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EP-4739350-A1 - PERIOCULAR DELIVERY OF AAV VECTORS FOR TREATING OPHTHALMIC PATHOLOGIES

EP4739350A1EP 4739350 A1EP4739350 A1EP 4739350A1EP-4739350-A1

Abstract

Provided herein is a method of delivering a pharmaceutical composition comprising an AAV vector to an ocular or periocular tissue, comprising injecting the AAV vector periocularly (e.g., periocular injection, optionally peribulbar injection). In some aspects, the method is for use in treating an ophthalmic pathology (e.g., thyroid eye disease (TED) in a subject in need thereof.

Inventors

  • STONE, MICHELE
  • CEPEDA, Diana
  • CASTELLANOS, Ruth
  • ENGLES, Michael
  • RAMASWAMY, SHANKAR
  • MURPHY, ANDREW
  • ECLOV, Rachel

Assignees

  • Kriya Therapeutics, Inc.

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. 1. A method of treating an ophthalmic pathology in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising an AAV vector, wherein the administration is a periocular injection.
  2. 2. The method of claim 1, wherein the periocular injection is a periorbital injection or a post- septal injection.
  3. 3. The method of claim 2, wherein the periorbital injection is a subtenon injection, a retrobulbar injection, a subconjunctival injection, or a peribulbar injection.
  4. 4. The method of claim 2 or 3, wherein the periorbital injection is a retrobulbar injection.
  5. 5. The method of claim 2 or 3, wherein the periorbital injection is a peribulbar injection.
  6. 6. The method of any one of claims 1-5, wherein the AAV vector contacts an orbital tissue(s) or an extraocular compartment(s)) selected from the group consisting of: extraocular adipose tissue, extraocular levantor muscle, extraocular lateral rectus muscles, extraocular medial rectus muscles, extraocular superior rectus muscles, extraocular inferior rectus muscles, extraocular inferior oblique muscles, extraocular superior oblique muscles, optic nerve, blood vessels, sclera, dural sheath, lamina cribrosa, eyelid, lacrimal gland, lacrimal sac, tear film, or any combination thereof.
  7. 7. The method of any one of claims 1-6, wherein the AAV vector contacts an orbital tissue(s) or an extraocular compartment(s) selected from the group consisting of: extraocular adipose tissue, extraocular lateral rectus muscles, extraocular medial rectus muscles, extraocular superior rectus muscles, extraocular inferior rectus muscles, extraocular inferior oblique muscles, extraocular superior oblique muscles, or any combination thereof.
  8. 8. A method of delivering a pharmaceutical composition comprising an AAV vector to an orbital tissue(s) or an extraocular compartment(s), comprising injecting the AAV vector periocularly, wherein the orbital tissue(s) or extraocular compartment(s) is selected from the group consisting of: extraocular adipose tissue, extraocular levantor muscle, extraocular lateral rectus muscles, extraocular medial rectus muscles, extraocular superior rectus muscles, extraocular inferior rectus muscles, extraocular inferior oblique muscles, extraocular superior oblique muscles, optic nerve, blood vessels, sclera, dural sheath, lamina cribrosa, eyelid, lacrimal gland, lacrimal sac, tear film, or any combination thereof.
  9. 9. The method of claim 8, wherein the orbital tissue(s) or extraocular compartment(s) is selected from the group consisting of extraocular adipose tissue, extraocular lateral rectus muscles, extraocular medial rectus muscles, extraocular superior rectus muscles, extraocular inferior rectus muscles, extraocular inferior oblique muscles, extraocular superior oblique muscles, or any combination thereof.
  10. 10. The method of any one of claims 1-9, wherein the administration or delivery comprises a volume of about 0.1 mL to about 10 mL of the pharmaceutical composition per periocular injection.
  11. 11. The method of any one of claims 1-9, wherein the administration or delivery comprises a volume of 0.1 mL to 1 mL of the pharmaceutical composition per periocular injection.
  12. 12. The method of any one of claims 1-11, wherein the administration comprises a volume of 0.1 mL to 0.5 mL of the pharmaceutical composition per periocular injection.
  13. 13. The method of any one of claims 1-12, wherein the administration comprises a volume of 0.3 mL to 0.5 mL of the pharmaceutical composition per periocular injection.
  14. 14. The method of any one of claims 2-13, wherein at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75 %, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100 % of the AAV vector contacts the ocular or periocular tissue.
  15. 15. The method of any one of claims 1-14, wherein the AAV vector transduces a target ocular or periocular cell.
  16. 16. The method of any one of claims 1-15, the AAV vector transduction efficiency is at least 5% (e.g., 5% to 95%, 10% to 95%, or 25% to 95%) of one or more of the target ocular or periocular cells.
  17. 17. The method of claim 15 or 16, wherein the target ocular or periocular cell is selected from the group consisting of a fibroblast cell, an adipocyte, a myofibroblast, a myocyte, a muscle cell, an epithelial cell, a neuroepithelial cell, a gliocyte, or any combination thereof.
  18. 18. The method of any one of claims 1-16, wherein the AAV vector comprises a capsid of a serotype selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVRh8, AAVrh9, AAV9, AAVrhlO, AAV10, AAV11, AAV12, and a modified version thereof.
  19. 19. The method of claim 18, wherein the capsid serotype is AAV8 or AAV9.
  20. 20. The method of any one of claims 1-19, wherein the AAV vector comprises a capsid, a vector genome, and an expression cassette.

