Müller Glia Reprogramming With bHLH Factors Without Retinal Injury
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Solution Overview
Problem
Current therapies are ineffective in regenerating lost retinal neurons in mammalian retinas, and existing methods for reprogramming Müller glia into neurogenic progenitors are limited by the need for retinal injury and additional reprogramming potentiating agents, complicating their application.
Innovation Solution
Intraocular delivery of nucleic acid molecules encoding two or more proneural bHLH transcription factors, such as Ascl1 and Atoh1, to reprogram Müller glia into retinal neurons without the need for retinal injury or additional agents, promoting robust neurogenesis and integration into retinal circuitry.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If existing methods for reprogramming Müller glia are used, then some neuron production is achieved, but the process requires retinal injury and co-administration of multiple reprogramming potentiating agents which complicates the therapy
Solution Approach 1:
The patent extracts and eliminates the requirement for retinal injury and reprogramming potentiating agents from the reprogramming protocol. By using a specifically designed nucleic acid molecule with optimized promoter and coding sequences, the invention achieves efficient Müller glia reprogramming through a single composition without needing additional potentiating agents or causing retinal injury.
Solution Approach 2:
The nucleic acid molecule composition serves multiple functions simultaneously: it delivers proneural transcription factors, drives their expression in Müller glia, and achieves reprogramming without requiring separate steps for injury induction or potentiating agent administration. This multi-functional approach simplifies the overall therapeutic protocol.
2Quantity of substance
If Ascl1 expression is induced in adult Müller glia with lentivirus, then neurogenic progenitor reprogramming is achieved, but only a small percentage of Müller glia are reprogrammed which limits therapeutic promise
Solution Approach 1:
The patent changes key parameters of the nucleic acid molecule including the promoter sequence (using enhanced promoters with higher activity), coding sequences (optimized for expression), and structural elements. These parameter optimizations result in significantly higher expression levels of proneural transcription factors and increase the percentage of reprogrammed Müller glia from single-digit to majority populations.
3Productivity
If multiple reprogramming potentiating agents are co-administered to enhance neurogenesis, then neuron production is improved, but the treatment becomes more complex and limits commercial application
Solution Approach 1:
The patent merges multiple functional elements into a single nucleic acid molecule composition. Instead of requiring separate administration of proneural transcription factor genes, potentiating agents, and injury induction, the invention combines these functions into one composition that achieves high-rate neuron production through optimized molecular design, thereby simplifying manufacturing and commercial application.
Data Source
AI summary
Nucleic acid molecules and compositions, and methods using the same are provided herein for intraocular gene-based delivery and expression of two or more proneural bHLH transcription factors in the retina. The nucleic acid molecules, compositions and methods disclosed herein stimulate regeneration of retinal interneurons from retinal Müller glia (MG) and reprogram the MG into bipolar, amacrine, horizontal, and/or ganglion cells. Such methods and nucleic acid molecules are used for vision restoration and/or treatment of a range of ocular diseases involving retinal degeneration after injury, disease, or vison loss.