CN-122003252-A - Periocular delivery of AAV vectors for the treatment of ophthalmic pathologies

Abstract

Provided herein is a method of delivering a pharmaceutical composition comprising an AAV vector to an eye or periocular tissue comprising periocular injection of the AAV vector (e.g., periocular injection, optionally periocular injection). In some aspects, the methods are used to treat ophthalmic pathologies (e.g., thyroid Eye Disease (TED)).

Inventors

• M. stone
• D. Sepeda
• R. Castellanos
• M. ENGELS
• S. RAMASWAMY
• A. MURPHY
• R. Eklov

Assignees

• 克里雅疗法股份有限公司

Dates

Publication Date

20260508

Application Date

20240705

Priority Date

20230707

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 periocular injection.
2. 2. The method of claim 1, wherein the periorbital injection is a periorbital injection or a retroseptal injection.
3. 3. The method of claim 2, wherein the periorbital injection is a sub-tenon's capsule 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 peri-bulbar injection.
6. 6. The method of any one of claims 1-5, wherein the AAV vector contacts an orbital tissue or an extraocular cavity selected from extraocular adipose tissue, extraocular levator, extraocular rectus, extraocular superior rectus, extraocular inferior oblique, extraocular superior oblique, optic nerve, blood vessel, sclera, dural sheath, lamina cribosa, 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 is contacted with an orbital tissue or an extraocular chamber selected from extraocular adipose tissue, extraocular rectus muscle, extraocular endorectus muscle, extraocular rectus muscle, extraocular oblique muscle, or any combination thereof.
8. 8. A method of delivering a pharmaceutical composition comprising an AAV vector to orbital tissue or an extraocular chamber comprising periocular injection of the AAV vector, wherein the orbital tissue or extraocular chamber is selected from the group consisting of: extraocular adipose tissue, extraocular levator, extraocular rectus, extraocular internal rectus, extraocular superior rectus, extraocular inferior oblique, extraocular superior oblique, optic nerve, blood vessel, sclera, dural sheath, lamina cribosa, eyelid, lacrimal gland, lacrimal sac, tear film, or any combination thereof.
9. 9. The method of claim 8, wherein the orbital tissue or extraocular chamber is selected from extraocular adipose tissue, extraocular rectus muscle, extraocular endorectus muscle, extraocular superior rectus muscle, extraocular inferior oblique muscle, extraocular superior oblique muscle, or any combination thereof.
10. 10. The method of any one of claims 1-9, wherein the administering or delivering comprises injecting a volume of about 0.1mL to about 10mL of the pharmaceutical composition per week of the eye.
11. 11. The method of any one of claims 1-9, wherein the administering or delivering comprises injecting a volume of 0.1ml to 1ml of the pharmaceutical composition per week of the eye.
12. 12. The method of any one of claims 1-11, wherein the administering comprises injecting a volume of the pharmaceutical composition of 0.1ml to 0.5ml per eye week.
13. 13. The method of any one of claims 1-12, wherein the administering comprises injecting a volume of 0.3ml to 0.5ml of the pharmaceutical composition per eye week.
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 eye or periocular tissue.
15. 15. The method of any one of claims 1-14, wherein the AAV vector transduces target ocular or periocular cells.
16. 16. The method of any one of claims 1-15, wherein the AAV vector transduction efficiency is at least 5% (e.g., 5% -95%, 10% -95%, or 25% -95%) of one or more of the target eye or periocular cells.
17. 17. The method of claim 15 or 16, wherein the target eye or periocular cell is selected from the group consisting of a fibroblast, an adipocyte, a myofibroblast, a myocyte, a muscle cell, an epithelial cell, a neuroepithelial cell, a glial cell, or any combination thereof.
18. 18. The method of any one of claims 1-16, wherein the AAV vector comprises a capsid selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVRh, AAVrh9, AAV9, AAVrh10, AAV11, AAV12, and modified versions 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 the treatment of ophthalmic pathologies Cross-reference to related applications The present application claims priority from U.S. provisional application No.63/512,546 filed 7 at 2023 and U.S. provisional application No.63/616,045 filed 29 at 2023, 12, each of which is incorporated herein by reference in its entirety. [ Reference to the electronically submitted sequence Listing ] The contents of the electronically submitted sequence listing (name: 4525_119PC02_sequence listing_ST26.Xml; size: 294,812 bytes; and creation date: 2024, 7, 5 days) are incorporated herein in their entirety. [ Field of technology ] The present disclosure relates to the medical arts and gene delivery, including AAV gene therapies for treating ocular pathologies. [ Background Art ] Ophthalmic pathologies significantly affect the quality of life of millions of people each year and can lead to serious discomfort, vision impairment or blindness. Delivery of therapeutic agents to the ophthalmic area and subsequent delivery of the kinetics of these therapies to the appropriate location within or near the eye is important for the treatment of a variety of ophthalmic pathologies. Delivering drugs to target tissues with minimal adverse effects and maximal efficacy is one of the major challenges faced in drug development. Due to the structural and metabolic characteristics of the ophthalmic region, different methods of administration (i.e., local, systemic, ocular, and periocular injection) can result in widely varying concentrations of therapeutic agent delivered to the site of action, often making it difficult to fit within the therapeutic window. Thus, effective engineering and delivery of therapeutic agents to ophthalmic tissues is a critical step in the development of successful therapies. Topical administration is the least invasive and one of the most ineffective routes of administration, e.g., the bioavailability of topical therapeutic agents is generally low and the penetration efficiency into the cornea and conjunctival epithelium is low. Systemic delivery may be achieved by oral administration in the form of tablets or liquid consumables or by parenteral routes (e.g., injectable forms of intravenous, intramuscular, subcutaneous and intradermal administration). Due to low ocular bioavailability and high systemic exposure, these methods are not typical methods of therapeutic agent delivery in the eye. Systemic metabolism is another obstacle to systemic administration and greatly reduces the concentration of therapeutic agents that can reach the ophthalmic area. Intraocular administration includes injection or implantation of a sterile solution or device into the eye via intravitreal, subretinal or suprachoroidal delivery routes. Intravitreal and subretinal injections are common routes of administration for carrier-based therapeutic agents for the treatment of intraocular diseases. Periocular delivery is another method of introducing therapeutic agents into the ophthalmic area. Subconjunctival space is most commonly used in clinical practice, but the bioavailability of therapeutic agents is often poor. After subconjunctival injection, it has been determined that the bioavailability of therapeutic agents is substantially 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）. There is a need to develop a delivery strategy to the ophthalmic area that allows for efficient delivery of carrier-based therapeutics while minimizing iatrogenic complications. [ Invention ] Certain aspects of the present disclosure relate 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 periocular injection. In some aspects, the periorbital injection is selected from periorbital injection or retroseptal injection. In some aspects, the periorbital injection is selected from the group consisting of sub-tenon's capsule 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 periocular injection. In some aspects, the AAV vector contacts an orbital tissue or an extraocular chamber selected from the group consisting of extraocular adipose tissue, extraocular levator, extraocular rectus, extraocular endorectus, extraocular rectus, extraocular inferior oblique, extraocular superior oblique, optic nerve, blood vessel, sclera, dural sheath, lamina cribosa, eyelid, lacrimal gland, lacrimal sac, tear film, or any combination thereof. In some aspects, the AAV vector contacts an orbital tissue or an extraocular chamber selected from the