Sjgren's syndrome (SS) is an autoimmune disease affecting more than 4 million Americans, over 90% of whom are women. SS is characterized by lymphocyte infiltration of lacrimal and salivary glands leading to dry eye and dry mouth, and resulting in severely compromised ocular surface and oral health. Some patients with SS also exhibit weight loss, fatigue, internal organ failure, and B-cell lymphoma. Despite its prevalence and severity, there are no approved therapies for treatment of SS. Treatments are based on management of ocular and oral dryness as well as use of general immunosuppressive drugs which are not optimized for the underlying autoimmune exocrinopathies. Although not developed for SS, RestasisT?, an ophthalmic emulsion of cyclosporine A approved for dry eye, has been explored for use in SS-mediated dry eye. While modestly effective in treating ocular surface symptoms, Restasis? does not restore tear production. This is unsurprising because the nasolacrimal ducts efficiently drain drugs administered topically, limiting drug access to the lacrimal gland and to other sites of systemic inflammation. Systemic administration of cyclosporine A and rapamycin, another potent immunosuppressant, has been challenging because of their low solubility, poor bioavailability and dose-limiting toxicities. Surprisingly, no attempts have been made in SS to deliver these immunosuppressants to inflamed lacrimal or salivary glands using state-of-the-art drug carriers. Such a strategy could not only treat the origin of the severe ocular and oral cavity symptoms at their source, but also potentially mitigate the systemic and life-threatening complications of the disease. The goal of this project is to enhance the activity of these two clinically-approved immunosuppressants to treat inflamed lacrimal and salivary glands and other sites of disease activity in SS through use of an emerging class of `protein polymer' nanomedicines based on elastin-like polypeptides (ELPs) to develop untargeted and targeted drug carriers. Our preliminary studies show that rapamycin administered intravenously in a novel protein nanoparticle in a mouse model of SS reduced lacrimal gland inflammation and restored function, while suppressing the renal toxicity associated with free drug. We propose three SPECIFIC AIMS: 1) Optimize the route of administration of untargeted ELP drug carriers using murine models of SS; 2) Construct and evaluate molecularly-targeted immunosuppressive ELP nanoparticles using murine models of SS; and 3) Complete comparative pharmacokinetics and toxicology of optimal therapies for local and systemic SS. When successful, this translational project will produce a significant advance in drug delivery technology by generating protein-polymer nanoparticles decorated with proteins that specifically carry rapamycin and cyclosporine A, and can be targeted to sites of inflammation. Our experiments will lay the solid preclinical foundation justifying further investment in their clinical development as therapeutics for SS and other autoimmune diseases.

Public Health Relevance

Sjgren's syndrome is an autoimmune disease affecting ~4 million Americans--predominantly women--that is characterized by immune cell infiltration into the glands that produce tears and saliva, and which leads to painful dry eye, dry mouth, vision problems, and elevated risk of B-cell lymphoma. In the absence of approved therapies, we propose to deliver the potent immunosuppressants, rapamycin and cyclosporine A, in ways that maximize drug bioavailability to the inflamed tissues at the root of this disease and minimize off-site toxicity, using safe and biodegradable protein nanoparticles. Knowledge from these preclinical studies will rapidly advance new therapies to clinical trials for this underserved autoimmune disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Schools of Medicine
Los Angeles
United States
Zip Code
Ju, Yaping; Janga, Srikanth Reddy; Klinngam, Wannita et al. (2018) NOD and NOR mice exhibit comparable development of lacrimal gland secretory dysfunction but NOD mice have more severe autoimmune dacryoadenitis. Exp Eye Res 176:243-251
Peddi, Santosh; Pan, Xiaoli; MacKay, John Andrew (2018) Intracellular Delivery of Rapamycin From FKBP Elastin-Like Polypeptides Is Consistent With Macropinocytosis. Front Pharmacol 9:1184
Guo, Hao; Lee, Changrim; Shah, Mihir et al. (2018) A novel elastin-like polypeptide drug carrier for cyclosporine A improves tear flow in a mouse model of Sjögren's syndrome. J Control Release 292:183-195
Klinngam, Wannita; Fu, Runzhong; Janga, Srikanth R et al. (2018) Cathepsin S Alters the Expression of Pro-Inflammatory Cytokines and MMP-9, Partially through Protease-Activated Receptor-2, in Human Corneal Epithelial Cells. Int J Mol Sci 19:
Janga, Srikanth R; Shah, Mihir; Ju, Yaping et al. (2018) Longitudinal analysis of tear cathepsin S activity levels in male non-obese diabetic mice suggests its potential as an early stage biomarker of Sjögren's Syndrome. Biomarkers :1-12
Edman, Maria C; Janga, Srikanth R; Meng, Zhen et al. (2018) Increased Cathepsin S activity associated with decreased protease inhibitory capacity contributes to altered tear proteins in Sjögren's Syndrome patients. Sci Rep 8:11044
Dhandhukia, Jugal P; Shi, Pu; Peddi, Santosh et al. (2017) Bifunctional Elastin-like Polypeptide Nanoparticles Bind Rapamycin and Integrins and Suppress Tumor Growth in Vivo. Bioconjug Chem 28:2715-2728
Dhandhukia, Jugal P; Li, Zhe; Peddi, Santosh et al. (2017) Berunda Polypeptides: Multi-Headed Fusion Proteins Promote Subcutaneous Administration of Rapamycin to Breast Cancer In Vivo. Theranostics 7:3856-3872
Meng, Zhen; Klinngam, Wannita; Edman, Maria C et al. (2017) Interferon-? treatment in vitro elicits some of the changes in cathepsin S and antigen presentation characteristic of lacrimal glands and corneas from the NOD mouse model of Sjögren's Syndrome. PLoS One 12:e0184781