Sustained Inhibition of VEGF and TNF-α Achieves Multi-Ocular Protection and Prevents Formation of Blood Vessels after Severe Ocular Trauma

Chengxin Zhou; Fengyang Lei; Jyoti Sharma; Pui-Chuen Hui; Natalie Wolkow; Claes H Dohlman; Demetrios G Vavvas; James Chodosh; Eleftherios I Paschalis

doi:10.3390/pharmaceutics15082059

Sustained Inhibition of VEGF and TNF-α Achieves Multi-Ocular Protection and Prevents Formation of Blood Vessels after Severe Ocular Trauma

Pharmaceutics. 2023 Jul 31;15(8):2059. doi: 10.3390/pharmaceutics15082059.

Authors

Chengxin Zhou^{1

2}, Fengyang Lei^{1

2}, Jyoti Sharma^{1

2}, Pui-Chuen Hui^{1

2}, Natalie Wolkow^{1

3}, Claes H Dohlman^{1

2}, Demetrios G Vavvas^{1

4}, James Chodosh^{1

2

5

6}, Eleftherios I Paschalis^{1

2

5}

Affiliations

¹ Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA.
² Boston Keratoprosthesis Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA.
³ David G. Cogan Laboratory of Eye Pathology and Ophthalmic Plastic Surgery Service, Massachusetts Eye and Ear, Boston, MA 02114, USA.
⁴ Angiogenesis Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA.
⁵ Disruptive Technology Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA.
⁶ Department of Ophthalmology and Visual Sciences, University of New Mexico School of Medicine, Albuquerque, NM 87108, USA.

Abstract

Purpose: This study aimed to develop a clinically feasible and practical therapy for multi-ocular protection following ocular injury by using a thermosensitive drug delivery system (DDS) for sustained delivery of TNF-α and VEGF inhibitors to the eye.

Methods: A thermosensitive, biodegradable hydrogel DDS (PLGA-PEG-PLGA triblock polymer) loaded with 0.7 mg of adalimumab and 1.4 mg of aflibercept was injected subconjunctivally into Dutch-belted pigmented rabbits after corneal alkali injury. Control rabbits received 2 mg of IgG-loaded DDS or 1.4 mg of aflibercept-loaded DDS. Animals were followed for 3 months and assessed for tolerability and prevention of corneal neovascularization (NV), improvement of corneal re-epithelialization, inhibition of retinal ganglion cell (RGC) and optic nerve axon loss, and inhibition of immune cell infiltration into the cornea. Drug-release kinetics was assessed in vivo using an aqueous humor protein analysis.

Results: A single subconjunctival administration of dual anti-TNF-α/anti-VEGF DDS achieved a sustained 3-month delivery of antibodies to the anterior chamber, iris, ciliary body, and retina. Administration after corneal alkali burn suppressed CD45⁺ immune cell infiltration into the cornea, completely inhibited cornea NV for 3 months, accelerated corneal re-epithelialization and wound healing, and prevented RGC and optic nerve axon loss at 3 months. In contrast, anti-VEGF alone or IgG DDS treatment led to persistent corneal epithelial defect (combined: <1%; anti-VEGF: 15%; IgG: 10%, of cornea area), increased infiltration of CD45⁺ immune cells into the cornea (combined: 28 ± 20; anti-VEGF: 730 ± 178; anti-IgG: 360 ± 186, cells/section), and significant loss of RGCs (combined: 2.7%; anti-VEGF: 63%; IgG: 45%) and optic nerve axons at 3 months. The aqueous humor protein analysis showed first-order release kinetics without adverse effects at the injection site.

Conclusions: Concomitant inhibition of TNF-α and VEGF prevents corneal neovascularization and ameliorates subsequent irreversible damage to the retina and optic nerve after severe ocular injury. A single subconjunctival administration of this therapy, using a biodegradable, slow-release thermosensitive DDS, achieved the sustained elution of therapeutic levels of antibodies to all ocular tissues for 3 months. This therapeutic approach has the potential to dramatically improve the outcomes of severe ocular injuries in patients and improve the therapeutic outcomes in patients with retinal vascular diseases.

Keywords: TNF; VEFG; biologics; burn; cornea; degeneration; injury; neovascularization; retina.

Abstract

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