. But however they are described, they are all designed to help alleviate the suffering caused by these predominantly severely debilitating diseases.

The BBB routinely blocks large or water-soluble molecules, but it is less strict about lipid compounds, which do not dissolve in water. Depending on your perspective, this is either good or bad – alcohol, nicotine and caffeine are lipid-soluble, so they slip seamlessly through – which is why you feel the buzz of a coffee or beer almost instantly.

Thicker than water

The CNS, like all major organs, requires a huge, constant supply of blood, which it receives via the carotid and vertebral arteries, delivering oxygen, nutrients, vitamins and hormones to every cell while removing harmful by-products such as carbon dioxide.

The brain needs about 20% of the body’s total oxygen consumption and is very sensitive to oxygen depletion, starting to lose cells within minutes when deprived.

Oxygen crosses the BBB via simple passive diffusion straight through the lipid membranes of endothelial cells, simply because an oxygen molecule is very small and lipid-soluble. Lipids are fatty, organic compounds that do not dissolve in water.

Stop right there

The endothelium is a one-cell-thick layer that lines the interior surface of blood vessels and the heart; the cells are tightly packed, leaving no gaps for large or water-soluble substances. The BBB prevents roughly 98% of small-molecule drugs and nearly 100% of large-molecule or protein-based therapeutics from passing. Only tiny, highly fat-soluble molecules can easily pass by slipping directly through the cell membranes.

And if something unexpected or unwanted, like pesticides and pollutants ingested through food or water, or excess steroid hormones such as cortisol or progesterone, does make it through, then special proteins actively eject it back out into the bloodstream.

Some drugs are chemically engineered to ‘piggyback’ on natural carrier systems that transport essential nutrients like glucose or amino acids into the brain, but nature already knows about such tricks; viruses like HIV infect white blood cells, certain types of which the BBB lets through to patrol the brain – the pathogens ride inside them like a Trojan horse.

Ways and means

The most frequently adopted mechanism for crossing the barrier is known as receptor-mediated transcytosis (RMT), which moves molecules across a cell layer by binding to cell-surface receptors.

For complex, large therapeutics like monoclonal antibodies and gene therapies, RMT is the primary and most successful strategy. The drug is attached to a ligand or antibody that binds to receptors on the surface of endothelial cells. Ligands are molecules that bind to a larger biomolecule, such as a receptor protein.

When ligands bind to receptors on bloodstream-side endothelial cells it triggers a process called endocytosis, in which the cell engulfs the receptor, the ligand and anything else attached. These are captured in a vesicle that moves through the inside of the cell to the CNS side, releasing its cargo out of the cell and into the CNS. The best-known example is the transferrin receptor, which transports iron into the brain.

Most success has been achieved by using antibodies as ligands to ferry an attached drug across the barrier. Researchers are also testing antibodies that can not only trigger RMT but also bind to targets once inside the brain. One such antibody, called trontinemab, is in phase 3 clinical trials for treating Alzheimer’s disease.

For smaller molecules, lipid nanoparticles are being developed to ferry gene-based therapeutics, such as antisense oligonucleotides (ASOs), into the brain. Another approach uses ultrasound waves.

By injecting tiny gas bubbles into the bloodstream and exposing them to ultrasound waves, the bubbles vibrate and gently push the tightly packed barrier cells apart for a few hours, letting medication slide through.

The gene genie

The range of advanced treatments that fall under the general term gene therapy can be grouped into three types. The first is gene editing, where DNA itself is modified. The second is virus-based therapy, where working versions of faulty genes are delivered directly into affected areas. The third is gene silencing, where mutated genes are prevented from producing their associated toxic proteins; critically, the gene itself is untouched.

In general, gene silencing causes fewer side effects and is highly suitable for monogenic diseases, those caused by a single-gene mutation. ASOs are a key gene-silencing technology, but they are large and cannot naturally pass through the BBB.

The current clinical standard for delivering ASOs into the CNS is injection directly into the cerebrospinal fluid (CSF), but ASOs are large molecules and cannot efficiently cross the BBB on their own. As noted above, they are quickly cleared by the liver and kidneys when delivered intravenously.

So advanced delivery strategies have been developed to allow intravenous (IV) or subcutaneous ASO administration, including the use of transferrin receptors to trigger endocytosis and get those drugs into the CNS.

Final analysis

The blood-brain barrier is one of evolution’s greatest achievements, protecting the brain from harmful, blood-borne substances while allowing in necessary supplies of the good stuff.

But neurological diseases are a huge global health challenge, one that cannot easily be addressed by conventional drugs, administered orally or intravenously, that are carried in the blood.

Recent advances in genomics, biology and computing have given us the understanding and ability to design drugs, and methods of delivering those drugs, that circumvent in one way or another the brain’s self-defence mechanism. This is especially important for those living with rare diseases, almost all of which have major neurological impacts.

Beyond the challenges of getting drugs into the brain, these patients have further problems with physical drug delivery mechanisms; for key therapies like gene-silencing drugs, today’s default approach of injecting directly into the spinal fluid is both risky and uncomfortable.

New and rapidly emerging approaches, based on piggybacking, smuggling and Trojan horses, are making IV-based solutions once more feasible and cost-effective – very good news for those living with a rare disease.