Restoration of visual responses by in vivo delivery of rhodopsin nucleic acids
Inventors
Pan, Zhuo-Hua • Dizhoor, Alexander M.
Assignees
SALUS UNIVERSITY • Wayne State University
Publication Number
US-11883463-B2
Publication Date
2024-01-30
Expiration Date
2027-05-04
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Abstract
Nucleic acid vectors encoding light-gated cation-selective membrane channels, in particular channelrhodopsin-2 (Chop2), converted inner retinal neurons to photosensitive cells in photoreceptor-degenerated retina in an animal model. Such treatment restored visual perception and various aspects of vision. A method of restoring light sensitivity to a retina of a subject suffering from vision loss due to photoreceptor degeneration, as in retinitis pigmentosa or macular degeneration, is provided. The method comprises delivering to the subject by intravitreal or subretinal injection, the above nucleic acid vector which comprises an open reading frame encoding a rhodopsin, to which is operatively linked a promoter and transcriptional regulatory sequences, so that the nucleic acid is expressed in inner retinal neurons. These cells, normally light-insensitive, are converted to a light-sensitive state and transmit visual information to the brain, compensating for the loss, and leading to restoration of various visual capabilities.
Core Innovation
The invention provides a method for restoring photosensitivity and, consequently, visual function to retinas in which photoreceptors have degenerated or died due to diseases such as retinitis pigmentosa or age-related macular degeneration. This is achieved by delivering nucleic acid vectors encoding light-gated cation-selective membrane channels, specifically channelrhodopsin-2 (Chop2), to surviving inner retinal neurons, such as ganglion cells, amacrine cells, and bipolar cells. The delivered nucleic acid is operatively linked to a promoter and relevant transcriptional regulatory sequences, ensuring its expression specifically in the target cells within the retina.
Upon expression of the microbial-type rhodopsin (e.g., Chop2), these normally light-insensitive inner retinal neurons are converted into photosensitive cells. This genetic modification results in the neurons being capable of responding to light, transmitting visual information to the brain when photoreceptors are absent. As demonstrated in animal models, such as photoreceptor-deficient mice, this genetic conversion led to robust membrane depolarization or action potential firing in response to light and restored visually evoked responses in the visual cortex.
This approach avoids the introduction of exogenous cells, tissues, or physical devices, and instead leverages viral-based gene therapy to achieve lasting restoration of visual capabilities. The method supports high spatial and temporal resolution of restored vision and may include additional strategies, such as modifying the light sensitivity or wavelength selectivity of Chop2, using other microbial rhodopsins, and applying patient training to enhance visual outcomes. The patent also addresses the underlying challenge that, while many inner retinal neurons survive degeneration, there have so far been no therapies effective in restoring vision after photoreceptor loss. This invention offers a new direction by directly imparting light-sensitive properties to these remaining neurons.
Claims Coverage
The patent claims are centered around one primary independent inventive feature that defines the method for restoring photosensitivity to retinal neurons using delivery and expression of a specific rhodopsin polypeptide.
Restoring photosensitivity to retinal neurons via nucleic acid vector encoding Chop2 fragment
A method for restoring photosensitivity to retinal neurons in a subject suffering from vision loss or blindness, comprising: - Delivery of a nucleic acid vector to the retina (in which photoreceptors are degenerating or have died). - The vector comprises a nucleic acid encoding a polypeptide of SEQ ID NO: 3 (a fragment of channelrhodopsin-2) or a polypeptide having 98% or 99% sequence identity thereto. - The nucleic acid is operably linked to a promoter sequence (which may be constitutive or cell type-specific). - Expression of the polypeptide in the retinal neurons renders the neurons photosensitive, thereby restoring photosensitivity to those neurons. The dependent claims further specify key features, such as use of recombinant adeno-associated virus (rAAV) vectors (including AAV serotypes 1–6); use of specific promoter types (hybrid CAG, CMV, mGluR6, Pcp2 [L7], neurokinin-3 [NK-3]); inclusion of regulatory elements (such as WPRE and bovine or human growth hormone polyadenylation sequences); targeting of visual conditions such as retinitis pigmentosa or age-related macular degeneration; and application in humans.
The claim coverage is focused on a method that enables the genetic transformation of surviving retinal neurons into photosensitive cells by delivering and expressing a specific channelrhodopsin-2 polypeptide, as defined by SEQ ID NO: 3 or close variants, in the absence of viable photoreceptors, thereby restoring light sensitivity to otherwise blind or vision-impaired subjects.
Stated Advantages
The invention does not require introducing exogenous cells, tissues, or physical devices, thus avoiding obstacles such as immune reactions and biocompatibility issues faced by cell transplantation or prosthetics.
The genetic modification allows for permanent restoration of vision loss or blindness caused by retinal degenerative diseases by producing photosensitivity in surviving retinal neurons.
Restored vision achieved with high spatial and temporal resolution due to targeting at the cellular level.
The method can offer functional improvement in vision even in subjects who are otherwise completely blind due to photoreceptor degeneration.
Long-term and stable expression of light-sensitive proteins in retinal neurons is achieved, making the approach durable and biocompatible.
The restored photosensitivity can be enhanced or combined with light-amplifying devices or patient training to improve practical outcomes.
Restoring light-induced activity in inner retinal neurons may prevent or delay the remodeling processes that degrade retinal circuitry after photoreceptor loss.
The method can also improve regulation of circadian rhythms, pupillary light reflexes, and other light-mediated physiological processes impaired by blindness.
Documented Applications
Treatment and/or restoration of at least partial vision to subjects with vision loss or blindness due to degenerative ocular disorders, such as retinitis pigmentosa and age-related macular degeneration.
Restoration of light sensitivity and various categories of visual response: light detection, light projection, light versus dark pattern resolution, and recognition.
Improvement or restoration of circadian rhythm regulation and related physiological light responses in blind individuals.
Application in conjunction with visual prostheses, such as retinal implants, cortical implants, lateral geniculate nucleus implants, or optic nerve implants.
Use in low vision rehabilitation with visual training including habituation, orientation, and mobility training for improved outcomes.
Potential use in treating other ocular disorders involving photoreceptor malfunction or absence, such as childhood-onset blinding diseases, macular degeneration, diabetic retinopathy, congenital stationary night blindness, and cone dystrophies.
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