Microbial Cholesterol Catabolism for Targeted Lipid Clearance
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Solution Overview
Problem
Existing treatments for excess cholesterol and lipid buildup in cells, such as those associated with atherosclerosis and fatty liver disease, primarily focus on altering native lipoprotein metabolism and fail to effectively target already accumulated lipids and cholesterol, which can be toxic and contribute to various cardiovascular, eye, and neurological diseases.
Innovation Solution
Introduction of microbial-derived catalytic genes and enzymes via cell therapy and/or gene therapy to deliver cholesterol-catabolizing transgenes to mammalian cells, using vectors like LNP and iPSCs, which express cholesterol degrading enzymes to reduce lipid and cholesterol levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If native lipoprotein metabolism is altered to treat excess cholesterol, then cholesterol levels may be reduced, but already accumulated toxic lipids and cholesterol cannot be effectively targeted
Solution Approach 1:
The patent introduces microbial cholesterol-catabolizing enzymes (intermediaries) that directly degrade accumulated cholesterol and toxic lipids in human cells. These enzymes act as mediators between the therapeutic goal and the target substrates, enabling effective breakdown of already accumulated lipids that native metabolism cannot handle.
Solution Approach 2:
The patent changes the biochemical parameters of cholesterol metabolism by introducing foreign microbial enzymes with different catalytic properties. These enzymes possess enhanced ability to catabolize cholesterol and toxic lipids compared to native human enzymes, thereby improving the effectiveness of cholesterol reduction.
2Productivity
If microbial cholesterol-catabolizing enzymes are introduced via gene therapy, then cholesterol degradation capability is enhanced, but delivery to specific mammalian cells becomes complex
Solution Approach 1:
The patent uses viral vectors (AAV, adenovirus, lentivirus) and lipid nanoparticles as intermediary delivery systems to transport microbial enzyme genes to specific mammalian cells. These vectors serve as mediators that simplify the delivery process while maintaining targeted gene transfer efficiency.
Solution Approach 2:
The patent employs self-assembling viral vectors and lipid nanoparticles that automatically target and deliver genetic material to specific cell types through inherent biological mechanisms, reducing the need for complex external delivery infrastructure.
3Quantity of substance
If cholesterol levels are reduced in liver and arterial tissues, then conditions like atherosclerosis and fatty liver disease are treated, but specificity of enzyme expression must be maintained
Solution Approach 1:
The patent employs tissue-specific promoters (liver-specific, arterial wall-specific) to drive expression of microbial cholesterol-catabolizing enzymes only in target tissues. This ensures localized cholesterol degradation in the liver and arterial walls while preventing off-target effects in other organs.
Solution Approach 2:
The patent uses tissue-specific promoters as intermediaries to control spatial expression of therapeutic enzymes. These promoters act as regulatory mediators that ensure enzyme activity is confined to specific tissues where cholesterol accumulation is problematic.
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
Reduces cholesterol and lipid levels in cells, including liver and arterial tissues, effectively targeting and degrading excess cholesterol, thereby treating or preventing conditions like atherosclerosis, fatty liver disease, and neurological disorders.
Implementation Method 1
microbial-derived catalytic genes and enzymes to deliver cholesterol-catabolizing transgenes to mammalian cells
Data Source
AI summary
Disclosed herein are compositions, constructs, cassettes, vectors, cells, nucleic acids, peptides, proteins, protocols and methods for reducing cholesterol and lipid buildup in mammalian subjects, via gene and/or cell therapeutic treatments. In many embodiments, the disclosed compositions, cells, constructs, cassettes, vectors, nucleic acids, peptides, proteins, protocols and methods may help to reduce lipid levels in mammals. In one embodiment, the disclosed compositions, cells, constructs, cassettes, vectors, nucleic acids, peptides, proteins, protocols and methods are useful in reducing lipid build-up, especially cholesterol, in liver cells.