SMN2 Base Editing for Durable Spinal Muscular Atrophy Correction
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Solution Overview
Problem
Current SMA therapies, such as ASO and gene therapy, provide transient SMN protein upregulation, are insufficient and can lead to toxicity, while precise genome editing for durable SMN protein restoration is not established.
Innovation Solution
Precise genome editing of SMN2 post-transcriptional and post-translational regulatory domains using base editors and nucleases to correct the C6T splice regulator, enhancing SMN protein levels and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If ASO or small-molecule splicing modifiers are used to upregulate SMN protein, then SMN protein levels increase by ~2-fold, but the therapeutic effect is transient and requires repeated treatment
Solution Approach 1:
The patent performs preliminary genome editing on the SMN2 gene to create permanent genetic modifications that will continuously produce full-length SMN protein. By editing the C6T splice regulator or disrupting terminal splice regulatory sequences beforehand, the therapy establishes a lasting correction that doesn't require repeated administrations like ASO or small-molecule modifiers.
2Duration of action of stationary object
If AAV-mediated gene complementation is used to produce SMN protein, then constitutive production is achieved, but SMN overexpression can cause aggregation, toxicity, and pathology in some tissues
Solution Approach 1:
The patent applies local quality by making precise, localized edits to specific regulatory domains of the SMN2 gene (C6T splice regulator or terminal splice regulatory sequences) rather than globally overexpressing SMN. This targeted approach restores normal splicing regulation locally at the SMN2 locus, allowing physiologically appropriate SMN protein levels to be produced without the toxic overexpression seen in AAV-mediated gene complementation.
3Reliability
If genome editing is used to restore endogenous gene expression, then permanent treatment is achieved, but precise editing of post-transcriptional and post-translational regulatory domains is not yet established
Solution Approach 1:
The patent employs base editing technology that allows the cellular machinery to perform the editing function with high precision. Base editors enable direct conversion of the C6T nucleotide without requiring double-strand breaks, and the cell's own repair mechanisms facilitate precise incorporation of the corrected base pair, achieving both permanence and precision in restoring endogenous SMN2 gene expression.
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
Achieves stable and physiologically normal restoration of SMN protein levels, surpassing existing therapies by providing long-term benefits without toxicity, as demonstrated in mouse models.
Implementation Method 1
deaminating a cytidine base at position 6 of exon 7 of the SMN2 gene
Implementation Method 2
contacting the SMN2 gene with a base editor in association with a guide RNA (gRNA)
Data Source
AI summary
Provided are compositions and methods for delivering biological moieties such as modified nucleic acids into cells to kill or reduce the growth of microorganisms. Such compositions and methods include the use of modified messenger RNAs, and are useful to treat or prevent microbial infection, or to improve a subject's heath or wellbeing.