I want you to think back to 2014: All About That Bass by Megan Trainor is playing on the radio, Gone Girl just came out in theaters and you can’t scroll through Facebook without seeing your family and friends dump ice water on their head for the ALS “Ice Bucket Challenge”. What may have been a fad that lasted a few months actually led to accelerated scientific research into ALS (Amyotrophic lateral sclerosis, also known as Lou Gehrig's disease). A report in 2019 showed that the money raised from the Ice Bucket Challenge increased ALS funding by 187% worldwide. Now, I don’t know for sure if there is a direct connection or not, but a new study from a lab out of Northwestern University in Chicago last month introduced the first chemical compound to reverse ALS-induced damage in the brains of mice. In this blog post, we are going to get into what ALS is, how this new compound seems to work, and the next steps in (hopefully!) developing a treatment for individuals with ALS. Let’s dive in!
ALS is a neurodegenerative disease that causes the death of cells in the nervous system that are responsible for controlling muscles. Early symptoms will appear as muscle twitching or stiffness that then progress to muscle wasting and trouble speaking and/or swallowing. Individuals with ALS (a person that usually comes to mind is Stephan Hawking) will eventually suffer from paralysis and respiratory failure that leads to their untimely death. It is a brutal disease because it is progressive and can affect individuals for years, and furthermore, treatments are lacking. Because the root of the problem in ALS are cells in the nervous system, to be a successful treatment, selected drugs need to be able to access the brain which is always a challenge for drug development.
Let’s zoom into the brain and get a more microscopic view of ALS. To initiate any voluntary movement (raising a hand, lifting a finger, kicking a foot…etc), cells in the brain (called “neurons”) send a signal to other neurons in the spinal cord. These spinal cord neurons can then send their own signal directly to whichever muscle needs to move. You can think of this kind of like a relay in track, where the runners are the neurons and the signal is the baton being passed. In neuroscience, the cells located in the brain are referred to as “upper motor neurons” and the cells in the spinal cord are referred to as “lower motor neurons”. Interestingly, ALS leads to the cellular death of both upper and lower motor neurons, though this new potential treatment focuses on just upper motor neurons (ie: the ones in the brain).
Let’s zoom in even further! For proteins that are made within the cells to be fully functional, they need to be folded into specific 3-D shapes. However, sometimes they can be misfolded due to genetic mutations, environmental factors, or simply through the process of ageing. When proteins are misfolded, they bunch together and form toxic aggregates inside of cells which can lead to dysfunctional cells or even cell death. This protein aggregation and accumulation is not unique to ALS, it also occurs in several other neurodegenerative diseases like Dementia, Parkinson’s Disease and Huntington’s Disease. Depending on the disease, these protein aggregates are called different names, in ALS, they are called “Bunina bodies” and in 95% of ALS cases, a specific protein called “TDP-43” is the culprit.
So, it makes sense that a treatment for ALS would have to accomplish several things to be considered successful. It would have to be able to access the brain (this is challenging because the brain is protected by a barrier that several compounds are unable to cross), it would have to decrease these TDP-43 proteins from aggregating, and it would have to repair the neurons that were damaged. A compound called NU-9 created in a lab at Northwestern University seems to check all of these boxes. Researchers gave this NU-9 compound to mice that they genetically altered to have ALS. Compared to mice treated with a vehicle (think of a “vehicle” as the “placebo” of animal studies), the mice with ALS given NU-9 had improved motor neuron health. Specifically, cellular components like the mitochondria (you may have heard it referred to as “the powerhouse of the cell”) and the endoplasmic reticulum (responsible for producing and folding proteins) regained health and integrity which improved their function and the function of the neuron as a whole. After 60 days of NU-9 treatment, the neurons that were once diseased began to resemble normal and healthy motor neurons. Behaviorally, mice with ALS that were treated with NU-9 performed better on motor-based tasks like hanging on a suspended wire, which normal mice are usually pretty good at.
Now, all of this sounds amazing, and it truly is! However, we are a long way away from seeing NU-9 be an ALS treatment in humans. Though this compound has been successful in a cell line and in mice, researchers must still perform more toxicology studies and pharmacology studies on the long-term effects and metabolism of NU-9 before it can be approved for a Phase 1 clinical trial. Even if it is approved to begin clinical trials, it faces an uphill battle. For drugs targeting the central nervous system, the probability of success through Phase 1 is 73%, Phase 2 is 52%, and Phase 3 is 51%. This makes the overall success rate of a drug making it through all three phases of clinical trials around 15%.
Regardless of whether NU-9 makes it to market, this research has contributed to our knowledge of neuroscience and potentially informed other researchers studying ALS and other neurodegenerative diseases. Though passing clinical trials and getting FDA approval is the ultimate goal, there are many other important achievements along the way. You all know that cheesy quote: “shoot for the moon, if you miss, you’ll land among the stars.” Well, science research is kind of like that.
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