Shimono K.,Thomas Jefferson University |
Shimono K.,Childrens Hospital of Philadelphia |
Tung W.-E.,Thomas Jefferson University |
Tung W.-E.,Childrens Hospital of Philadelphia |
And 13 more authors.
Nature Medicine | Year: 2011
Heterotopic ossification consists of ectopic bone formation within soft tissues after surgery or trauma. It can have debilitating consequences, but there is no definitive cure. Here we show that heterotopic ossification was essentially prevented in mice receiving a nuclear retinoic acid receptor-γ (RAR-γ) agonist. Side effects were minimal, and there was no significant rebound effect. To uncover the mechanisms of these responses, we treated mouse mesenchymal stem cells with an RAR-γagonist and transplanted them into nude mice. Whereas control cells formed ectopic bone masses, cells that had been pretreated with the RAR-γ agonist did not, suggesting that they had lost their skeletogenic potential. The cells became unresponsive to rBMP-2 treatment in vitro and showed decreases in phosphorylation of Smad1, Smad5 and Smad8 and in overall levels of Smad proteins. In addition, an RAR-γ agonist blocked heterotopic ossification in transgenic mice expressing activin receptor-like kinase-2 (ALK2) Q207D, a constitutively active form of the receptor that is related to ALK2 R206H found in individuals with fibrodysplasia ossificans progressiva. The data indicate that RAR-γ agonists are potent inhibitors of heterotopic ossification in mouse models and, thus, may also be effective against injury-induced and congenital heterotopic ossification in humans. © 2011 Nature America, Inc. All rights reserved.
Chandraratna R.A.S.,Io Therapeutics, Inc.
American Journal of Translational Research | Year: 2016
Retinoid x receptors (RXRs) are master regulators that control cell growth, differentiation, and survival and form heterodimers with many other family members. Here we show that treatment with the RXR agonist IRX4204 enhances the differentiation of CD4+ T cells into inducible regulatory T cells (iTreg) and suppresses the development of T helper (Th) 17 cells in vitro. Furthermore in a murine model of multiple sclerosis (experimental autoimmune encephalomyelitis (EAE)), treatment with IRX4204 profoundly attenuates both active and Th17-mediated passive disease. In the periphery, treatment with IRX4204 is associated with decreased numbers of CD4+ T cells that produce pro-inflammatory cytokines. In addition, CD4+ T cells express decreased levels of Ki-67 and increased expression of CTLA-4. Our findings demonstrate IRX4204 treatment during EAE results in immune modulation and profound attenuation of disease severity. © 2016, E-Century Publishing Corporation. All rights reserved.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2014
DESCRIPTION (provided by applicant): Io Therapeutics is developing a novel agonist for the Retinoid X Receptors (RXR), IRX4204, to treat multiple sclerosis (MS) and other autoimmune diseases. RXR is a key nuclear receptor involved in inflammation. It has arole in regulating immunity through the enhancement of Treg activities and suppression of inflammatory Th17 activities. Because of the importance of RXR in controlling immunity, small molecule agonists and antagonists for these nuclear receptors have become attractive drug candidates. Io developed IRX4204 as a second-generation RXR specific agonist that belongs to the rexinoid class of compounds. It binds with very high affinity and selectivity to the RXRs, IRX 4204 has very limited affinity for the Retinoic Acid Receptors (RAR). In functional transactivation assays, IRX4204 is at least 2,000 fold more potent in activating RXR homodimers than RAR-RXR heterodimers and IRX4204 does not activate other heterodimers such as RXR-PPAR , RXR-LXR, and RXR-FXR.
Io Therapeutics, Inc. and Dartmouth College | Date: 2015-02-19
The present specification provides RXR agonist compounds, compositions comprising such RXR agonists, and methods using such compounds and compositions to treat an autoimmune disorder, inflammation associated with an autoimmune disorder and/or a transplant rejection as well as use of such RXR agonists to manufacture a medicament and use of such compounds and compositions to treat an autoimmune disorder, inflammation associated with an autoimmune disorder and/or a transplant rejection.
Io Therapeutics, Inc. | Date: 2016-01-12
A method of treating cancer is disclosed comprising administering to a patient in need of such treatment a RXR agonist at a level below the RAR activating threshold and at or above the RXR effective dose.