Modified RNA DNASE Production for Sustained cfDNA Treatment
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Solution Overview
Problem
Current treatments for diseases associated with cell-free DNA (cfDNA), such as cancer and inflammatory conditions, suffer from severe side effects and lack long-term efficacy due to the short half-life of recombinant DNASE enzymes, necessitating frequent administrations.
Innovation Solution
A modified RNA composition comprising a synthetic cap structure and a coding region encoding DNASE1 or DNASE1L3, delivered via lipid-formulated mRNA nanoparticles, enables sustained enzymatic activity and continuous production of DNASE within the body, overcoming the limitations of recombinant proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If recombinant DNASE enzymes are administered to treat cfDNA-associated diseases, then therapeutic effect is achieved, but the half-life is too short requiring frequent administrations
Solution Approach 1:
The patent employs mRNA technology to enable the patient's own cells to produce the therapeutic DNASE enzyme endogenously. The modified mRNA encodes DNASE1 or DNASE1L3 and is delivered via lipid nanoparticles, allowing sustained in vivo expression of the enzyme. This self-service approach eliminates the need for frequent external administrations while maintaining therapeutic levels of the enzyme throughout the body.
2Reliability
If frequent administrations of recombinant DNASE are performed to maintain therapeutic effect, then disease symptoms are controlled, but severe side effects occur
Solution Approach 1:
By utilizing the patient's cellular machinery to produce the therapeutic enzyme through mRNA delivery, the treatment achieves sustained disease control without the need for repeated external administrations. This single or infrequent dosing regimen maintains reliable therapeutic effects while minimizing the cumulative side effects associated with frequent recombinant protein administrations.
Solution Approach 2:
The patent modifies the pharmacokinetic parameters of the therapeutic enzyme by changing its delivery form from exogenous recombinant protein to endogenously produced protein via mRNA. This parameter change extends the half-life and maintains steady-state concentrations of the enzyme, achieving reliable disease control with reduced dosing frequency and minimized side effects.
3Object-affected harmful factors
If single administration of recombinant DNASE is given to minimize side effects, then treatment safety is improved, but therapeutic effect is insufficient due to short half-life
Solution Approach 1:
The mRNA-based therapeutic enables the body to continuously produce the DNASE enzyme after a single administration, transforming the short half-life limitation of recombinant proteins into a sustained endogenous production system. This approach maintains reliable therapeutic effects throughout the treatment period while minimizing side effects through reduced dosing frequency.
Data Source
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AI summary
The invention relates to a modified RNA with a synthetic cap structure and a modified coding region encoding for DNASE1 and/or DNASE1 L3. The invention further relates to a saRNA and/or a circular RNA, and to a vector encoding the modified RNA. The invention also relates to a pharmaceutical composition for the use of treating a disease associated with the formation of extracellular DNA, including extracellular traps released from leukocytes, such as NETs.