tRNA-pre-miRNA Polynucleotides for HCC Treatment
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Solution Overview
Problem
Hepatocellular carcinoma (HCC) poses a significant challenge due to its low survival rates and limited therapeutic options, with current treatments like sorafenib and regorafenib offering only short-term survival benefits and adverse effects, while recent immunotherapy advancements have been slow compared to other solid tumors.
Innovation Solution
Development of bioengineered polynucleotides comprising tRNA operably linked to pre-microRNA molecules, specifically let-7c, which are delivered using liposomal-branched polyethylenimine polyplexes (LPP) to inhibit HCC cell growth by modulating target gene expression and inducing apoptosis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional miRNA mimics or synthetic molecules are used, then miRNA replacement therapy can be achieved, but the molecules are not well-tolerated in cells and have poor biocompatibility
Solution Approach 1:
The patent uses tRNA molecules as intermediary carriers to deliver pre-miRNA sequences into cancer cells. The tRNA acts as a natural mediator that cells already tolerate, avoiding the toxicity of synthetic miRNA mimics. The tRNA is engineered to contain the therapeutic pre-miRNA sequence within its structure, allowing it to serve as both a delivery vehicle and the active therapeutic agent.
Solution Approach 2:
The patent changes the physical and chemical parameters of the miRNA delivery system by using endogenous tRNA structures rather than synthetic double-stranded RNA mimics. This parameter change from synthetic to biologic molecules fundamentally alters cellular compatibility while maintaining therapeutic function.
2Productivity
If polyethylenimine (PEI)-based polyplexes are used for RNA delivery, then delivery efficiency is high, but toxicity increases
Solution Approach 1:
The patent extracts and eliminates the toxic PEI delivery component by using the cell's own tRNA processing machinery. Instead of requiring external polyplexes for delivery, the engineered tRNA/pre-miRNA constructs are delivered in a tolerable form and processed endogenously, separating the delivery function from the toxic carrier.
Solution Approach 2:
The patent enables self-service delivery by designing the tRNA/pre-miRNA construct to be processed by the cell's own enzymatic machinery. The cell's endogenous tRNA processing enzymes automatically process the construct into active miRNA, eliminating the need for toxic external delivery vehicles like PEI polyplexes.
3Duration of action of moving object
If current pharmacological interventions like sorafenib are used, then HCC treatment is available, but survival benefit is limited to three months and adverse effects occur
Solution Approach 1:
The patent substitutes pharmacological chemical intervention with a biologic molecular therapy approach. Instead of using small molecule kinase inhibitors like sorafenib that require systemic circulation and target multiple pathways non-specifically, the patent uses sequence-specific RNA molecules that directly target oncogenic pathways at the molecular level, providing more precise and durable therapeutic effects.
Data Source
AI summary
Provided are hybrid tRNA/pre-microRNA and tRNA molecules and their use in methods of preventing and treating hepatocellular carcinoma (HCC). In some embodiments, provided are polynucleotides that include a tRNA operably linked to one or more pre-microRNA (pre-miRNA), where the tRNA and/or pre-miRNA are operably linked to one or more inserted RNA molecules that inhibit the growth or proliferation of a hepatocellular carcinoma (HCC) cell.