Small Molecule Anti-Inflammatories for Ocular Graft Versus Host Disease

PROJECT SUMMARYABSTRACT Ocular graft versus host diseaseOGVHDis a severe ocular surface inflammatory diseaseOSIDoccurring in patients undergoing allogenic hematopoietic stem cell transplantationHSCTOGVHD is characterized by dry eyemeibomian gland dysfunctionconjunctival scarringlid margin scarringkeratopathyand corneal ulcerationcausing significant ocular morbidity and vision loss for affected patientsPresentlythere are no effective disease modifying therapies for OGVHDThe purpose of this STTR Phase I grant application is to develop novel and effective therapies for the treatment of OGVHD and potentially other OSIDsThe current proposal represents a collaborative effort between Eyedesis Biosciencesa biotechnology company focused on developing calciumcalmodulin dependent protein kinase kinaseCaMKKtargeted therapies for ocular diseasesand scientists at Duke University School of MedicinePreliminary data demonstrate thatOGVHD is associated with infiltration of T cells and macrophagestwo types of inflammatory cells in which CaMKKhas been previously shown to modulate and amplify effector functionthe Eyedesis team has developed a proprietary library of small molecule inhibitors of CaMKKSMICsselected candidate SMICs have been confirmed to inhibit CaMKKactivity in vitrothe major histocompatibility mismatch mouse model reproduces clinical findings and pathologic features of OGVHDlocal ocular application of the tool compound CaMKKinhibitor STOin this OGVHD model reduces severity of OGVHD findings as compared to control treated mice in preliminary in vivo studieswithout signs of apparent drug toxicityThismonth Phase I STTR will fund feasibility studies crucial to the development of novel SMICs invented by EyedesisDuring STTR Phase I fundingthe study team will work to demonstrate thatnovel SMICs are potent inhibitors of T cells and macrophage CaMKKand effector function in vitrothese molecules are potent CaMKKinhibitors without significant off target activitythese molecules are well tolerated when applied topically to the eyeandtopical administration of SMICs is efficacious in treating OGVHD in a mouse modelThe key deliverable will be the identification of at least one candidate SMIC for topical therapy for OGVHD that meets these goals and is suitable for moving forward into formal pre IND formulation developmentSuccessful realization of the Phase I milestones will justify additional development of SMICs in Phase IIincludingclinical formulation for topical administrationandperformance of IND enabling studiesi eGLP toxicology and formal pharmacokinetics studiesPROJECT NARRATIVERELEVANCE The goal of this project is to develop new drugs to treat ocular graft versus host diseaseOGVHDOGVHD is a severe ocular surface disease that occurs in patients undergoing bone marrow transplantationwhen their new donor immune cells begin to attack their front of the eye tissues and tear glandsThere are no effective treatments for OGVHDand patients have significant paindiscomfortand vision lossThis new class of drugs will attempt to target inflammatory cells in the eye that cause OGVHDThis project is a collaboration between Eyedesis Biosciencesa drug development company and Duke University scientistswho will work together to develop new treatments that could be effective not only for OGVHD but also other ocular surface diseases