Identification of mutations in channelopsin variants having improved light sensitivity and methods of use thereof
Inventors
Pan, Zhuo-Hua • GANJAWALA, TUSHAR • Lu, Qi • Abrams, Gary
Assignees
Publication Number
US-12234267-B2
Publication Date
2025-02-25
Expiration Date
2037-08-29
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The invention provides compositions and kits including at least one nucleic acid or polypeptide molecule encoding for a mutant CoChop protein. Methods of the invention include administering a composition comprising a mutant CoChop to a subject to preserve, improve, or restore phototransduction. Preferably, the compositions and methods of the invention are provided to a subject having impaired vision, thereby restoring vision to normal levels.
Core Innovation
The invention provides compositions and kits that include at least one nucleic acid or polypeptide molecule encoding a mutant CoChop protein. These mutant CoChop (mCoChop) proteins exhibit amino acid modifications that confer improved light sensitivity compared to wild-type CoChR, requiring less light for activation and generating greater ion or proton flux at the same light intensity. The invention also covers isolated nucleic acid molecules encoding these polypeptides, optionally operably linked to a promoter, as well as vectors, cells, and pharmaceutical compositions containing them.
The core methods of the invention involve administering a composition comprising a mutant CoChop to a subject, especially one suffering from impaired vision, to preserve, improve, or restore phototransduction and vision. The invention particularly targets conditions where photoreceptor loss or dysfunction severely compromises light sensitivity, such as retinal degenerative diseases like retinitis pigmentosa and age-related macular degeneration. By delivering the mutant CoChop gene or protein, photosensitivity of the retina is restored or improved, increasing visual responsiveness to lower levels of light.
A principal aspect of the invention is the identification of specific CoChop mutants (with sequences including SEQ ID NOs: 3-10) that possess higher light sensitivity and altered channel kinetics, allowing therapeutic methods to lower the threshold light intensity required for retinal activation. The invention encompasses both compositions for gene delivery and defined protocols for administration by routes including intravitreal or subretinal injection, with the goal of achieving expression of the light-activated ion channel in retinal neurons of the subject and thereby restoring visual function.
Claims Coverage
There are two independent claims covering two main inventive features related to methods of treating ocular diseases using compositions encoding specific mutant CoChop proteins.
Method of treating ocular disease by administering nucleic acid encoding mutant CoChop protein
A method is described for treating an ocular disease or disorder that can be improved by restoring light sensitivity to retinal neurons. This method comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition containing a nucleic acid encoding a polypeptide with the amino acid sequence of any one of SEQ ID NOs: 3-10. The nucleic acid must be operably linked to a promoter, and expression of the polypeptide in the cell membrane of a retinal neuron is achieved following administration.
Method of improving light sensitivity in an eye by administering nucleic acid encoding mutant CoChop protein
This inventive feature is directed to a method for improving light sensitivity in an eye by administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a nucleic acid encoding a polypeptide with the amino acid sequence of any one of SEQ ID NOs: 3-10. The nucleic acid must be operably linked to a promoter, and the resulting polypeptide is expressed in a cell membrane of a cell in the eye after administration.
The inventive features focus on the administration of nucleic acids encoding defined mutant CoChop polypeptides to achieve restoration or improvement of light sensitivity in retinal neurons or eye cells through expression in cellular membranes.
Stated Advantages
Mutant CoChop polypeptides require less light than wild-type CoChR for activation, increasing light sensitivity.
At equivalent light intensities, mutant CoChop produces a greater level of ion flux and/or proton flux than wild-type.
Administration of mutant CoChop results in lowering the threshold light intensity required to elicit a photocurrent.
Mutant CoChop expression leads to increased visual evoked potential in the visual cortex.
Therapeutic methods using mutant CoChop can restore, improve, or preserve phototransduction and visual function in individuals with impaired vision.
Mutant CoChop achieves activation at light intensities within the range of normal outdoor lighting conditions.
The invention demonstrates stable and long-term expression of mutant CoChop in retinal neurons following administration.
Documented Applications
Treatment of retinal degenerative diseases, including retinitis pigmentosa and age-related macular degeneration.
Improvement, preservation, or restoration of vision in subjects with impaired vision due to photoreceptor loss or dysfunction.
Prophylactic treatment to prevent or delay onset of age-related macular degeneration or retinitis pigmentosa.
Treatment of other ocular diseases or disorders such as congenital cone dystrophies and diabetic retinopathy.
Use in subjects suffering from vision loss, including increasing light sensitivity and lowering the threshold for visually guided behavior.
Interested in licensing this patent?