Thomas F Conway1, Laura Hammer2, Stacia Furtado3, Edith Mathiowitz4, Ferdinando Nicoletti5, Katia Mangano5, Nejat K Egilmez6, Dominick L Auci2. 1. TherapyX , Buffalo, NY, USA State University of New York, at Buffalo, NY, USA. 2. TherapyX , Buffalo, NY, USA. 3. TherapyX , Buffalo, NY, USA Brown University, Department Biomedical and Molecular Pharmacology, Providence, RI, USA. 4. Brown University, Department Biomedical and Molecular Pharmacology, Providence, RI, USA. 5. University of Catania, Department of Biomedical and Biotechnological Sciences, Catania, Italy. 6. TherapyX , Buffalo, NY, USA State University of New York, at Buffalo, NY, USA nejat.egilmez@louisville.edu.
Abstract
BACKGROUND AND AIMS: We investigated oral delivery of transforming growth factor beta 1 [TGFβ]- and all-trans retinoic acid [ATRA]-loaded microspheres as therapy for gut inflammation in murine models of inflammatory bowel disease [IBD]. METHODS: ATRA and TGFβ were separately encapsulated in poly [lactic-co-glycolic] acid or polylactic acid microspheres [respectively]. TGFβ was encapsulated using proprietary phase-inversion nanoencapsulation [PIN] technology. RESULTS: PIN particles provided sustained release of bioactive protein for at least 4 days and were stable for up to 52 weeks when stored at either 4(0)C or -20(0)C. In the SCID mouse CD4 + CD25- T cell transfer model of IBD, oral treatment starting at disease onset prevented weight loss, significantly reduced average disease score [~ 50%], serum amyloid A levels [~ 5-fold], colon weight-to-length ratio [~ 50%], and histological score [~ 5-fold]. CONCLUSIONS: Both agents given together outperformed either separately. Highest TGFβ doses and most frequent dose schedule were most effective. Activity was associated with a significant increase [45%] in Foxp3 expression by colonic lamina propria CD4+ CD25+ T-cells. Activity was also demonstrated in dextran sulphate sodium-induced colitis. The data support development of the combination product as a novel, targeted immune based therapy for treatment for IBD.
BACKGROUND AND AIMS: We investigated oral delivery of transforming growth factor beta 1 [TGFβ]- and all-transretinoic acid [ATRA]-loaded microspheres as therapy for gut inflammation in murine models of inflammatory bowel disease [IBD]. METHODS:ATRA and TGFβ were separately encapsulated in poly [lactic-co-glycolic] acid or polylactic acid microspheres [respectively]. TGFβ was encapsulated using proprietary phase-inversion nanoencapsulation [PIN] technology. RESULTS: PIN particles provided sustained release of bioactive protein for at least 4 days and were stable for up to 52 weeks when stored at either 4(0)C or -20(0)C. In the SCIDmouseCD4 + CD25- T cell transfer model of IBD, oral treatment starting at disease onset prevented weight loss, significantly reduced average disease score [~ 50%], serum amyloid A levels [~ 5-fold], colon weight-to-length ratio [~ 50%], and histological score [~ 5-fold]. CONCLUSIONS: Both agents given together outperformed either separately. Highest TGFβ doses and most frequent dose schedule were most effective. Activity was associated with a significant increase [45%] in Foxp3 expression by colonic lamina propria CD4+ CD25+ T-cells. Activity was also demonstrated in dextran sulphate sodium-induced colitis. The data support development of the combination product as a novel, targeted immune based therapy for treatment for IBD.
Authors: D L Wang; M Marko; A R Dahl; K S Engelke; M E Placke; A R Imondi; J L Mulshine; L M De Luca Journal: Clin Cancer Res Date: 2000-09 Impact factor: 12.531
Authors: Kevin M Elias; Arian Laurence; Todd S Davidson; Geoffrey Stephens; Yuka Kanno; Ethan M Shevach; John J O'Shea Journal: Blood Date: 2007-10-19 Impact factor: 22.113
Authors: T F Zioncheck; S A Chen; L Richardson; M Mora-Worms; C Lucas; D Lewis; J D Green; J Mordenti Journal: Pharm Res Date: 1994-02 Impact factor: 4.200
Authors: Victoria Klepsch; Alexander R Moschen; Herbert Tilg; Gottfried Baier; Natascha Hermann-Kleiter Journal: Front Immunol Date: 2019-05-14 Impact factor: 7.561
Authors: Neal Bhutiani; Qingsheng Li; Charles D Anderson; Heather C Gallagher; Magdia De Jesus; Rajbir Singh; Venkatkrishna R Jala; Mostafa Fraig; Tao Gu; Nejat K Egilmez Journal: Oncoimmunology Date: 2018-08-23 Impact factor: 8.110