US-12624357-B2 - Methods and compositions to promoting retinal regeneration using prox1 migration inhibitor as active ingredient

US12624357B2US 12624357 B2US12624357 B2US 12624357B2US-12624357-B2

Abstract

The present invention relates to a technique capable of treating a retinal neurodegenerative disease through regeneration of a retinal nerve by targeting Prox1 in the mammalian retina using an inhibitor which inhibits Prox1 expression or migration. According to the present invention, inducing the regeneration of the damaged retina in mammals, and thus can be commonly applied to the treatment of various retinal neurodegenerative diseases causing vision loss, and furthermore, when combining with a selective retinal nerve differentiation method or the like, it is expected that the method can be used for the development of an innovative retinal regeneration method capable of selectively regenerating only specific degenerating retinal neurons.

Inventors

Jin Woo Kim
Eun Jung Lee

Assignees

KOREA ADVANCED INSTITUTE OF SCIENCE AND TECHNOLOGY

Dates

Publication Date: 20260512
Application Date: 20220616
Priority Date: 20200625

Claims (7)

1 . A method for preventing or treating a retinal neurodegenerative disease, the method comprising: administering an effective amount of a neutralizing antibody which specifically binds to and inhibits prospero homeobox 1 (Prox1) to an individual in need thereof.
2 . The method of claim 1 , wherein the neutralizing antibody suppresses the migration of a Prox1 protein from retinal neurons to Muller glia.
3 . The method of claim 1 , wherein the retinal neurodegenerative disease is any one selected from the group consisting of retinitis pigmentosa, Leber congenital amaurosis (LCA), retinal detachment, macular degeneration, diabetic retinopathy, glaucoma, central serous retinopathy and senile retinal degeneration.
4 . The method of claim 1 , wherein the neutralizing antibody which specifically binds to prospero homeobox 1 (Prox1) promotes regeneration of retinal neurons by suppressing the proliferation of microglia which induce phagocytosis and inflammatory responses.
5 . The method of claim 1 , wherein the neutralizing antibody which specifically binds to prospero homeobox 1 (Prox1) is administered in combination with a neuronal differentiation-promoting drug.
6 . The method of claim 1 , wherein the neutralizing antibody which specifically binds to prospero homeobox 1 (Prox1) is a pharmaceutical preparation, wherein the pharmaceutical preparation is an injection formulation, an infusion formulation, a spray formulation or a liquid formulation.
7 . The method of claim 1 , wherein the neutralizing antibody is administered via intraocular administration.

Description

RELATED APPLICATIONS The present invention is a Continuation of PCT Serial No. PCT/KR2021/008044, filed on Jun. 25, 2021, which claims priority from Korean Patent Application No. 10-2020-0078016 filed on Jun. 25, 2020 and Korean Patent Application No. 10-2021-0077060 filed on Jun. 14, 2021; the entireties of both are hereby incorporated herein by reference. TECHNICAL FIELD The present invention relates to a technique capable of treating a retinal neurodegenerative disease through regeneration of the retinal nerve in the mammalian retina, and more specifically, to a pharmaceutical composition for preventing or treating a retinal neurodegenerative disease, comprising a Prox1 expression or migration inhibitor as an active ingredient and a pharmaceutical preparation comprising the composition. BACKGROUND ART The retina is a transparent nerve tissue that covers the innermost part of the eyeball, and the light entering the eyeball passes through the inner layer of the retina and is detected by the visual cells of the retina. The visual cells convert light information back into electrical information, which passes through neurons and optic nerves of the inner layer of the retina, allowing us to see things through this process. The outermost part of the eyeball is an avascular fibrous layer (cornea, sclera), and the intermediate layer is a vascular tissue, the uvea (iris, ciliary body, choroid), and the clear nerve tissue that covers the inside of the intermediate layer, the choroid, is the retina. The retina is a thin, transparent membrane with a varying thickness, and the central part of the retina is subdivided into the fovea, parafovea, and perifovea, depending on the position. The fovea is clinically called the macula. Meanwhile, a retinal neurodegenerative disease may occur due to congenital or acquired damage to the retina or complications of a chronic disease such as hypertension and diabetes. Specific examples thereof include a congenital retinal degenerative disease such as retinitis pigmentosa, which shows nyctalopia which is an inability to see well in the dark as an initial symptom and Leber congenital amaurosis (LCA) which is hereditary retinal dystrophy, retinal detachment in which the retina tears and peels away, macular degeneration, diabetic retinopathy caused by diabetes, central serous retinopathy, senile retinal degeneration, and the like. Due to these diseases, symptoms such as decreased vision acuity, nyctalopia including visual field disturbances, color amblyopia, color blindness, photopsia (lights appear to flash when moving eyes), myodesopsia (something appears to float in front of the eyes like mayflies), metamorphopsia (an object looks bent), and central scotoma (center of visual field looks black) appear. However, unlike lower vertebrates, which are capable of regenerating retinal neurons, mammals do not regenerate retinal neurons and retinal neurons cannot be transplanted, so once damaged, the retina does not recover, and thus may result in blindness. Despite a rapid increase in the incidence rate of such retinal neurodegenerative diseases, there are currently few effective therapeutic agents or therapeutic methods. Recently, studies on cell therapeutic agents using various stem cells for the replacement and protection of retinal cells have been conducted, but the clinical application thereof has not yet been made (Korean Patent No. 10-1268741), and Stargardt's disease gene therapy targeting retinal pigment epithelial cells has been clinically applied, but is limited only to patients with some genetic mutations, and there is no technology capable of restoring visual function by regenerating the degenerated retina. Therefore, there is an urgent need for developing a safe and economical therapeutic agent that can be widely applied to various diseases caused by retinal degeneration in mammals including humans who are fundamentally unable to regenerate retinal nerves. DISCLOSURE Technical Problem As a result of intensive studies to develop a technology capable of inducing regeneration of a retinal nerve under the aforementioned background, the present inventors discovered a mechanism by which a Prox1 protein expressed in retinal neurons in a mammal migrates to the Muller glia after retinal damage for the first time, and based on this, confirmed that the cell division of Muller glia, which is the first stage of retinal nerve regeneration can be induced by suppressing the expression of Prox1 in the retina or migration of Prox1 from the retinal neurons to the Muller glia, thereby completing the present invention based on this. Thus, an object of the present invention is to provide a pharmaceutical composition for preventing or treating a retinal neurodegenerative disease, comprising a prospero homeobox 1 (Prox1) inhibitor as an active ingredient. Further, another object of the present invention is to provide a pharmaceutical preparation for preventing or treating a retinal neurodegenerative d