Genetically Modified Cells for Timed Biologic Delivery
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Solution Overview
Problem
Current chronotherapy methods for delivering biologic drugs are cumbersome, requiring constant daily injections or inconvenient timing to align with specific times of day for optimal efficacy, particularly in conditions like osteoporosis and rheumatoid arthritis where inflammatory flares occur at specific times.
Innovation Solution
Development of genetically modified cells with synthetic chronogenetic circuits that utilize the mammalian circadian clock to drive the timed expression of therapeutic biologics, such as IL-1Ra, through integration of circadian-responsive gene promoters into cells like induced pluripotent stem cells, allowing for controlled delivery of anti-inflammatory and regenerative therapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If constant daily injections are used to deliver biologic drugs, then the drug can be delivered at the required frequency, but the ease of operation deteriorates due to the cumbersome nature of frequent injections
Solution Approach 1:
The patent employs genetically modified cells that autonomously produce and secrete therapeutic biologics in a circadian-rhythm-controlled manner. The cells serve themselves by containing the genetic circuitry (promoters, transcription factors) necessary to regulate their own therapeutic production, eliminating the need for external daily injections while maintaining required delivery frequency.
Solution Approach 2:
The therapeutic biologics are produced and stored within the genetically modified cells before being secreted at the appropriate circadian time. This preliminary production and storage within the cell allows the drug to be delivered at the optimal time without requiring daily external administration.
2Reliability
If drugs are delivered at inconvenient times to align with circadian rhythms, then the therapeutic efficacy is improved by targeting diurnal inflammatory patterns, but the ease of operation worsens due to inconvenient timing
Solution Approach 1:
The genetically modified cells contain circadian clock genes and associated regulatory elements that enable them to autonomously sense the circadian time and regulate therapeutic production accordingly. The cells serve themselves by internally maintaining the circadian rhythm machinery needed to deliver drugs at the biologically optimal time without external intervention.
Solution Approach 2:
The circadian regulatory circuits within the genetically modified cells use feedback mechanisms where circadian clock proteins regulate the expression of therapeutic genes, which in turn are influenced by the cell's metabolic state and circadian phase. This feedback loop ensures drugs are delivered at the optimal time for maximum efficacy against diurnal inflammatory patterns.
3Ease of operation
If synthetic chronogenetic circuits are integrated into cells to enable timed drug delivery, then the ease of operation improves by eliminating frequent injections, but the device complexity increases due to the genetic circuitry required
Solution Approach 1:
The patent merges the circadian rhythm regulatory elements (promoters, transcription factors, clock genes) with the therapeutic gene into a single integrated genetic circuit within the cell. This combining of multiple functional elements into one unified system allows the cell to simultaneously maintain circadian rhythms and produce therapeutics at the appropriate times, reducing overall system complexity compared to separate control and production systems.
Solution Approach 2:
The genetically modified cells serve multiple functions: they act as both the circadian clock mechanism and the therapeutic production factory. The same cell that contains the circadian regulatory circuitry also produces and secretes the therapeutic biologic, eliminating the need for separate control systems and reducing overall device 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
Enables targeted and timed delivery of therapeutic biologics, enhancing their efficacy by aligning drug release with natural circadian rhythms, reducing the need for frequent injections and improving treatment outcomes for conditions with diurnal inflammatory patterns.
Implementation Method 1
The mammalian circadian clock has evolved as an adaptation to the 24-h light/darkness cycle on earth. Known to involve a core set of clock genes that regulate large networks of gene transcription in part by direct transcriptional activation/repression.
Implementation Method 2
a nucleic acid sequence encoding a therapeutic biologic operably linked to... drive expression of a therapeutic biologic... allowing for controlled delivery of anti-inflammatory and regenerative therapies
Data Source
AI summary
Among the various aspects of the present disclosure is the provision of compositions and methods of making genetically modified cells comprising a synthetic circuit that is responsive to a circadian input to the cell and methods of use thereof. This disclosure uses a cells circadian rythym to provide gene-based delivery of biologic drugs at prescribed times, phases and frequencies. Once reprogrammed, the cells can be reimplanted in the body for this purpose.