AAV FGF21 Expression Construct for Long-Acting Native Secretion
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Solution Overview
Problem
Current treatments for diabetes, obesity, liver inflammation and fibrosis, and cancer are inadequate, with existing FGF21 therapies exhibiting poor pharmacokinetics, susceptibility to degradation, and potential immunogenicity, requiring multiple administrations and posing significant burdens to patients.
Innovation Solution
AAV vector-mediated gene therapy strategies for FGF21 expression in liver, adipose tissue, and skeletal muscle to produce native FGF21 in vivo, reducing immunogenicity and enabling long-lasting secretion with a single administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If engineered FGF21 mimetics are used to extend half-life and improve stability, then pharmacokinetic properties are improved, but immunogenicity increases and multiple administrations are required
Solution Approach 1:
The patent uses AAV vectors to deliver the native FGF21 gene, creating an in vivo copy of the endogenous gene that produces authentic FGF21 protein. This copying approach ensures the protein is immunologically identical to native human FGF21, eliminating immunogenicity concerns while maintaining stable expression over time through viral vector-mediated gene delivery.
2Reliability
If engineered FGF21 mimetics are administered to achieve therapeutic effects, then metabolic parameters are improved, but treatment burden increases due to multiple administrations
Solution Approach 1:
The AAV vector delivers the FGF21 gene and establishes long-term expression before therapeutic effect is needed. The vector integrates or maintains the transgene in host cells, creating a persistent source of FGF21 production that lasts for months to years after a single administration, eliminating the need for repeated dosing.
Solution Approach 2:
The viral vector-mediated gene therapy establishes continuous FGF21 production from the delivered transgene. The AAV vector maintains stable transgene expression over extended periods, providing uninterrupted therapeutic action without requiring periodic re-administration, thus converting discrete treatments into continuous therapy.
3Object-affected harmful factors
If native FGF21 is administered to reduce immunogenicity, then safety is improved, but half-life is short and stability deteriorates
Solution Approach 1:
The AAV vector acts as an intermediary carrier that delivers the native FGF21 gene without directly administering the protein. This intermediary approach allows the endogenous transcription and translation machinery to produce authentic FGF21 with native post-translational modifications and structural features, ensuring immunological compatibility while the vector system provides sustained delivery and expression.
Data Source
AI summary
The invention relates to a viral expression construct and related viral vector and nucleic acid molecule and composition and to their use wherein said construct and vector are suitable for expression in a mammal and comprise a nucleotide sequence encoding a Fibroblast growth factor 21 (FGF21) to be expressed in liver, adipose tissue and/or skeletal muscle.