July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Elastin-like polypeptide mediate subcutaneous delivery of Rapamycin in a murine model of Sjögren’s Syndrome
Author Affiliations & Notes
  • Changrim Lee
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States
  • Hao Guo
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States
  • Wannita Klinngam
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States
  • Srikanth Reddy Janga
    Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States
  • Frances Yarber
    Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States
  • Maria C. Edman
    Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States
  • Santosh Peddi
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States
  • Sarah F Hamm-Alvarez
    Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States
  • J. Andrew MacKay
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States
    Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States
  • Footnotes
    Commercial Relationships   Changrim Lee, None; Hao Guo, None; Wannita Klinngam, None; Srikanth Janga, None; Frances Yarber, None; Maria Edman, None; Santosh Peddi, None; Sarah Hamm-Alvarez, WO2014059385 (P); J. Andrew MacKay, WO2014059385 (P)
  • Footnotes
    Support  R01EY026635, R01GM114839, Whittier Foundation
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 5677. doi:
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    • Get Citation

      Changrim Lee, Hao Guo, Wannita Klinngam, Srikanth Reddy Janga, Frances Yarber, Maria C. Edman, Santosh Peddi, Sarah F Hamm-Alvarez, J. Andrew MacKay; Elastin-like polypeptide mediate subcutaneous delivery of Rapamycin in a murine model of Sjögren’s Syndrome. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5677.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Sjögren’s Syndrome (SS) is a systemic autoimmune disease that causes severe dysfunction of the salivary and lacrimal glands (LG) and has limited treatment options. Our recent work showed that either topical or intravenous formulations of the USFDA-approved immunosuppressant Rapamycin (Rapa) reduced dacryoadenitis in the non-obese diabetic (NOD) model of SS. To explore an alternative route of administration, Rapa was encapsulated in an elastin-like polypeptide (ELP)-based carrier and administered by subcutaneous (SC) injection.

Methods : Copies of the FK506-binding protein 12 (FKBP, 12kD), an endogenous Rapa binding protein, were fused to the N- and C-terminus of the ELP A192 (amino acid sequence: (VPGAG)192) to create a biodegradable drug carrier known as FAF. Rapa was complexed with FAF and administered to 14-week male NOD mice SC every other day for 14 days at a dose of 1 mg/kg BW. Controls included vehicle (Polysorbate 80 + PEG 400), free Rapa and FAF alone. Therapeutic endpoints measured included histological evaluation and quantitation of lymphocytic infiltration and RT-qPCR of disease-related gene expression.

Results : RT-qPCR analysis revealed decreased gene expression of IFN-γ in both FAF-Rapa (1.7-fold, p=0.031) and free Rapa-treated mice (1.5-fold, p=0.036) compared to FAF or vehicle-treated mice, respectively. Free Rapa significantly decreased MHC II gene expression (1.7-fold, p=0.0015) but not FAF-Rapa (1.6-fold, p=0.07). Interestingly, FAF-Rapa significantly decreased type I collagen (Col1A1) expression in the LG (4-fold, p=0.0005), to a greater extent than free Rapa (1.5-fold, p=0.0046). Both FAF-Rapa (9±5.6%, p<0.0001) and free Rapa (7±3.7%, p=0.04) significantly suppressed lymphocytic infiltration in the LG compared to their respective control, FAF alone (15±8.4%) and vehicle (21±10.3%, percent area covered, mean±SD).

Conclusions : FAF facilitates carrier-mediated delivery of Rapa following SC administration resulting in reduction of autoimmune dacryoadenitis. While free Rapa also elicits a therapeutic effect on the LG, SC administration of free Rapa results in local drug precipitation, edema, and necrosis at the injection site. This alternative route of administration and formulation of Rapa may enable systemic and sustained treatment of the symptoms of SS, overcoming limitations to oral and topical formulations of Rapa, both of which suffer poor bioavailability.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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