Methods and compositions for modulating ocular damage
Methods for modulating eye damage associated with a disease or disorder, and/or damage incident to trauma including but not limited to trauma associated with ocular surgery are provided. In some embodiments, the methods include administering an effective amount of a modulator of a migration inhibitory factor (MIF) polypeptide biological activity to a subject. Also provided are methods for modulating the severity of delaying the onset of and/or inhibiting and/or preventing the development of an ocular disease, and methods for modulating the severity of delaying the onset of and/or inhibiting and/or preventing the development of scarring and/or other consequence of wound healing incident to ocular surgery, as well as modulating the survival, function, and/or differentiation of engrafted cells that can be employed as part of tissue engineering procedures to correct structural, functional, and/or cellular defects of the eye.
1. A method for modulating eye damage, the method comprising administering to a subject an effective amount of a modulator of a migration inhibitory factor (MIF) polypeptide biological activity, wherein the eye damage is associated with a disease or disorder, damage incident to trauma including but not limited to blunt trauma, penetrating trauma, and trauma associated with ocular surgery, or a combination thereof, and further wherein the modulator has the following structure:
wherein:
each R is independently H, halo, OH, alkyl, substituted alkyl, aryl, amino, or carboxyl;
R 1 is H, halo, OH, alkyl, substituted alkyl, or aryl:
R 2 is H, halo, OH, alkyl, substituted alkyl, aryl, or amino; and
n is an integer from 0 to 5.
2. The method of claim 1 , wherein the disease or disorder is selected from the group consisting of dry macular degeneration; wet macular degeneration; retinopathy of prematurity; background diabetic retinopathy;
proliferative diabetic retinopathy; sickle cell retinopathy; other vascular retinopathies; intraocular scarring; proliferative vitreoretinopathy; autoimmune uveitis; autoimmune uveoretinitis; uveitis of various etiologies; dry eye syndrome with and without Sjogren's syndrome; blunt, penetrating, or perforating ocular trauma and related ocular pathologies; open angle glaucoma; and secondary glaucoma; as well as various structural disorders of the eye that require cell transplantation for tissue engineering.
3. The method of claim 1 , wherein the damage incident to ocular surgery comprises scar formation and/or the administering step modulates a wound healing response in the eye on which the surgery was performed.
4. The method of claim 1 , wherein the disease or disorder is dry macular degeneration or wet macular degeneration.
5. The method of claim 1 , wherein R 1 is iodo, and optionally wherein R 2 is H and n is 0.
6. The method of claim 1 , wherein the modulator is 4-iodo-6-phenylpyrimidine, 4-(2-fluorophenyl)-6-iodopyrimidine, or an analog or derivative thereof.
7. The method of claim 1 , wherein the modulator comprises or encodes a nucleotide sequence that downregulates expression of a MIF gene product by RNA interference.
8. The method of claim 1 , wherein the modulator comprises an anti-MIF antibody, or a fragment or derivative thereof.
9. The method of claim 1 , wherein the MIF polypeptide is a mammalian MIF polypeptide.
10. The method of claim 9 , wherein the MIF polypeptide:
(i) is a human MIF polypeptide;
(ii) comprises an amino acid sequence at least 95% identical to SEQ ID NO: 2; and/or
(iii) is encoded by a human MIF genetic locus present on chromosome 22.
11. The method of claim 1 , wherein the modulator is provided in a pharmaceutically acceptable composition, and optionally wherein the pharmaceutically acceptable composition is acceptable for use in a human.
12. The method of claim 11 , wherein the pharmaceutically acceptable composition comprises a liposome and/or a nanoparticle in which the modulator is encapsulated and/or attached, optionally wherein the liposome and/or the nanoparticle comprises a targeting ligand that targets the liposome and/or the nanoparticle to the eye or a structure within the eye.
13. The method of claim 1 , wherein the modulator of a migration inhibitory factor (MIF) polypeptide biological activity is 4-(2-fluorophenyl)-6-iodopyrimidine (Compound 1) or is 4-iodo-6-phenylpyrimidine (4-IPPI; Compound 2).