G6PC Gene Editing for GSD1a Metabolic Correction
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Solution Overview
Problem
Current treatments for Glycogen Storage Disease type 1a (GSD1a) are incomplete and unsatisfactory, with limited success in addressing the underlying genetic defect, leading to ongoing symptoms such as hepatomegaly and hypoglycemia, and existing gene therapies have limitations in precision and long-term effectiveness.
Innovation Solution
The use of genome engineering tools to create permanent changes in the G6PC gene by introducing DNA endonucleases to effect single-strand or double-strand breaks, allowing for permanent insertion, correction, or modulation of glucose-6-phosphatase protein activity, either ex vivo in induced pluripotent stem cells or directly in liver cells, to restore normal glucose metabolism.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for GSD1a, then symptoms can be managed temporarily, but the underlying genetic defect remains uncorrected leading to ongoing hepatomegaly and hypoglycemia
Solution Approach 1:
The patent applies preliminary action by using genome editing tools (CRISPR/Cas9, TALENs, ZFNs) to correct the underlying G6PC gene mutation before symptoms can progress, thereby preventing rather than just managing the disease. The ex vivo genome editing of patient cells followed by transplantation restores glucose-6-phosphatase activity permanently, addressing the root cause rather than providing temporary symptom relief.
Solution Approach 2:
The patent replaces mechanical/surgical interventions (liver transplantation) with a molecular-level solution (genome editing). Instead of physically replacing the entire liver organ, the invention uses precise molecular tools to correct the genetic defect in situ or in ex vivo cultured cells, substituting a complex surgical mechanical approach with a targeted molecular repair mechanism.
2Manufacturing precision
If genome engineering tools are used to create permanent changes in the G6PC gene, then normal glucose metabolism can be restored, but the precision and complexity of the editing process presents challenges
Solution Approach 1:
The patent uses intermediary molecules and systems to bridge the complexity gap: guide RNAs (gRNAs) serve as intermediaries that direct Cas9 endonucleases to specific genomic locations, while donor DNA templates act as intermediaries providing the correct genetic sequence for homology-directed repair. These intermediary components enable precise genetic correction without requiring direct manual manipulation of the complex editing machinery.
Solution Approach 2:
The patent extracts and isolates the specific defective portion of the G6PC gene through targeted genome editing. By using sequence-specific endonucleases to create double-strand breaks at precise locations and providing exogenous donor DNA, the invention extracts only the necessary corrective action from the complex genome editing process, leaving the rest of the genome undisturbed and simplifying the overall intervention.
3Reliability
If existing gene therapies are applied, then some therapeutic benefit can be achieved, but they lack the precision and durability of permanent genetic correction
Solution Approach 1:
The patent performs preliminary genetic correction through genome editing before the disease can progress or recur. By establishing the correct G6PC gene sequence permanently in the patient's cells (either ex vivo or in vivo), the treatment creates a lasting therapeutic effect that eliminates the need for repeated administrations, thereby saving time in the long term despite the initial complexity of the editing process.
Solution Approach 2:
The patent employs partial action by targeting only the specific mutated G6PC gene rather than attempting to modify the entire genome or use broad-spectrum gene therapy approaches. This focused, partial intervention achieves durable therapeutic outcomes with greater precision, avoiding the time-consuming trial-and-error that would result from less targeted approaches.
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
This approach enables permanent correction of the underlying genetic defect, potentially offering a single treatment solution that can restore normal glucose metabolism and alleviate symptoms of GSD1a, providing a more effective and durable therapeutic outcome compared to existing methods.
Implementation Method 1
introducing into the human cell one or more deoxyribonucleic acid (DNA) endonucleases to effect one or more single-strand breaks (SSBs) or one or more double-strand breaks (DSBs) within or near the G6PC gene
Data Source
AI summary
The present application provides materials and methods for treating a patient with Glycogen Storage Disease type 1a (GSD1a) both ex vivo and in vivo. In addition, the present application provides materials and methods for modulating the expression, function, and/or activity of the glucose-6-phosphatase, catalytic (G6PC) and/or the glucose-6-phosphatase (G6Pase) protein in a cell by genome editing.