Description

PERIOCULAR DELIVERY OF AAV VECTORS FOR TREATING OPHTHALMIC PATHOLOGIES CROSS REFERENCE TO RELATED APPLICATIONS [0001] The present application claims the priority benefit of U.S. Provisional Application No. 63/512,546, filed July 7, 2023; and U.S. Provisional Application No. 63/616,045, filed December 29, 2023; each of which is hereby incorporated by reference in its entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY [0002] The content of the electronically submitted sequence listing (Name: 4525_119PC02_SequenceListing_ST26.xml; Size: 294,812 bytes; and Date of Creation: July 5, 2024), filed with the application, is incorporated herein by reference in its entirety. FIELD OF DISCLOSURE [0003] The present disclosure pertains to the medical field and gene delivery, including AAV gene therapy for treating ocular pathologies. BACKGROUND [0004] Ophthalmic pathologies significantly affect the quality of life of millions of people each year, and can lead to severe discomfort, impaired vision, or blindness. [0005] The delivery of therapeutics to ophthalmic regions and the subsequent kinetics of such therapies to the appropriate location(s) within or near the eye are of great importance for the treatment of a variety of ophthalmic pathologies. [0006] Drug delivery with minimal adverse effects and maximal efficacy to the target tissue is one of the biggest challenges faced during drug development. Due to the structural and metabolic properties of the ophthalmic regions, different methods of administration (i.e., topical, systemic, ocular, and periocular injections) can result in vastly different concentrations of the therapeutic delivered to the site of action, often making it a challenge to be within the therapeutic window. Thus, effectively engineering and delivering therapeutics to the ophthalmic tissues is a crucial step in developing successful therapies. [0007] Topical instillation, the least invasive route of administration, is also one of the least efficacious, e.g., bioavailability of topical therapeutics is generally low and penetration into the cornea and conjunctival epithelium is inefficient. [0008] Systemic delivery can be accomplished through oral administration in the form of a tablet or liquid consumable or through parenteral routes, such as intravenous, intramuscular, subcutaneous, and intradermal administration in an injectable form. Due to low ocular bioavailability and high systemic exposure, these methods are atypical for therapeutics delivery in ophthalmology. Systemic metabolism is another hurdle for systemic administration, and greatly reduces the concentration of therapeutics that can reach the ophthalmic region. [0009] Intraocular administration includes the injection or implantation of a sterile solution or device within the eye via intravitreal, subretinal, or suprachoroidal delivery routes. Intravitreal and subretinal injections are common routes of administration for vector-based therapeutics that treat diseases within the eye. [0010] Periocular delivery is another method to introduce therapeutics into an ophthalmic region. The sub-conjunctival space is the most commonly used in clinical practice, but the therapeutic bioavailability is typically poor. Upon sub -conjunctival injection, therapeutic bioavailability has been determined to be roughly similar to topical administration and much lower than intravitreal administration (Subrizi, A. et al., Design Principles of Ocular Drug Delivery Systems: Importance of Drug Payload, Release Rate, and Material Properties. Drug Discov. Today 2019, 24, 1446-1457). [0011] There is a need for the development of delivery strategies to the ophthalmic region that allow efficient delivery of the vector-based therapeutic while minimizing the iatrogenic complications. BRIEF SUMMARY [0012] Certain aspects of the disclosure are directed to a method of treating an ophthalmic pathology in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising an AAV vector, wherein the administration is a periocular injection. In some aspects, the periocular injection is selected from a periorbital injection or a post-septal injection. In some aspects, the periorbital injection is selected from the group consisting of a subtenon injection, retrobulbar injection, subconjunctival injection, or peribulbar injection. In some aspects, the periorbital injection is a retrobulbar injection. In some aspects, the periorbital injection is a peribulbar injection. [0013] In some aspects, the AAV vector contacts orbital tissues or extraocular compartment(s) selected from the group consisting of: extraocular adipose tissue, extraocular levantor muscle, extraocular lateral rectus muscles, extraocular medial rectus muscles, extraocular superior rectus muscles, extraocular inferior rectus muscles, extraocular inferior oblique muscles, extraocular superior oblique muscles, optic nerve, blood vessels, sclera, dural sheath, lamina