Sonochemically-Active Microspheres for ABCA1 Gene Delivery
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Solution Overview
Problem
Current methods to increase blood HDL-c levels are ineffective, particularly for treating cardiovascular diseases and Tangier disease, with unpredictable effects from targeting individual proteins involved in reverse cholesterol transport, and no effective treatment exists for Tangier disease.
Innovation Solution
A composition comprising a plasmid vector encoding an active form of ATP-binding cassette transporter A1 (ABCA1) combined with sonochemically-active microspheres, which are disruptable by ultrasonic acoustic energy to facilitate expression of ABCA1 in mammalian cells, enhancing HDL biogenesis and secretion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If current methods target individual proteins involved in reverse cholesterol transport to increase blood HDL-c levels, then HDL-c levels may be increased, but the effects are unpredictable and ineffective
Solution Approach 1:
The patent combines multiple therapeutic elements into a single integrated system: plasmid vectors encoding ABCA1 and apoA1 are co-administered with sonochemically-active microspheres. This merging of gene delivery components with ultrasound-responsive carriers creates a synergistic system that overcomes the unpredictability of targeting individual proteins separately, achieving reliable and significant increases in HDL-c levels through coordinated action of multiple elements.
Solution Approach 2:
The invention changes the physical and chemical parameters of gene delivery by using sonochemically-active microspheres that respond to ultrasonic acoustic energy. This parameter change enables controlled release and enhanced cellular uptake of plasmid DNA, transforming an ineffective gene delivery approach into an effective therapeutic system that reliably increases ABCA1 expression and HDL-c levels.
2Quantity of substance
If ABCA1 transcription is enhanced by liver X factor (LXR) to induce HDL biogenesis, then HDL levels increase, but lipogenesis increases leading to hepatic steatosis
Solution Approach 1:
The patent extracts the harmful side effect (lipogenesis-induced hepatic steatosis) from the therapeutic process by using direct ABCA1 gene delivery instead of LXR-mediated transcriptional enhancement. This extraction separates the beneficial effect (HDL biogenesis) from the harmful effect (increased lipogenesis), achieving HDL elevation without the adverse metabolic consequences of LXR activation.
Solution Approach 2:
The plasmid vectors encoding ABCA1 serve as intermediaries that directly deliver functional ABCA1 protein to cells, bypassing the LXR signaling pathway entirely. This intermediary approach achieves the desired HDL biogenesis effect while avoiding the harmful downstream effects of LXR activation, particularly unwanted lipogenesis and hepatic steatosis.
3Quantity of substance
If gene delivery methods are used to increase ABCA1 expression, then HDL biogenesis is enhanced, but delivery efficiency to target tissues is insufficient
Solution Approach 1:
The patent applies mechanical vibration in the form of ultrasonic acoustic energy to enhance gene delivery efficiency. The sonochemically-active microspheres respond to this mechanical vibration through cavitation and mechanical disruption, which significantly improves cellular uptake of plasmid DNA and enhances delivery efficiency to target tissues, thereby achieving high ABCA1 expression levels that were previously unattainable with conventional gene delivery methods.
Solution Approach 2:
The invention uses composite materials consisting of plasmid DNA encapsulated within sonochemically-active microsphere carriers. This composite structure combines the genetic material with ultrasound-responsive particles, creating a delivery system that achieves both high target tissue specificity and high delivery efficiency, overcoming the limitations of naked plasmid administration.
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 composition significantly increases plasma HDL-c levels, as demonstrated in a rat study, with ABCA1 plasmid achieving higher serum concentrations than apoA1 plasmid, offering a novel approach to treat atherosclerosis and Tangier disease.
Implementation Method 1
Sonochemical induction of ABCA1 expression and compositions therefor
Implementation Method 2
sonochemically-active microspheres in a pharmaceutically acceptable aqueous carrier, wherein the vector comprises an expressible open reading frame encoding the active form of ABCA1 and at least one sequence adapted to promote expression of the open reading frame in a mammalian cell; and wherein the sonochemically-active microspheres comprise gas bubbles encapsulated within shells comprising a protein, a lipid, or a combination thereof, the microspheres being disruptable upon exposure to ultrasonic acoustic energy to release the encapsulated gas bubbles
Data Source
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AI summary
The present invention provides compositions useful for transfecting cells (e.g., liver cells) to express ABCA1. The compositions described herein comprise a pharmaceutically acceptable aqueous carrier containing sonochemically-active microspheres together with a plasmid DNA construct encoding an active form of ABCA1 and at least one promoter for the expression thereof. Preferably, the sonochemically-active microspheres comprise, consist essentially of, or consist of gas bubbles (e.g., a fluorocarbon gas, such as octafluoropropane) encapsulated within protein-containing or lipid-containing shells (e.g., human serum albumin shells). The microspheres are disruptable by exposure to ultrasonic acoustic energy to release the encapsulated gas.