In Vivo Somatic Cell Reprogramming for Ischemic Tissue Rescue
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Solution Overview
Problem
Current pro-angiogenic cell therapies for ischemic disorders face challenges due to limited cell sources and the need for complex and risky ex vivo cell pre-processing steps, highlighting the need for direct cell reprogramming methods to derive blood vessels in vivo.
Innovation Solution
The use of polynucleotides encoding ETV2, FOXC2, and FLI1 proteins, delivered via non-viral vectors or extracellular vesicles, to reprogram somatic cells into vasculogenic or endothelial cells directly in vivo, with optional miR-200b inhibition to enhance the reprogramming process.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ex vivo cell pre-processing steps (induced pluripotency, expansion, differentiation) are used, then cell therapy effectiveness is improved, but procedural complexity and risk increase
Solution Approach 1:
The invention extracts and eliminates the complex ex vivo pre-processing steps (induced pluripotency, expansion, differentiation) from the therapeutic protocol, replacing them with direct in vivo reprogramming of somatic cells at the site of ischemia, thereby simplifying the overall procedure while maintaining therapeutic effectiveness
Solution Approach 2:
The invention enables the patient's own somatic cells to perform the reprogramming function in vivo, converting them directly into endothelial cells at the ischemic site without requiring external laboratory processing, thus making the system self-sufficient and eliminating complex pre-processing steps
2Quantity of substance
If ex vivo cell expansion is performed, then sufficient cell numbers for therapy are obtained, but treatment time and cost increase
Solution Approach 1:
Instead of performing cell expansion in advance ex vivo, the invention initiates the reprogramming process directly in vivo at the time of treatment, allowing cells to convert and proliferate in place, thereby eliminating the time loss associated with preliminary ex vivo expansion steps
Solution Approach 2:
The somatic cells perform their own reprogramming and expansion function in vivo under the influence of delivered transcription factors, eliminating the need for external laboratory expansion processes and reducing overall treatment time
3Productivity
If viral vectors are used for gene delivery, then high transfection efficiency is achieved, but safety risks increase
Solution Approach 1:
The invention employs non-viral, transient gene delivery systems (such as plasmid DNA or mRNA) that are temporarily expressed and then degraded, replacing persistent viral vectors with short-lived, non-integrating delivery vehicles that maintain transfection efficiency while eliminating safety risks associated with viral integration and immunogenicity
Data Source
AI summary
Disclosed herein are compositions and methods that involve using compositions containing one or more of ETV2, FOXC2, FLI1 and a miR-200b inhibitor for directly reprogramming somatic cells into induced vasculogenic cells both in vitro and in vivo. These compositions and methods are useful for a variety of purposes, including the development of pro-angiogenic therapies.