G6PC Gene Editing Vectors for Persistent Liver Regeneration
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Solution Overview
Problem
Current gene therapy approaches for glycogen storage diseases, such as GSD Ia, using non-integrating viral vectors like AAV, provide temporary relief due to the loss of vector persistence, leading to rapid waning of therapeutic effects.
Innovation Solution
Development of gene editing systems for stable integration of a therapeutic G6PC transgene into the genome, utilizing nucleic acids and vectors that include a Cas9 endonuclease and guide RNA, enabling persistent expression of glucose-6-phosphatase through homologous recombination.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-integrating viral vectors (AAV) are used for gene therapy, then initial therapeutic effect is achieved, but the effect wanes quickly due to loss of vector persistence
Solution Approach 1:
The patent extracts the transient nature of AAV vectors and replaces it with integrating gene editing systems (CRISPR/Cas9, TALENs, ZFNs) that permanently modify the host genome, thereby eliminating the time-limitation problem of non-integrating vectors while maintaining therapeutic benefit
Solution Approach 2:
The patent performs preliminary genomic integration of the therapeutic transgene before the therapeutic effect is needed to wear off, ensuring long-term persistence. The gene editing system is designed to create stable, heritable modifications that last indefinitely, preparing the system in advance to maintain therapeutic effect throughout the patient's life
2Reliability
If gene therapy is used to treat GSD Ia, then G6PC deficiency is corrected, but the correction is temporary due to vector loss
Solution Approach 1:
The patent removes the unstable, transient AAV vector system and replaces it with stable integrating gene editing systems that permanently alter the host genome, thereby achieving both reliable correction stability and long-term expression stability without the time-limitation problem
Solution Approach 2:
The patent creates a composite therapeutic system combining gene editing machinery (CRISPR/Cas9, TALENs, or ZFNs) with a therapeutic transgene, where the editing system integrates the transgene into the host genome. This composite approach ensures both the stability of the correction and the persistence of expression, as the integrated transgene becomes a permanent part of the host's genetic material
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
Stable integration and expression of the G6PC transgene leads to sustained correction of G6PC deficiency, effectively managing and preventing the progression of glycogen storage diseases by restoring cellular homeostasis and metabolic function.
Implementation Method 1
utilizing nucleic acids and vectors that include a Cas9 endonuclease and guide RNA, enabling persistent expression of glucose-6-phosphatase through homologous recombination
Data Source
AI summary
Embodiments of the instant disclosure relate to novel gene editing vectors, compositions, and methods for editing a G6PC gene to treat glucose storage diseases (e.g., GSD Ia). In certain embodiments, vectors described herein comprise one or more CRISPR/Cas9 components to allow for integration of a G6PC transgene into a target gene locus in a subject in need thereof, thereby allowing for stable expression of a therapeutic protein (e.g., glucose-6-phosphatase) and reversal and/or treatment of disease symptoms in the subject.