VR3.0 Channelrhodopsin for Fast, Light-Sensitive Retinal Optogenetics
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Solution Overview
Problem
Current optogenetic tools for treating retinal photoreceptor degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration, fail to meet the dual requirements of high light sensitivity and fast photoresponse kinetics, and exhibit ion selectivity discrepancies and side effects like intracellular acidification.
Innovation Solution
A novel light-activated channel protein VR3.0, comprising truncated channelrhodopsin variants with specific amino acid sequences and peptides for enhanced cell membrane expression, encoded by specific nucleic acid molecules, delivered via recombinant adeno-associated viruses, to restore retinal photosensitivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If microbial photosensitive proteins (e.g., Channelrhodopsin-2) are used for optogenetic therapy, then fast photoresponse kinetics are achieved, but light sensitivity is insufficient
Solution Approach 1:
The patent merges the fast kinetic characteristics of microbial channelrhodopsins with the high light sensitivity of mammalian GPCR rhodopsins by creating a chimeric protein structure. The channelrhodopsin-derived transmembrane domain provides rapid ion channel gating, while the rhodopsin-derived GPCR domain contributes enhanced photopigment light absorption and sensitivity, achieving both fast response and high sensitivity simultaneously.
Solution Approach 2:
The invention creates a composite photosensitive protein combining elements from two different protein families: microbial channelrhodopsin and mammalian rhodopsin. This composite structure integrates the functional advantages of both parents - the rapid ion channel behavior of channelrhodopsin and the high light sensitivity of rhodopsin - to produce a protein that satisfies both requirements.
2Reliability
If mammalian photosensitive proteins (e.g., rhodopsin) are used for optogenetic therapy, then high light sensitivity is achieved, but photoresponse kinetics are insufficient
Solution Approach 1:
The patent merges the fast kinetic characteristics of microbial channelrhodopsins with the high light sensitivity of mammalian GPCR rhodopsins by creating a chimeric protein structure. The channelrhodopsin-derived transmembrane domain provides rapid ion channel gating, while the rhodopsin-derived GPCR domain contributes enhanced photopigment light absorption and sensitivity, achieving both fast response and high sensitivity simultaneously.
Solution Approach 2:
The invention creates a composite photosensitive protein combining elements from two different protein families: microbial channelrhodopsin and mammalian rhodopsin. This composite structure integrates the functional advantages of both parents - the rapid ion channel behavior of channelrhodopsin and the high light sensitivity of rhodopsin - to produce a protein that satisfies both requirements.
3Ease of manufacture
If existing optogenetic tools are used, then treatment approach is established, but ion selectivity discrepancies and side effects occur
Solution Approach 1:
The patent applies local quality by creating a chimeric protein with distinct functional domains: the channelrhodopsin-derived transmembrane region provides controlled ion selectivity and permeability, while the rhodopsin-derived GPCR region provides regulated activation. This localized functional differentiation within the protein structure enables precise control over ion flow and cellular responses, reducing unwanted side effects like intracellular acidification while maintaining therapeutic effectiveness.
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
VR3.0 exhibits wide photosensitive wavelengths, higher sensitivity, faster photoresponse kinetics, and maintains stable photocurrent signals under high-frequency stimulation, effectively treating retinal degenerative diseases by restoring visual function.
Implementation Method 1
VR3.0 exhibits wide photosensitive wavelengths, higher sensitivity, faster photoresponse kinetics
Implementation Method 2
comprising a channelrhodopsin comprising an amino acid sequence shown in SEQ ID NO.1
Data Source
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AI summary
The application provides a novel light-activated channel protein VR3.0 and uses thereof. The light-activated channel protein VR3.0 series provided in this application has a wide range of photosensitive wavelengths, higher sensitivity to light response, faster photoresponse kinetics, maintaining stable photocurrent signals under high-frequency stimulation while exhibiting good response amplitude and frequency under light stimulation of various wavelengths (especially white light, natural light). The light-activated channel protein VR3.0 series provided in this application has a clear therapeutic effect on retinal photoreceptor cell degenerative diseases, and can be used to prepare drugs for restoring the photoreceptor function of the retina, restoring the visual or photosensitive ability of subjects, and treating retinal degenerative diseases.