Cell Engineering Platform for Red Blood Cell Mediated Treatment of Autoimmune Diseases

Project Summary Autoimmune diseaseswhich affect more thanmillion Americansarise when the immune system targets naturally occurring proteinsself antigensmounting a response against normal tissues and causing a disease stateCurrent therapies only treat the symptoms of the diseasewithout curing the underlying autoimmune conditiontypical treatments are limited to systemic immunosuppressive therapy that can lead to dangerous sideeffectsOne potential method for generating curative therapies for autoimmune disorders is to induce immune tolerance to the self antigen that the immune system is aberrantly attackingThis can be achieved using red blood cellsRBCswhich undergo a process where dying RBCs are filtered out in the liver and spleen and are processed in a way that tolerizes the immune system to proteins on or inside the RBCsHoweverprevious attempts to deliver material to RBCs to tolerize against a specific antigensuch as binding antigens to the RBC surfaceled to unwanted immune responsesAnother strategy involves hypotonic loading of RBCswhich is time consuming and can process a limited amount of bloodmaking clinical translation difficultIdeallyantigens are loaded inside RBCs in a high throughputcost effective manner that does not lead to significant disruption of RBC behaviorWe propose to deliver self antigen proteins to human RBCs to induce antigen specific T cell tolerance following the clearance of the antigen containing RBCsOur goal is to create off the shelf RBC therapies for various autoimmune disorders by engineering donated O negative blood with disease specific antigen in a sterilerapidand cost effective mannerSQZ Biotech has a vector free microfluidic delivery platform that can deliver any cargoregardless of sizechargeor chemical structureto a variety of cell typesincluding RBCsThe SQZ platform flows cells through a constriction narrower than the cell diametertemporarily disrupting the cell membrane and allowing material diffusion into the cell with little disruption of cell functionOur platform is capable of rapidhigh throughput deliveryandgtM cells can be processed in minutesmaking the platform amenable to clinical translationPreliminary data demonstrates that the SQZ platform can deliver antigens to both human and mouse RBCs and that delivery of antigen to mouse RBCs leads to a tolerogenic response in vivoThe ability of the SQZ platform to deliver complex antigen mixturessuch as those generated from digested tissue of the affected organcould lead to a robust tolerance response precluding antigen identificationWe believe that we are uniquely positioned to successfully generate antigen specific treatment for autoimmune disorders Project Narrative Autoimmune disorderssuch as type I diabetesT Dand multiple sclerosisMSoccur when the aberrant immune system recognizes and attacks proteins normally presented in healthy tissueself antigensresulting in detrimental co morbiditiesMost autoimmune disease therapies only manage symptoms and often involve regimented administration of immunosuppressantswhich can reduce the rate of disease progression but can also cause life threatening immune system deteriorationAt SQZwe are currently developing a potentially curative alternative by using our unique cell engineering platform to deliver disease associated self antigens to red blood cells and therapeutically tolerize the immune system to the self antigenshalting disease progression