4-Phenylbutyric Acid Mitigates ER Stress in Lysosomal Storage Disease
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Solution Overview
Problem
Current treatments are ineffective for lysosomal storage diseases such as Sandhoff and Tay-Sachs, which are characterized by progressive neural degeneration due to intralysosomal accumulation of GM2 ganglioside, leading to severe motor deficits and early mortality.
Innovation Solution
Administration of 4-phenylbutyric acid (4-PBA) or its pharmaceutically acceptable salts, co-crystals, polymorphs, solvates, analogs, and pro-drugs to mitigate ER stress, thereby inhibiting the unfolded protein response pathway and reducing apoptosis in motor neurons.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for lysosomal storage diseases, then disease progression is not halted, but patients experience progressive neural degeneration and early mortality
Solution Approach 1:
The patent converts the harmful accumulation of GM2 ganglioside and associated ER stress into a beneficial therapeutic target. By administering 4-PBA, the compound mitigates ER stress and inhibits the unfolded protein response pathway, transforming the harmful cellular stress response into a treatable condition that protects motor neurons from apoptosis
Solution Approach 2:
The patent introduces 4-phenylbutyric acid (4-PBA) as an intermediary substance that mediates between the harmful intralysosomal accumulation and the neuronal damage. 4-PBA acts as a pharmacological chaperone and ER stress mitigator, interfering with the pathological pathway and protecting motor neurons from apoptosis without directly removing the GM2 ganglioside accumulation
2Reliability
If ER stress is not mitigated, then unfolded protein response pathway remains active, but motor neurons undergo apoptosis and neurological symptoms progress
Solution Approach 1:
The patent applies preliminary anti-action by administering 4-PBA before significant neuronal apoptosis occurs. The compound preemptively mitigates ER stress and inhibits the unfolded protein response pathway, preventing the activation of apoptotic cascades before they can cause extensive motor neuron death and irreversible neurological damage
Data Source
AI summary
This application relates to the use of 4-phenylbutyric acid, as well as pharmaceutically acceptable salts, co-crystals, polymorphs, solvates, analogs and/or pro-drugs thereof for the treatment of lysosomal storage disease, in particular gangliosidoses such as Tay Sachs disease (TSD) and Sandhoff disease (SD), alone, or in combination with other compounds and/or treatments.