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CN-122005866-A - Therapeutic effect of vectors complementing wild-type SLC4A11 genes and/or proteins on corneal endothelial cell dysfunction

CN122005866ACN 122005866 ACN122005866 ACN 122005866ACN-122005866-A

Abstract

The invention provides a vector for supplementing wild SLC4A11 genes and/or proteins for treating abnormal functions of corneal endothelial cells, belonging to the technical field of gene medicines. The invention provides application of a reagent for supplementing wild SLC4A11 genes and/or proteins in preparation of a medicament for treating corneal endothelial cell dysfunction, and provides a gene therapy technical scheme for targeting corneal endothelial cells by taking SLC4A11 related CHED as a representative disease model. The invention provides a gene therapy vector for cornea endothelial cell dysfunction, which comprises an AAV vector carrying a wild type SLC4A11 gene, adopts a mode of supplementing the wild type SLC4A11 gene and/or protein to treat the cornea endothelial cell dysfunction, realizes the efficient, specific and long-term expression of an exogenous SLC4A11 gene in the cornea endothelial cell, thereby recovering the pumping function of the endothelial cell, relieving cornea edema and improving transparency.

Inventors

  • XIE LIXIN
  • ZHANG BINING
  • CONG LIN
  • ZHOU QINGJUN
  • LIN PING

Assignees

  • 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院)

Dates

Publication Date
20260512
Application Date
20260211

Claims (10)

  1. 1. Use of an agent that supplements the wild-type SLC4a11 gene and/or protein in the manufacture of a medicament for the treatment of corneal endothelial cell dysfunction.
  2. 2. The use according to claim 1, wherein the cause of the corneal endothelial cell dysfunction comprises congenital genetic endothelial cell malnutrition, surgery, ultraviolet light, freezing or other genetic diseases.
  3. 3. The use of claim 1, wherein the nucleotide sequence of the wild-type SLC4a11 gene is set forth in SEQ ID No.1 when it is derived from a mouse source.
  4. 4. The use of claim 1, wherein the nucleotide sequence of the wild-type SLC4a11 gene is shown in SEQ ID No.2 when it is derived from human source.
  5. 5. The use of claim 1, wherein said agent comprises a vector carrying said wild-type SLC4a11 gene.
  6. 6. The use of claim 5, wherein the type of vector comprises an AAV vector.
  7. 7. The use of claim 6, wherein the serotype of the AAV vector comprises any of AAV2, AAV5, AAV6, AAV8, and AAV9.
  8. 8. A gene therapy vector for corneal endothelial cell dysfunction, comprising an AAV vector carrying the wild type SLC4a11 gene.
  9. 9. The gene therapy vector of claim 8, wherein the serotype of the AAV vector comprises AAV6.
  10. 10. The gene therapy vector of claim 8 or 9, wherein the gene therapy vector is injected into the anterior chamber by injection.

Description

Therapeutic effect of vectors complementing wild-type SLC4A11 genes and/or proteins on corneal endothelial cell dysfunction Technical Field The invention belongs to the technical field of gene medicines, and particularly relates to a vector for supplementing wild SLC4A11 genes and/or proteins for treating abnormal functions of corneal endothelial cells. Background Corneal endothelial cells (corneal endothelial cells, CEC) are located in the innermost layer of the cornea and are composed of a monolayer of hexagonal cells and play an irreplaceable role in maintaining corneal transparency and normal physiological function. Healthy adult corneal endothelial cell densities are about 3000 per mm 2 and decrease year by year with age. The cornea endothelium maintains cornea transparency through two core mechanisms, namely, a tight physical barrier is formed between endothelial cells to limit passive diffusion of aqueous humor and macromolecular substances to cornea stroma, and a Na +/K+ -ATPase plasma pump system on a cell membrane is relied on to actively transport ions and establish an osmotic gradient, so that moisture is driven to transfer from the cornea stroma to the anterior chamber to maintain a cornea relative dehydration state. In addition, the corneal endothelium is involved in the transport of nutrients from aqueous humor to avascular corneal tissue and in the removal of metabolic waste products. When the number of corneal endothelial cells is reduced or the function is impaired, corneal oedema, turbidity and even severe vision impairment will be directly caused. Corneal endothelial disease caused by genetic mutation is one of the main indications of current corneal endothelial transplantation. Among them, congenital hereditary corneal endothelial cell malnutrition (congenital hereditary endothelial dystrophy, CHED) is a severe autosomal recessive genetic disease, the main causative gene of which is SLC4a11. The gene codes a transmembrane transport protein and participates in maintaining ion and osmotic pressure steady state in corneal endothelial cells. SLC4A11 dysfunction or mutation can lead to severe dysfunction of the corneal endothelial pump. CHED patients often develop significant binocular corneal oedema and turbidness during birth or infancy, and corneal transparency is severely impaired, often resulting in irreversible visual dysfunction if not intervened in time. At present, no effective treatment means aiming at the etiology exists in clinic aiming at CHED, and the treatment means mainly depend on surgical modes such as penetrating cornea transplantation or post-elastic layer endothelial cornea transplantation. However, the cornea donor is seriously short for a long time, and the problems of rejection reaction, high operation risk, unstable long-term curative effect and the like exist in the transplantation operation, and the cornea donor is particularly unfavorable for infant patients. Thus, there is a need to develop new therapeutic strategies that replace cornea transplants, and that can correct endothelial dysfunction from the molecular level. In recent years, gene therapy provides a new treatment concept for hereditary eye diseases. However, gene therapy against corneal endothelial cells still faces multiple technical bottlenecks. On one hand, the cornea endothelium is derived from neural crest cells and has similar embryo sources with tissues such as cornea stroma, iris stroma and trabecular meshwork, so that the cell type specific transduction is difficult to realize in the existing delivery mode, and on the other hand, the cornea endothelium is exposed to a continuously flowing aqueous environment for a long time, so that the gene carrier is easy to dilute or clear, the transduction efficiency is low, and meanwhile, the non-targeted transfection risk is high. The anterior chamber injection (INTRACAMERAL INJECTION) technique commonly used at present is mainly used for targeting trabecular meshwork, and has no systematic evaluation for the specificity, safety and long-term expression effect of corneal endothelium. Disclosure of Invention The invention provides a treatment effect of a vector for supplementing wild SLC4A11 genes and/or proteins on the dysfunction of the endothelial cells, and the dysfunction of the endothelial cells can be effectively relieved by injecting the vector into the anterior chamber. The invention provides an application of a reagent for supplementing wild SLC4A11 genes and/or proteins in preparing a medicament for treating corneal endothelial cell dysfunction. In one embodiment of the invention, the cause of the corneal endothelial cell dysfunction comprises congenital genetic endothelial cell malnutrition, surgery, ultraviolet light, freezing or other genetic diseases. In a specific embodiment of the invention, when the wild type SLC4A11 gene is derived from a mouse source, the nucleotide sequence is shown as SEQ ID No. 1. In a specific embodiment of the inve