UCP1-Regulated VGLL4 Construct for Brown Fat Expansion
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Solution Overview
Problem
Current compositions and methods for increasing brown adipose tissue (BAT) are lacking, hindering effective treatments for obesity, diabetes, and liver disease, which are rooted in the imbalance between BAT and white adipose tissue (WAT).
Innovation Solution
A polynucleotide construct comprising a cis-regulatory element and a nucleotide sequence encoding a vestigial like 4 protein (Vgll4) is used, specifically driven by an uncoupling protein 1 (Ucp1) enhancer and promoter, to promote Vgll4 expression in BAT and liver cells, enhancing mitochondrial gene expression and reducing WAT volume.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional gene delivery methods (viral vectors, lipofection, calcium phosphate transfection) are used to deliver genes to adipose tissue, then gene delivery can be achieved, but the procedure becomes complex, time-consuming, and requires specialized facilities and expertise
Solution Approach 1:
The invention extracts and utilizes the natural mechanism of adipose-specific apoptosis that occurs during lipoaspirate processing. By leveraging this endogenous apoptotic process, the patent eliminates the need for complex external delivery systems (viral vectors, lipofection reagents, calcium phosphate). The apoptotic cells naturally release DNA that is then taken up by surviving adipocytes, providing a simplified, extraction-based delivery mechanism that maintains reliability while dramatically reducing procedural complexity
Solution Approach 2:
The invention enables the lipoaspirate sample to perform self-delivery of the gene of interest. The apoptotic adipocytes within the sample automatically release their DNA content, which is then naturally taken up by viable adipocytes without requiring external delivery agents or complex equipment. This self-service mechanism eliminates dependence on specialized facilities and expertise, transforming a complex technical challenge into a self-executing biological process
2Reliability
If conventional gene delivery methods are used, then genes can be delivered to target cells, but the procedure is time-consuming and requires specialized facilities and expertise
Solution Approach 1:
The method extracts and leverages the naturally occurring apoptotic process that happens during standard lipoaspirate processing. This endogenous DNA release mechanism eliminates the need for time-consuming external transfection protocols, allowing gene delivery to occur as a natural byproduct of the liposuction procedure itself, thereby dramatically reducing procedure time while maintaining transfection success
Solution Approach 2:
The invention performs the gene delivery action preliminarily during the liposuction procedure itself. By injecting the gene of interest into the lipoaspirate sample immediately after collection, the DNA is delivered during the existing surgical workflow rather than requiring separate, time-consuming transfection steps afterward. This preliminary integration into the surgical procedure eliminates additional time requirements
3Productivity
If adipose-specific genes are introduced into adipocytes to increase adipogenesis, then adipose tissue formation improves, but the method requires complex gene delivery systems
Solution Approach 1:
The invention enables the lipoaspirate sample to self-deliver the adipose-specific gene (aP2 gene) to viable adipocytes through natural apoptotic DNA release. This self-service mechanism eliminates dependence on complex viral vectors or chemical transfection systems, allowing efficient adipogenesis enhancement through a simple, equipment-free delivery approach that maintains high productivity while reducing system complexity
Data Source
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AI summary
Provided is a polynucleotide, including a cis-regulatory element and a nucleotide sequence encoding a vestigial like 4 protein, wherein the cis-regulatory element includes an uncoupling protein 1 enhancer and an uncoupling protein 1 promoter. Also provided is a viral vector including said polynucleotide. Also provided is a method of transfecting a cell or a subject with said polynucleotide or said viral vector.