Spatial Transcriptomics In Vivo Therapeutic Screening
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Solution Overview
Problem
Current methods for gene therapy and clinical interventions face challenges in translating in vitro research to in vivo therapies, particularly when disease etiology is unknown or complex, and in efficiently screening therapies that account for intracellular and extracellular factors impacting therapy design, safety, and efficacy.
Innovation Solution
The method involves administering pooled expression cassettes with therapeutic moieties and barcodes to biological entities, combined with spatial transcriptomics, allowing for the measurement of intervention effects in specific tissue locations through reverse transcription, sequencing, and imaging, enabling the identification of candidate therapeutic moieties that affect nearby cells and secreted factors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional in vitro screening methods are used, then screening throughput is limited, but translating to in vivo therapies becomes difficult due to missing intracellular and extracellular factors
Solution Approach 1:
The patent combines pooled expression cassettes containing multiple therapeutic moieties with spatial transcriptomics technology to create an integrated in vivo screening system. This merging allows simultaneous testing of hundreds of therapeutics in a single animal while capturing spatial and cellular context through transcriptomic analysis, thereby achieving both high throughput and physiological relevance
Solution Approach 2:
The patent uses spatial transcriptomics as an intermediary technology to bridge the gap between in vivo intervention and high-throughput screening. The transcriptomic analysis serves as a mediator that captures the physiological effects of therapeutic moieties while enabling systematic data collection and analysis, thus translating in vivo results into screenable data
2Reliability
If multiple animal tests are conducted to account for in vivo environments, then physiological relevance is improved, but the number of animals required and time consumption increase significantly
Solution Approach 1:
The patent merges multiple therapeutic interventions into a single pooled library that can be administered to one animal at a time. The spatial transcriptomics approach then simultaneously analyzes the effects of all therapeutics in the pool, reducing the need for multiple sequential animal studies while maintaining physiological relevance through in vivo administration
Solution Approach 2:
The patent segments the analysis process into spatial transcriptomic profiling that can distinguish effects of individual therapeutic moieties within the pool. By segmenting the data analysis through spatial and transcriptomic dimensions, the system can evaluate multiple therapeutics simultaneously in a single animal, reducing time consumption while maintaining physiological relevance
3Productivity
If pooled expression cassettes with multiple therapeutic moieties are administered, then screening efficiency is improved, but identifying the specific effect of each moiety becomes more difficult
Solution Approach 1:
The patent applies local quality through spatial barcodes that provide unique spatial coordinates for each measurement location in the tissue. This spatial encoding allows the system to distinguish and attribute transcriptomic changes to specific therapeutic moieties administered in the pool, as each location's response can be traced back to the locally administered therapeutic
Solution Approach 2:
The patent implements feedback through spatial transcriptomics that provides detailed information about which specific therapeutic moieties are present in which spatial locations and what their effects are. This feedback loop allows the system to identify and characterize the specific effects of individual moieties within the pooled administration, resolving the difficulty of attribution
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
This approach significantly enhances the efficiency of screening therapeutic candidates by allowing the testing of hundreds of secreted factors in a single animal, improving upon traditional methods by accounting for in vivo environments and reducing the need for multiple animal tests, thereby accelerating drug discovery and clinical translation.
Implementation Method 1
spatial transcriptomics, in some embodiments, may involves placing two-dimensional tissue slices on a coated surface (such as a glass slide) covered with 'surface probes' and subsequently initiating a reverse transcription reaction that will label mRNA molecules in the tissue slice with two barcodes comprising nucleotides, a first barcode identifying the individual mRNA molecule and a second barcode containing two-dimensional coordinates
Implementation Method 2
fluorescent tags for imaging
Data Source
AI summary
Provided herein are compositions and methods of use thereof for screening a plurality of uniquely identifiable therapeutic moiety in vivo by identifying one or more reporters indicative of a cell state.