Engineered B Cells for Tunable Therapeutic Protein Expression
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Solution Overview
Problem
Current enzyme replacement therapies for lysosomal storage diseases require frequent intravenous infusions, leading to high enzyme levels that wane between treatments, necessitating improved treatment options for sustained and tunable gene product expression.
Innovation Solution
Engineering B cells to express selected antibodies and gene products through targeted genetic constructs at intronic regions, with mechanisms to amplify or reduce expression based on antigen binding and a suicide gene to maintain therapeutic levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If enzyme replacement therapy is administered through frequent intravenous infusions, then sufficient enzyme levels are provided to treat lysosomal storage diseases, but the treatment requires continuous bi-weekly infusions and enzyme levels wane between treatments
Solution Approach 1:
The patent modifies B cells in advance to contain genetic constructs that will continuously produce the desired enzyme. The B cells are engineered with a first genetic construct encoding an antibody and a second genetic construct encoding the therapeutic enzyme, both under control of inducible promoters. This preliminary genetic modification eliminates the need for repeated enzyme administrations, as the modified B cells will continuously produce the enzyme in vivo.
Solution Approach 2:
The patent creates a self-sustaining system where modified B cells continuously produce the therapeutic enzyme without external intervention. The B cells are equipped with inducible promoter systems that allow them to self-regulate enzyme production based on physiological conditions. The system serves itself by using the B cell's own biological machinery (antibody production pathways) to continuously generate the therapeutic protein.
2Duration of action of stationary object
If continuous gene product expression is achieved through B cell engineering, then frequent infusions are eliminated, but mechanisms are needed to control and adjust expression levels to maintain safety
Solution Approach 1:
The patent incorporates inducible promoter systems that respond to physiological feedback signals. The promoters can be activated or repressed based on the presence of specific molecules or cellular conditions, allowing the enzyme production to be dynamically adjusted. This feedback mechanism enables the system to maintain enzyme levels within a safe and effective range without requiring complex external control systems.
Solution Approach 2:
The patent uses inducible promoters that can change their activity state in response to specific parameters or conditions. By modifying the promoter's responsiveness to different inducers or environmental cues, the expression levels of the therapeutic enzyme can be tuned and adjusted. This allows for flexible control of gene expression without adding significant system complexity.
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
Provides prolonged and tunable expression of gene products, eliminating the need for frequent infusions and ensuring safe, efficient gene product levels.
Implementation Method 1
Binding of the antigen to the selected antibody activates the B cell, such that expression of the gene product will be amplified
Data Source
AI summary
A number of medical disorders are caused by either an insufficiency of a gene product or a defective gene product. Gene therapy can be used to provide a sufficient amount of a gene product when a disorder is caused by an insufficiency and can also be used to inactivate genes that produce defective gene products. Examples of disorders that can be treated by providing a sufficient amount of a gene product include lysosomal storage diseases, clotting disorders, diabetes, and alpha-1 antitrypsin deficiency. Systems and methods to produce B cells that express selected antibodies and gene products are described. The systems and methods can be used to provide prolonged and tunable expression of the gene products for the treatment of diseases such as lysosomal storage diseases, clotting disorders, diabetes, or other protein deficiencies.