AAV Gene Therapy Constructs for Inner Ear Supporting Cells
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Solution Overview
Problem
Current treatments for hearing loss, particularly sensorineural hearing loss, lack effective methods for repairing or mitigating damage to inner ear structures, such as hair cells and supporting cells, which are often permanent and irreversible.
Innovation Solution
Development of constructs comprising polynucleotides encoding therapeutic polypeptides, specifically designed for selective expression in inner ear supporting cells using promoters like GJB2, which are operably linked to minimize expression in hair cells, delivered via adeno-associated virus (AAV) particles to promote therapeutic protein expression and reduce toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If universal promoters are used to drive therapeutic polypeptide expression in inner ear cells, then expression level is improved, but cell-type specificity is lost leading to toxicity in hair cells
Solution Approach 1:
The patent applies local quality by designing promoters with specific nucleotide sequences that are selectively active only in supporting cells of the inner ear, not in hair cells. This creates localized gene expression in the target cell type while leaving non-target cells unaffected, thereby achieving therapeutic efficacy in supporting cells without ototoxicity to hair cells.
2Reliability
If gene therapy constructs are designed for high expression in supporting cells, then therapeutic benefit is improved, but risk of off-target expression and toxicity increases
Solution Approach 1:
The patent applies parameter changes by modifying the nucleotide sequence parameters of promoter regions to create cell-type-specific expression patterns. By changing the sequence composition and regulatory elements of the promoter, the construct achieves high expression in supporting cells while minimizing off-target expression in other cell types, thus improving therapeutic benefit without increasing toxicity risk.
Data Source
AI summary
The present disclosure provides constructs comprising a coding sequence operably linked to a promoter, wherein the coding sequence encodes a polypeptide (e.g., a therapeutic polypeptide). Exemplary constructs include AAV constructs. Also provided are methods of using disclosed constructs for the treatment of hearing loss and/or deafness.