Sigma-1 Receptor Activator for Wolfram Syndrome
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Solution Overview
Problem
Current treatments lack effectiveness for Wolfram Syndrome and Wolfram-like Syndrome, which are caused by mutations in the WFS1 gene, leading to severe neurosensory impairments, diabetes, and hearing loss, with no available cure beyond palliative care.
Innovation Solution
Activation of the Sigma-1 receptor (SIG-1R) using activators such as PRE-084 or overexpression of the SIG-1R protein to alleviate the functional alterations associated with wolframin deficiency, thereby addressing the underlying mitochondrial dysfunction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If palliative treatment is provided for diabetes, then survival time is extended, but disease progression is not halted and patients die on average at 35 years old
Solution Approach 1:
The patent applies preliminary action by activating the Sigma-1 receptor before severe mitochondrial dysfunction and neurosensory impairments fully develop. The activator prevents the progression of Wolfram Syndrome by stabilizing IP3R1 conformation and maintaining proper calcium homeostasis in the endoplasmic reticulum, thereby preventing the cascade of pathological events that lead to organ failure and death
Solution Approach 2:
The Sigma-1 receptor activator serves as an intermediary substance that mediates between the mutated WFS1 gene product (wolframin) and the downstream mitochondrial dysfunction. By binding to and activating SIG-1R, the compound compensates for wolframin deficiency and restores proper ER-mitochondria communication, preventing the harmful effects of mitochondrial dysfunction
2Reliability
If WFS1 gene mutations are present, then Wolfram Syndrome and related pathologies develop, but no effective treatment is currently available
Solution Approach 1:
The patent applies parameter changes by modifying the functional state of the Sigma-1 receptor through pharmacological activation. The activator changes the conformational parameters of IP3R1 and the calcium release parameters from the endoplasmic reticulum, thereby restoring normal cellular function despite the presence of WFS1 mutations. This provides a new therapeutic parameter (SIG-1R activation) that can be targeted to treat Wolfram Syndrome
3Reliability
If SIG-1R is activated, then mitochondrial function is improved and behavioral symptoms are alleviated, but the underlying genetic mutation remains untreated
Solution Approach 1:
The patent converts the harmful effect of WFS1 mutation (wolframin deficiency leading to mitochondrial dysfunction) into a beneficial therapeutic opportunity. By identifying that SIG-1R activation can compensate for wolframin deficiency and restore mitochondrial function, the patent transforms the genetic defect into a target for pharmacological intervention. The harmful genetic mutation becomes the rationale for using SIG-1R activators as a disease-modifying treatment
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The activation of SIG-1R has been shown to alleviate behavioral symptoms, memory deficits, anxiety, and hyperlocomotion in animal models of Wolfram Syndrome, indicating its potential as a therapeutic target for treating pathologies associated with WFS1 mutations.
Implementation Method 1
By stabilizing the conformation of inositol 1,2,4-trisphosphate receptor type 1 (IP3R1), SIG-1R enhances the efflux of Ca2+
Data Source
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AI summary
The present invention pertains to a compound for its use in the prevention or the treatment of a pathology associated with a mutation of the WFS1 gene. More particularly, the present invention concerns an activator of the Sigma-1 receptor (SIG-1R) for the prevention or the treatment of a pathology associated with a mutation of the WFS1 gene, in particular for the prevention or the treatment of Wolfram Syndrome and of Wolfram-like syndrome.