Material guided drug delivery for pigmented villonodular synovitis using an implantable biomaterial and bio-orthogonal chemistry

Abstract Pigmented villonodular synovitisPVNSis a chronicprogressive neoplastic process that causes the synovial lining of a jointbursaor tendon sheath to thicken and overgrow in an aggressive manner with a very low risk of metastasisThis rare condition affects approximatelypeople per million or aboutper year in the U Smost commonly appearing in those agedtoyears oldPVNS can be focal or diffuseIn the diffuse formthe disease process accelerates tendon and joint wear and has arate of local recurrence with traditional treatment strategieswhich significantly impacts a patient s quality of lifeThe benign but aggressive behavior of PVNS makes treatment challenging as clinicians have to weigh the morbidity of treatment relative to the natural history of the disease processWith the discovery of CSFoverexpression in PVNSnew medical therapies targeting the CSFreceptorCSF Rare within reachwith the potential to reduce surgical morbidity and preserve patient quality of lifePreliminary results are promisinghoweverno form of chemotherapy has yet been approved for treatment of PVNS and systemic side effects remain a prohibitive problemShasqi envisions that methods to locally deliver and activate therapeuticsthus limiting systemic side effects of medications are the solution to conditions such as diffuse PVNSThereforeShasqi is developing a drug delivery technology designed to improve the therapeutic index of drugs that has potential to be applicable to PVNS treatmentThe technology consists of a biocompatible biomaterialand a prodrugan inactivated drugBoth components contain bioorthogonal reagents that enable them to react only with each otherThe biomaterial is physically placed at the desired location in the bodyInactive prodrugs are injected into the blood stream when they are neededWhen the prodrugs are proximal to the biomaterialthe bioorthogonal agents quickly react with each otherthus concentrating the prodrug at the biomaterial in the desired locationFinallythe active drug is spontaneously released from the gel to perform its functionThis system effectively turns systemic drugs into localized medicinesIn PVNS patientsShasqi proposes application of its technology in adjuvant settingsFollowing surgical resectionthe surgeon would place the biomaterial around the surgical cavity and treat the patient with a prodrug of a CSF R inhibitor to secure clean marginsAdditional gel injections can be given at sites of unresectable tumorsAlternativelyin the case of tumors that or too large to be removed or would require invasive surgical interventionthe technology would be used as a neoadjuvant treatment to improve the outcome of subsequent surgical resectionFor this Phase I projectwe will synthesize a CSF R inhibitor prodrugevaluate the Shasqi platform in a CSFdependent cell lineand determine in vivo efficacy in a rat model with established precedent for evaluating CSF R inhibitors to treat PVNSIn Phase IIwe will conduct studies required for INDenabling safety and efficacy studies in animalsFollowing Phase IIwe will enter human clinical trials Project Narrative Pigmented villonodular synovitisPVNSis a chronicprogressive condition that causes the synovial lining of a jointbursaor tendon sheath to thicken and overgrow in a locally aggressive and recurrent manner that can significantly harm a patient s quality of lifeTreatment is necessary to mitigate loss of function and destruction of the synovial liningand with recent new knowledge of the biology behind PVNSnew targeted medical therapies are within reachFor this Phase I projectShasqi will investigate the preclinical efficacy of its novel drug delivery technology to determine feasibility in providing targeted treatment of diffuse PVNS