Splice-Sensor Nucleic Acid Sequence Regulates Transgene Expression
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Solution Overview
Problem
Current gene therapy approaches for conditions like myotonic dystrophy lack tight control over transgene expression, leading to potential unwanted effects in healthy tissues due to excessive expression of therapeutic transgenes.
Innovation Solution
A chimeric nucleic acid molecule with a splice-sensor sequence that regulates transgene expression based on the activity of proteins like MBNL, ensuring expression only when the protein's activity is reduced, thereby preventing unnecessary expression in healthy tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic transgene is expressed in gene therapy, then therapeutic effect is improved, but unwanted effects in healthy tissues occur due to excessive expression
Solution Approach 1:
The patent applies local quality by creating tissue-specific control of transgene expression through splice-sensor sequences that respond to MBNL protein activity levels. Healthy tissues with normal MBNL activity maintain repression, while diseased tissues with reduced MBNL activity allow expression, providing localized therapeutic effect without systemic side effects
Solution Approach 2:
The patent implements feedback control where the transgene expression is regulated by the splicing activity of MBNL protein. When MBNL activity is reduced (disease state), the splice-sensor allows exon inclusion and transgene expression. When MBNL activity is normal (healthy state), the splice-sensor represses expression, creating a self-regulating feedback system
2Object-affected harmful factors
If transgene expression is controlled tightly, then side effects in healthy cells are minimized, but therapeutic impact in affected cells may be reduced
Solution Approach 1:
The patent uses parameter changes by exploiting the differential MBNL protein activity parameter between healthy and diseased tissues. The splice-sensor sequence is designed to respond to changes in MBNL activity levels, transitioning from exon exclusion (repression) in healthy tissues to exon inclusion (expression) in diseased tissues, thereby optimizing both safety and efficacy
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 system effectively controls transgene expression, ensuring it is only active in tissues with reduced MBNL activity, minimizing side effects in healthy cells and maximizing therapeutic impact in affected cells.
Implementation Method 1
a first nucleic acid sequence, the primary transcript of which comprises an exon, said primary transcript being subject to splicing by a protein regulating alternative splicing
Data Source
AI summary
The present invention relates to the field of gene therapy. In particular, the invention relates to a nucleic acid molecule comprising a nucleic acid sequence able to regulate the expression of a transgene of interest, to a vector or a cell comprising said nucleic acid molecule, and uses thereof.