Note: This educational article is presented by the ALS Therapy Development Institute (ALS TDI). ALS TDI is a nonprofit biotech and the world’s most comprehensive drug discovery institute dedicated solely to ALS. To learn more about ALS TDI and our work to end ALS, click here.

Amyotrophic lateral sclerosis (ALS) is a disease of the central nervous system. It causes motor neurons, the cells that create movement and carry signals from the brain to the muscles throughout the body, to atrophy and die. In order to treat ALS, researchers often seek out medications that can reach these affected motor neurons in the brain.

This task can be complicated because of something known as the blood brain barrier (BBB). The BBB serves to protect the brain by preventing potentially harmful pathogens like viruses and bacteria, as well as some chemical poisons, from reaching the central nervous system through the blood. While its name may conjure an image of a physical wall around the brain and spine, it is made up of specialized blood vessels.

The Circulatory System, the Brain, and the BBB

Blood vessels, the tubular structures that allow blood to move throughout the body, are part of the circulatory system. There are three types of blood vessels: arteries, which carry blood from the heart to the organs, veins, which carry blood from the organs back to the heart, and capillaries, which connect veins and arteries. The heart is pumping blood through this system with every beat – carrying oxygen and nutrients to the rest of the body and removing waste products from tissues, among many other functions.

The blood vessels that connect the central nervous system to the circulatory system are different from those throughout the rest of the body. The cells in the capillaries of the brain are very tightly packed together and are much more selective about the substances that they will allow the blood to carry into the brain.  This allows molecules such as oxygen or carbon dioxide to pass in and out of the brain, while severely limiting the ability of other compounds from reaching it.  The cells in these capillaries also contain active pumps that will shuttle potentially toxic substances out of the BBB.  

The BBB and ALS Drug Development 

The BBB serves an essential purpose, protecting the central nervous system, which controls all other functions in the body, from infection and toxicity. However, its presence creates a challenge for researchers investigating treatments for many neurologic diseases, including ALS. Many of the most common routes of administration for drugs, such as taking a tablet or liquid orally or having intravenous infusions, require the treatment’s active ingredients to travel through the bloodstream to their target. Any treatment that researchers hope will reach the central nervous system through the blood must be able to pass through the BBB to reach its target. All large molecule and the majority of small molecule drugs, two of the most common types of therapeutics, are very limited in their ability to pass the BBB.  

Pharmaceutical researchers have devised some ways of getting around this issue, although they all have their limitations.

  • Many therapies for neurodegenerative diseases, including many investigational ALS treatments, are delivered by intrathecal, or spinal, injection. This releases a drug or other treatment directly into the cerebrospinal fluid, bypassing the circulatory system entirely. These injections are invasive and must be performed by a specialized healthcare provider, meaning it usually requires a patient to go to a hospital or clinic to receive each dose of their medication.
  • Another strategy is to engineer a drug to attach to a “Trojan horse molecule.” By binding the active molecule in a drug to a second molecule that can pass through the BBB, drug developers can, in some cases, “trick” the blood vessels around the brain into allowing a treatment through. This process can be very technically challenging, only works for certain molecules, and often carries a risk of toxicity.
  • Researchers have also developed some ways of temporarily increasing the permeability of the BBB, making it easier for molecules to cross over into the brain. This can be accomplished pharmaceutically or through physical techniques such as ultrasound, which has been tested in ALS. This could potentially allow therapeutics that could not normally cross the BBB to reach the brain without any modification. However, making the BBB more permeable also carries the risk of allowing the pathogens that it normally defends the brain against an opportunity to pass through.
  • However, even if a drug makes it past the BBB into the CNS, there are more obstacles it must face. A protein found in cells in the BBB called P-glycoprotein (P-gp) can actively pump molecules that have reached the brain back out into the bloodstream. This process of pumping certain molecules out of the brain’s cells is known as “P-GP transporter efflux.” P-gp can target a wide variety of molecules – including many of the kinds used as drugs – to transport back across the BBB. This can even affect drugs delivered directly to the CNS through intrathecal injection. One potential solution to this challenge is to use a second drug that suppresses this protein in conjunction with a treatment that needs to pass the BBB.

Another Way Around the BBB Issue – Treating Other Parts of the Body

While many investigational ALS treatments rely on reaching the central nervous system – and therefore must find a way to get past the BBB – this is not always the case. There are many therapies that seek to treat ALS by modulating the immune system. These include monoclonal antibody treatments such as tegoprubart, a drug invented by the ALS Therapy Development Institute (ALS TDI) that recently successfully completed a phase 2a clinical trial. Other treatments might seek to address the functional  effects of ALS, such as Cytokinetics’ reldesemtiv, which directly targets the muscles of people with ALS to potentially help them contract better.

At ALS TDI, we know that it will take many treatments to end ALS. That’s why every day we’re working in our lab to address challenges like identifying drugs that can pass the BBB – or that are able to work effectively without reaching the brain. As the Drug Discovery Engine for ALS, it is our mission to continue this work until there are effective treatments for the disease.

To learn more about our research to end ALS, visit:

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