Genetically Modified Bacteria Mucin Binding Gastrointestinal Retention
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Solution Overview
Problem
There is a need for microbial strains with improved pharmacokinetic and pharmacodynamic properties, and for targeted and controlled methods to treat various diseases using genetically modified bacteria that can effectively adhere to mucosal tissues and deliver therapeutic molecules.
Innovation Solution
Genetically modified microorganisms, such as bacteria or yeast, are engineered to express fusion proteins containing cell-adhesion and mucin-binding polypeptides like CmbA and trefoil factors, which enhance their ability to bind to intestinal epithelial cells and mucins, allowing for controlled delivery of bioactive molecules to the gastrointestinal tract.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If genetically modified bacteria are used to deliver therapeutic molecules to mucosal tissues, then therapeutic delivery capability is improved, but control over gastrointestinal retention and transit times is insufficient
Solution Approach 1:
The patent modifies the bacterial surface properties by expressing fusion proteins with altered adhesion characteristics. Specifically, bacteria are engineered to express fusion proteins containing cell-adhesion domains (such as CmbA from Lactobacillus reuteri) combined with therapeutic polypeptides. This changes the physical-chemical parameters of bacterial-mucosa interaction, enabling controlled retention. The modified bacteria demonstrate enhanced binding to intestinal epithelial cells and mucins, thereby extending gastrointestinal residence time in a controlled manner to improve therapeutic delivery reliability.
2Reliability
If bacteria are engineered to express fusion proteins with cell-adhesion polypeptides, then adherence to intestinal mucosa is improved, but complexity of genetic modification increases
Solution Approach 1:
The patent combines multiple functional elements into a single fusion protein construct. The fusion protein merges a cell-adhesion domain (CmbA or similar adhesins from Gram-positive bacteria) with the therapeutic polypeptide sequence. This consolidation achieves two objectives simultaneously: (1) enhances bacterial adherence to intestinal mucosa through the adhesion domain, and (2) delivers the therapeutic payload through the integrated polypeptide. The genetic modification involves constructing this fusion gene and introducing it into the bacterial host, which, while requiring genetic engineering, simplifies the overall system compared to using separate adhesion-modified bacteria and separate therapeutic delivery 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
The modified microorganisms exhibit increased adherence to intestinal mucosa and mucins, leading to prolonged gastrointestinal transit times and enhanced delivery of therapeutic peptides, thereby modulating pharmacokinetic and pharmacodynamic properties of bioactive molecules.
Implementation Method 1
bacteria exhibiting increased in vitro binding to Caco-2 cells, and increased in vitro binding to mucins
Implementation Method 2
expression, secretion and anchoring of a fusion protein containing a trefoil factor (TFF) and a cell-adhesion polypeptide, such as CmbA
Data Source
AI summary
The present disclosure provides genetically modified microorganisms (e.g., bacteria or yeast) with enhanced mucin-binding and/or cell-adhesion properties. For example, the present disclosure provides bacteria exhibiting increased in vitro binding to Caco-2 cells, and increased in vitro binding to mucins. Such microorganisms (e.g., bacteria) can be used, e.g., to deliver bioactive polypeptides to the gastrointestinal tract of a mammalian subject. Modifying the microorganism in the described manner allows for the modulation of gastrointestinal retention and transit times for the microorganism (e.g., bacterium). Exemplary microorganisms (e.g., lactic acid bacteria, such as Lactococcus lactis) contain an exogenous nucleic acid encoding a fusion protein containing a cell-adherence polypeptide, such as CmbA, and a mucin-binding polypeptide, such as a trefoil factor (TFF), e.g., human TFF3. The current disclosure further provides method for making and using the described microorganisms (e.g., bacteria).