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The Potential of Small Molecule Drugs for KAND:

KIF1A-Associated Neurological Disorder, or KAND, is a disorder stemming from the pathogenic mutation in the KIF1A gene in DNA. This harmful mutation comes in many different types known as variants, which can result in an improperly functioning KIF1A protein.

In humans, KIF1A proteins are responsible for the transport of substances in neurons. Because these proteins are critical tools for cells, having a protein that does not work as intended can lead to disease. The specifics of why mutated KIF1A proteins do not function properly is still under investigation. 

For many diseases, genetic mutations lead to misfolded proteins, where the protein is the wrong shape. Just like trying to use a hammer to saw wood, the protein that is the wrong shape will not perform its function properly.

Another way genetic mutations can impact protein function is by changing the way they interact with other parts of the cell. The proteins may not accept their same raw material they normally accept, or they may not bind to the same parts of the cell they normally bind to. It’s as if the locks on the front door were suddenly changed. Now the key no longer fits or functions properly.

Whether a genetic mutation causes a misfolded protein, or a change in the active site, for a small molecule drug to treat KAND, it would have to be able to correct the underlying protein dysfunction. Currently, there are no small molecule drugs that treat the underlying cause of KAND. Some small molecule drugs have shown efficacy, or effectiveness, at treating symptoms.  For example, baclofen has been prescribed to treat spasticity, a condition where muscles stiffen or tighten, becoming rigid. The mechanism of action for baclofen is thought to lie in its ability to slow the nervous system by interacting with a protein called GABA receptor.  This in turn causes the muscles to relax, thereby alleviating spasticity.  

Another drug is Keppra, which is sometimes prescribed to treat seizures. Also called levetiracetam, its mechanism of action is to attach to a protein called SV2A. This attachment is thought to help regulate neuron activity in the brain, thereby alleviating seizures.

As mentioned, in order to treat the underlying cause of KAND, a small molecule drug would need to repair whatever it is that disrupted normal KIF1A protein function. This may not be the same for every KIF1A variant. The problem could be misfolding, changes in the active site, or some other mechanisms.

Though no small molecule drugs treatment currently repairs the KIF1A protein, there are clinically available small molecule drugs for other disorders that do try to correct proteins. Understanding how these small molecule correctors work may provide some insight into the type of strategies that can be adapted and repurposed into KAND therapies.

If the disrupted protein function is caused by mutations in the gene, one approach is to potentially bypass the harmful mutation. This is the mechanism of action of a novel drug called Evrysdi, which was approved in August of 2020 to treat spinal muscular atrophy, or SMA. They do not correct mutated gene, but bypass the mutated portions, allowing for normally functioning protein to be created even if the underlying genetic information is mutated.

If the abnormal protein function is caused by misfolding, an approach could be to use small molecules to help the protein fold correctly. This class of drug is referred to as pharmaceutical chaperones. One example is KUVAN, which was approved in 2007 as a treatment for Phenylketonuria or PKU, a disease characterized by misfolding of a protein called Phenylalanine hydroxylase. The mechanism of action is thought to lie in the small molecule drug’s ability to stabilize the Phenylalanine hydroxylase protein, preventing it from becoming an incorrect shape, and thereby treating the disease.

Although Evrysdi and KUVAN are in no way treatments for KAND, they do provide insight into how a small molecule drug might work to treat the underlying causes of KIF1A-Associated Neurological Disorder, and could create a roadmap of research strategies going forward.


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