CRISPR-Cas9 Editing of GUCY2D Mutations for Autosomal Dominant CORD
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Solution Overview
Problem
Current treatments are inadequate for preventing or reversing the development of autosomal dominant Cone-Rod Dystrophy (CORD), particularly those associated with mutations in the GUCY2D gene, which leads to significant visual impairment and blindness.
Innovation Solution
A novel method involving the use of CRISPR-Cas systems to edit the GUCY2D gene by introducing DNA endonucleases to create single-strand or double-strand breaks, allowing for deletion, insertion, or correction of mutations such as R838H, R838C, or R838S, thereby reducing or eliminating the expression of the defective protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for CORD, then patient safety is maintained, but treatment effectiveness is insufficient to prevent or reverse disease progression
Solution Approach 1:
The patent extracts and removes the harmful mutant GUCY2D allele from the genome using CRISPR-Cas9 gene editing technology. By specifically targeting and eliminating the mutated gene responsible for autosomal dominant CORD, the treatment addresses the root cause of the disease rather than merely managing symptoms, thereby significantly improving treatment effectiveness while maintaining patient safety
Solution Approach 2:
The patent changes the genetic parameter of the GUCY2D gene by introducing precise mutations or deletions through CRISPR-Cas9 editing. This alters the genetic sequence to correct the pathogenic mutation, transforming the disease-causing allele into a non-harmful or corrected version, thus resolving the contradiction between treatment effectiveness and safety
2Manufacturing precision
If gene editing is performed to correct mutations, then treatment precision is improved, but procedural complexity increases
Solution Approach 1:
The patent uses guide RNA (gRNA) as an intermediary molecule that directs the CRISPR-Cas9 complex to the specific target sequence in the GUCY2D gene. This intermediary enables precise targeting of the mutant allele while simplifying the overall process by providing sequence-specific recognition without requiring complex targeting mechanisms, thus maintaining high precision while managing system complexity
Solution Approach 2:
The patent employs a simplified CRISPR-Cas9 system that replicates the natural bacterial immune mechanism for targeted gene editing. By copying and adapting this natural system for therapeutic use, the patent achieves high precision in mutation correction while avoiding the need for more complex artificial gene editing technologies
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 can potentially ameliorate or eliminate autosomal dominant CORD by correcting the genetic mutation, offering a precise and effective treatment with the possibility of achieving results in a single treatment session, thereby slowing or preventing disease progression.
Implementation Method 1
introducing into the human cell one or more DNA endonucleases to effect one or more SSBs or DSBs within or near the GUCY2D gene
Data Source
AI summary
The present application provides materials and methods for treating a patient with autosomal dominant CORD, both ex vivo and in vivo; materials and methods for editing a GUCY2D gene in a human cell; and materials and methods for editing a R838H, R838C, or R838S mutation in a GUCY2D gene in a human cell. The present application also provides one or more gRNAs or sgRNAs for editing a GUCY2D gene; one or more gRNAs or sgRNAs for editing a R838H, R838C, or R838S mutation in a GUCY2D gene; and a therapeutic comprising at least one or more gRNAs or sgRNAs for editing a R838H, R838C, or R838S mutation in a GUCY2D gene. The present application provides a therapeutic for treating a patient with autosomal dominant CORD. The present application also provides a kit for treating a patient with autosomal dominant CORD. In addition, the present application provides a self-inactivating CRISPR-Cas system.