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Pharmacological Chaperone Monotherapy
Endogenous Protein Instability in Human Genetic Diseases Many natural (endogenous) proteins are made in the endoplasmic reticulum (ER) and sent to other parts of the cell. Unstable, unfolded or misfolded proteins are generally eliminated or retained in the ER rather than being transported to the intended destination in the cell. The accumulation of unfolded or misfolded proteins in the ER and the interruption of trafficking of important proteins to their proper cellular locations can cause several types of problems:
Complete or partial loss of appropriate protein function
Accumulation of lipids and other substances that should be degraded
Disruption of cellular function and eventual cell death
These defects may lead to various types of human genetic diseases, including lysosomal storage disorders (LSDs).
Overview Pharmacological chaperones as orally administered monotherapy agents have the potential to deliver new benefits to patients with human genetic diseases. Examples include certain LSDs, such as Gaucher and Fabry disease, as well as neurodegenerative diseases such as Parkinson’s disease.
Proposed Mechanism of Action
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As monotherapy agents for lysosomal storage diseases, pharmacological chaperones are designed to bind to and stabilize endogenous protein (lysosomal enzyme) for proper trafficking to the lysosome, which also alleviates the toxic build-up of mutant proteins in the ER. Once in the lysosome, the pharmacological chaperone disassociates and the enzyme is free to break down substrate. Based on this mechanism, individuals with genetic mutations that result in some residual biological activity are potentially eligible for pharmacological chaperone monotherapy.
