Dry eye disease (DED) is a multifactorial disease of the ocular surface causing visual disturbance and tear film instability and can be due to either aqueous tear insufficiency originating with defects in aqueous tear production by the lacrimal gland (LG) or evaporative dry eye associated with meibomian gland insufficiency. Our lab has been focused on the treatment of DED using elastin-like polypeptides as a tool. The treatment strategy consists of two arms.
One is to explore the feasibility of restoring the natural basal tearing mechanism and health of cells in contact with tears by using regulatory tear proteins such as lacritin, a secreted glycosylated human tear protein found in tears and saliva, and its synthetic peptides, lacripep. Lacritin has prosecretory activity in the lacrimal gland and mitogenic activity at the corneal epithelium. Motivated by the rationale that a thermo-responsive coacervate containing lacritin would have better retention upon administration, our lab members have constructed lacritin-ELP fusion proteins. While maintaining the thermo-responsive phase separation property of ELPs, the fusion protein also gained the prosecretory activity of human lacritin. Interestingly, ELP modification also influences cell uptake speed, enhances local retention time in the LG, and provides lacritin-mediated signaling.
Since many cases of DED are associated with inflammation, our second arm is to topically and systemically deliver immunosuppressant drugs, such as rapamycin, using ELP fusion proteins to control the lacrimal gland inflammation. Drug carrier capacity was achieved by fusing their corresponding cognate protein target to ELPs through molecular cloning. These fusion carriers have been shown to improve the bioavailability and safety profile of these immunosuppressant drugs while maintaining their potency.
Selected Publications
Rapamycin eye drops suppress lacrimal gland inflammation in a murine model of Sjögren's syndrome
Mihir Shah, Maria C. Edman, Srikanth Reddy Janga, Frances Yarber, Zhen Meng, Wannita Klinngam, Jonathan Bushman, Tao Ma, Siyu Liu, Stan Louie, Arjun Mehta, Chuanqing Ding, J. Andrew MacKay, and Sarah F. Hamm-Alvarez
Invest Ophthalmol Vis Sci. 2017 Jan; 58(1): 372–385.
Tear-mediated delivery of nanoparticles through transcytosis of the lacrimal gland
Pang-Yu Hsueh, Maria C. Edman, Guoyong Sun, Pu Shi, Shi Xu, Yi-an Lin, Honggang Cui, Sarah F. Hamm-Alvarez, and J. Andrew MacKay
J Control Release. 2015 Jun 28;208:2-13.
A thermo-responsive protein treatment for dry eyes
Wan Wang, Aarti Jashnani, Suhaas R. Aluri, Joshua A. Gustafson, Pang-Yu Hsueh, Frances Yarber, Robert L. McKown, Gordon W. Laurie, Sarah F. Hamm-Alvarez, and J. Andrew MacKay
J Control Release. 2015 Feb 10; 199: 156–167.
A rapamycin-binding protein polymer nanoparticle shows potent therapeutic activity in suppressing autoimmune dacryoadenitis in a mouse model of Sjögren's syndrome.
Mihir Shah*, Maria C. Edman*, Srikanth R. Janga, Pu Shi, Jugal Dhandhukia, Siyu Liu, Stan G. Louie, Kathleen Rodgers, J. Andrew MacKay, and Sarah F. Hamm-Alvarez
J Control Release. 2013 Nov 10;171(3):269-79.
