Base Editor System for SBDS Gene T258C Mutation Correction
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Solution Overview
Problem
Shwachman-Diamond Syndrome (SDS) patients suffer from bone marrow failure due to a mutation in the SBDS gene, leading to defective splicing and loss of protein expression, with current treatments being limited to bone marrow transplantation from a matched donor.
Innovation Solution
The use of base editing technology to genetically modify the SBDS gene by employing a base editor system comprising a base editor protein with a polynucleotide programmable DNA binding domain and a cytosine deaminase domain, specifically targeting the T258C mutation to correct splicing and restore protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If base marrow transplantation is performed, then curative treatment is achieved, but treatment complexity and donor availability constraints increase
Solution Approach 1:
The patent extracts and corrects only the specific mutated nucleotide (T258C) in the SBDS gene using base editing technology, rather than replacing the entire bone marrow. This targeted approach corrects the genetic defect while preserving the patient's own bone marrow function, eliminating the need for complex donor matching and transplantation procedures
Solution Approach 2:
The patent introduces base editor proteins (comprising a polynucleotide programmable DNA binding domain and a cytosine deaminase domain) as intermediary tools to mediate the correction of the genetic mutation. These editors serve as precise molecular mediators that convert the mutated thymine to cytosine, restoring normal gene function without requiring full bone marrow replacement
2Manufacturing precision
If T258C mutation is present, then splicing defect occurs, but base editing can correct it
Solution Approach 1:
The patent changes the nucleotide parameter at position 258 from mutated thymine (T) to correct cytosine (C) using base editing. This single parameter change in the DNA sequence restores proper splicing signals, enabling accurate splicing of the SBDS gene pre-mRNA and production of functional protein
3Productivity
If SBDS gene expression is lost, then protein synthesis decreases, but base editing restores expression
Solution Approach 1:
The patent performs preliminary base editing correction of the T258C mutation in the SBDS gene before the complete loss of gene expression leads to severe bone marrow failure. By correcting the mutation early, the cell's own transcription and translation machinery can resume production of functional SBDS protein, restoring normal ribosome biogenesis and cell proliferation
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
The base editing system effectively corrects the T258C mutation in the SBDS gene, leading to improved splicing, increased SBDS gene product expression, enhanced cell proliferation, and increased protein synthesis, potentially reversing the symptoms of SDS.
Implementation Method 1
a cytosine deaminase domain
Data Source
AI summary
Provided herein is a base editor system for editing the SBDS gene comprising a base editor protein and a guide polynucleotide, wherein the base editor protein comprises a polynucleotide programmable DNA binding domain and a cytosine deaminase domain. Methods, edited cells, and compositions thereof are also described herein.