Engineered Oxalate Decarboxylases for Hyperoxaluria Treatment
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Solution Overview
Problem
Current treatments for hyperoxaluria, such as dietary restrictions and enzyme-based therapies, have limitations in effectively reducing oxalate levels and preventing kidney damage, with existing enzyme therapies showing variable efficacy and potential side effects.
Innovation Solution
Engineered oxalate decarboxylase (ODC) polypeptides with enhanced catalytic activity, reduced protease sensitivity, and increased stability at low pH environments are developed, providing a more robust therapeutic option for hyperoxaluria by degrading oxalate in the gastrointestinal tract.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing enzyme-based therapies are used to reduce oxalate levels, then oxalate degradation is achieved, but the therapies show variable efficacy and potential side effects
Solution Approach 1:
The patent applies parameter changes by modifying the enzyme's amino acid sequence to alter its catalytic properties, pH stability, and protease resistance. This resolves the contradiction by creating an enzyme with optimized parameters that achieves more reliable oxalate degradation while reducing side effects through improved stability and reduced immunogenicity
Solution Approach 2:
The patent creates a recombinant copy of the oxalate decarboxylase enzyme from Gemmata sp. SH-PL17, producing an engineered version that replicates the natural enzyme's function while incorporating beneficial mutations. This copying approach allows optimization of the enzyme's properties to improve efficacy and reduce harmful effects without changing the fundamental catalytic mechanism
2Object-affected harmful factors
If dietary calcium is increased to bind oxalate in the colon, then oxalate precipitation is reduced, but CaOx urine supersaturation increases
Solution Approach 1:
The patent introduces an intermediary approach by using engineered oxalate decarboxylase as a mediator that converts oxalate to formate and CO2 before calcium can bind to it. This resolves the contradiction by eliminating the need for calcium-oxalate binding, thereby preventing both colonic oxalate absorption and urinary supersaturation through a different mechanistic pathway
3Object-affected harmful factors
If bile acid sequestration agents are used to reduce oxalate adsorption, then oxalate absorption is reduced, but steatorrhea and malabsorption worsen
Solution Approach 1:
The patent uses engineered oxalate decarboxylase as an intermediary that directly degrades oxalate in the gastrointestinal tract, converting it to formate and CO2. This resolves the contradiction by providing a targeted approach that reduces oxalate absorption without affecting fat absorption, thereby avoiding steatorrhea and vitamin malabsorption associated with bile acid sequestration agents
4Productivity
If engineered ODC polypeptides are developed with enhanced catalytic activity, then oxalate degradation efficiency is improved, but protein stability and resistance to proteases must be maintained
Solution Approach 1:
The patent applies parameter changes by systematically modifying the enzyme's amino acid sequence to simultaneously optimize catalytic activity and stability parameters. The engineered polypeptides incorporate mutations that enhance active site efficiency while also improving structural stability and protease resistance, resolving the contradiction between productivity and composition stability
5Quantity of substance
If treatments are designed to increase urine excretion to dilute oxalate, then oxalate concentration is reduced, but fluid intake requirements increase
Solution Approach 1:
The patent introduces oxalate decarboxylase as an intermediary that degrades oxalate in the gastrointestinal tract before absorption occurs, converting it to formate and CO2. This resolves the contradiction by preventing oxalate entry into circulation, thereby reducing urinary oxalate excretion needs and eliminating the requirement for high fluid intake to maintain dilution
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 engineered ODC polypeptides effectively reduce oxalate levels in urine and plasma, potentially reducing the risk of kidney stones and chronic kidney disease, offering a more sustainable and less restrictive treatment approach compared to existing methods.
Implementation Method 1
oxalate decarboxylase (ODC) polypeptides... degrading oxalate in the gastrointestinal tract
Data Source
AI summary
The present disclosure provides engineered oxalate decarboxylase (ODC) polypeptides and compositions thereof, as well as polynucleotides encoding the engineered oxalate decarboxylase polypeptides. The present disclosure also provides methods of using the engineered enzymes and compositions thereof for treating diseases or conditions associated with abnormal metabolism of oxalate.