Trehalose Inhibits AKT to Activate CLEAR Network for Lysosomal Clearance
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Solution Overview
Problem
Current treatments lack effective solutions for lysosomal storage disorders and disorders characterized by lysosomal dysfunction, with no cures or approved treatments available for conditions like Batten disease, and existing drug development challenges due to insufficient understanding of the in vivo pathways regulating TFEB and the CLEAR network.
Innovation Solution
Administration of a therapeutically effective amount of a composition comprising a protein kinase B inhibitor, such as trehalose or MK-2206, to inhibit AKT, thereby activating the CLEAR gene network and enhancing lysosomal clearance, which includes using trehalose alone or in combination with a trehalase inhibitor like miglustat.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If no treatment is administered for lysosomal storage disorders, then the natural progression of the disease continues with accumulation of undegraded materials, but current available treatments also fail to effectively clear these materials and provide cure
Solution Approach 1:
The patent changes the biochemical parameter of AKT activity through inhibition, which triggers a cascade effect leading to increased lysosomal clearance. By modifying the activity state of AKT (from active to inhibited), the system transitions to a state where lysosomal degradation is enhanced, thereby clearing undegraded materials that accumulate in lysosomal storage disorders
Solution Approach 2:
The patent introduces AKT as an intermediary regulator between cellular metabolism and lysosomal function. By targeting AKT with inhibitors, the treatment indirectly activates the CLEAR network and enhances lysosomal clearance without directly modifying the defective lysosomal enzymes, thus providing a novel therapeutic approach
2Ease of manufacture
If drug development targets TFEB and CLEAR network directly, then potential treatment efficacy may be achieved, but the insufficient understanding of in vivo pathways regulating TFEB makes drug development challenging
Solution Approach 1:
The patent uses AKT as an upstream intermediary that connects to the TFEB-CLEAR network. By targeting AKT instead of directly targeting TFEB or the CLEAR network, the invention provides a more accessible drug development target with better understood pharmacology, while still achieving the desired effect of enhancing lysosomal clearance through the AKT-TFEB pathway
Solution Approach 2:
The patent performs preliminary action by inhibiting AKT upstream in the signaling pathway, which subsequently leads to activation of TFEB and the CLEAR network. This upstream intervention simplifies drug development by targeting a well-characterized kinase with existing inhibitor tools, rather than attempting to directly modulate the less understood TFEB regulation mechanisms
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
Inhibiting AKT with trehalose or MK-2206 leads to enhanced clearance of undegraded materials, improved symptoms in neurodegenerative diseases, and extended lifespan in animal models of lysosomal storage disorders like juvenile Neuronal Ceroid Lipofuscinosis, demonstrating potential for treating lysosomal storage disorders and disorders characterized by lysosomal dysfunction.
Implementation Method 1
Administration of a therapeutically effective amount of a composition comprising a protein kinase B inhibitor, such as trehalose or MK-2206, to inhibit AKT
Data Source
Figure 1a~1d
Figure 2
Figure 3a~3b
AI summary
The present invention relates to compositions and methods of treating lysosomal storage diseases and methods of using trehalose.