| Description |
- Background: Targeted immunotherapies are needed in inflammatory ocular surface diseases as an alternative to the blanket immunosuppression of steroids, which can cause a host of undesirable side-effects. Mesenchymal stem cell-derived exosomes (MSC-exo) have shown immunomodulatory and anti-fibrotic effects in corneal injury models. This study tested the therapeutic potential of MSC-exo in chronic ocular surface disease using a preclinical model of Stevens Johnson Syndrome (SJS), a disease which features severe, vision-threatening ocular surface inflammation and scarring.
Methods: Transgenic mice expressing an active isoform of IKZF1, a transcription factor associated with SJS in humans, were used as a unique model of SJS. To induce chronic ocular surface inflammation in mice with this SJS-like background, mice were immunized with intraperitoneal (IP) ovalbumin in Alum and pertussis toxin and subsequently challenged with topical ovalbumin. MSC-exo were prepared from immortalized human embryonic stem cell-derived MSCs. Treatment groups (n=3) included: 1. naïve (negative control); 2. balanced salt solution (positive control), 3. low dose (LD, 0.4μg) and 4. high dose (HD, 4μg) MSC-exo, and 5. loteprednol (0.5%), all given topically 4 times daily; 6. Subconjunctival (SC) MSC-exo (4μg) given twice weekly; and 7. IP prednisolone (1mg/kg) given daily. Clinical disease was evaluated daily for 7 days by tearing, conjunctival redness, eyelid edema, and chemosis (scale of 0-3). Pharmacokinetics of topical and SC Alexa Fluor 488-labelled MSC-exo were tracked using in vivo multiphoton confocal microscopy.
Results: Topical MSC-exo treatment reduced total clinical scores (composite of all four scales, 0-12) of induced ocular surface inflammation in a dose-dependent manner (p<0.001, LD and HD MSC-exo vs. BSS), with SC MSC-exo showing the greatest score reduction that was comparable to that of corticosteroids (p<0.001, SC MSC-exo vs. BSS). Labelled MSC-exo were detectable for <3 hours after topical administration, while lasting in the SC space for at least 72 hours post-SC injection. Additionally, SC MSC-exo localized into the conjunctival stroma overtime.
Conclusion:
MSC-exo have therapeutic potential for targeted treatment of inflammatory ocular surface diseases such as SJS and may address a critical gap in treatment. Periocular administration of MSC-exo showed greater clinical effect and longer-lasting pharmacokinetics and opens possibilities as a novel therapy.
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