Reverse-Conditional Gene Model for Lysosomal Disease Treatment Timing
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Solution Overview
Problem
Current treatments for mucopolysaccharidosis VI, such as enzyme replacement therapy, provide incomplete or ineffective recovery from skeletal manifestations due to the inability of exogenous enzymes to reach affected cells or because the disease may not be reversible at the time of therapy.
Innovation Solution
Development of non-human animal models with a reverse-conditional null endogenous lysosomal storage disease gene, which can be converted to a functional gene upon treatment with a recombinase, allowing for the assessment of disease reversibility and treatment efficacy independently.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If enzyme replacement therapy is administered to treat mucopolysaccharidosis VI, then the disease progression is slowed, but complete recovery from skeletal manifestations is not achieved
Solution Approach 1:
The patent creates animal models with conditionally activatable functional genes that can be activated before irreversible skeletal damage occurs. This preliminary action allows the disease phenotype to be corrected at optimal time points, preventing permanent harm rather than attempting to reverse it after damage has occurred.
Solution Approach 2:
Instead of administering exogenous enzymes that fail to reach affected cells effectively, the patent inverts the approach by enabling the endogenous gene to produce its own functional enzyme. This eliminates the delivery problem entirely, as the enzyme is produced where it is needed rather than being administered systemically.
2Ease of operation
If exogenous enzyme is administered via enzyme replacement therapy, then some disease symptoms are improved, but the therapy is ineffective for skeletal manifestations
Solution Approach 1:
The patent enables the animal model to produce its own functional enzyme through activation of the endogenous gene. The affected cells and tissues serve themselves by producing the enzyme they need, eliminating the need for external enzyme administration and ensuring proper cellular uptake and function.
3Loss of time
If disease therapy is delayed until symptoms are manifest, then treatment can be initiated, but the disease may no longer be reversible
Solution Approach 1:
The patent creates animal models that can be treated at predetermined optimal time points before irreversible damage occurs. The conditional gene activation system allows therapy to be initiated at the precise moment when it will be most effective, preventing permanent skeletal manifestations rather than attempting reversal after damage has occurred.
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
These models enable the evaluation of the maximal possible correction of lysosomal storage disease phenotypes, separating treatment efficacy from disease reversibility, and providing insights into optimal therapeutic strategies.
Implementation Method 1
a critical region of the endogenous lysosomal storage disease gene is inverted and flanked by recombinase recognition sites in the reverse-conditional null endogenous lysosomal storage disease gene, wherein the recombinase recognition sites are oriented such that the critical region is reinverted upon treatment with the recombinase
Data Source
AI summary
Non-human animals comprising a reverse-conditional null endogenous lysosomal storage disease gene and methods of making such non-human animals are provided. Also provided are methods of using the non-human animals for assessing reversibility of a phenotype of the lysosomal storage disease or for determining an optimal timeframe for treatment of a phenotype of the lysosomal storage disease.