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May 8
2019

Research Byte: How resistance to treatments happens over time in ALS

Research Bytes
A new research study offers profound insight as to why this diminishing response to treatment occurs.

The US Food and Drug Administration has approved only two drugs for the treatment of amyotrophic lateral sclerosis (ALS).  Although these drugs can moderately slow disease progression, ALS patients often become unresponsive to the medications over time. A new research study led by Packard Center Scientific Director Dr Piera Pasinelli and Packard investigator Dr. Davide Trotti, both of the Weinberg ALS Center at Thomas Jefferson University, offers profound insight as to why this diminishing response to treatment occurs. Their work, published this month in Experimental Neurology, unlocks the mechanism behind the drug-resistance phenomenon, and offers novel targets that could be used to improve the efficacy of existing ALS treatments as well as improvements in trial design for new and better drugs.

One of the most critical signaling molecules in your brain is glutamate, which stimulates communication between brain cells like neurons and astrocytes. Glutamate is best in moderation - too little and cells can’t effectivity communicate, but too much leads to overstimulation of neurons and cell death. Excess glutamate in blood and fluid surrounding the brain is a characteristic of ALS, and one of the approved ALS drugs, riluzole, works by blocking excess glutamate signaling.

The blood brain barrier (BBB) is the name for a collective network of cells that is designed to regulate the movement of substances between your bloodstream and your brain. Similar to how security guards at a concert only allow ticketholders to enter the venue, the BBB allows specific molecules from your blood to enter the brain while preventing harmful toxins or pathogens gaining entry.  A component of the BBB that controls the movement of compounds out of the brain and into the blood is called P-glycoprotein, or P-gp. The transporter not only stimulates BBB passage of naturally occurring compounds in your body, such as glutamate, but also promotes the exit of many exogenous drug treatments, including the ALS medication riluzole.  Previous research from Drs. Pasinelli and Trotti and others has shown that BBB levels of P-gp increase in neurological diseases including ALS. This creates quite a dilemma for patients, because P-gp is moving drugs like riluzole out of the brain… where they need to be in order to work! 

Until now, the mechanism of how P-gp expression levels increase in ALS has been unknown. Using tissues and cells from patients with both sporadic ALS and the SOD1 mutation, along with a variety of complex molecular techniques, the team of scientists led by Drs. Pasinelli and Trotti definitively showed that glutamate is responsible for the increased number and activity of Pg-p transporters in ALS.  The researchers also showed the reverse effect to be true - that blocking glutamate signaling inhibits Pg-p function.  The authors reiterate that this P-gp upregulation phenomenon is, “a major barrier for riluzole and many other existing and new therapies to cross the BBB and reach their therapeutic targets.”

This exciting research from the Jefferson Weinberg ALS Center verifying that glutamate is what causes P-gp upregulation in the BBB in ALS patients raises several new ideas regarding how to improve ALS treatments. Future studies are planned by the laboratories to test if blocking glutamate signaling and similar pathways could stop P-gp overexpression, which would help to identify a drug that could be used in combination with riluzole and other ALS therapies to improve their efficacy.  The ALS community will eagerly anticipate these next steps, as the work is relevant for not only the smaller population of patients with the SOD1 mutation, but also the ~90% of all ALS patients who have a sporadic form of the disease. 

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