SQZ Biotechnologies Company — Department of Health and Human Services SBIR Phase I: NIAID

Description

PROJECT SUMMARYImmunity to viral vectors precludes repeat dosing and decreases efficacy of vector based gene therapieswhich have otherwise shown promise in treating a range of genetic diseasesFor increased efficacious implementation of viral vector gene therapiesthere is a critical need to address immunity to the therapeutic vector and transgene in a potentantigen specific mannerWithout an appropriate solution to the immunogenicity of vector based gene therapiesthe clinical efficacy of many promising gene therapies will likely remain lowThe long term goal of SQZ Biotech is to develop a cell therapy to induce immune tolerance to viral vectors and their transgenes in patients receiving gene therapyUsing the patented Cell Squeezesystemmaterials like proteins and peptides can be reproducibly delivered to red blood cellsRBCsAdministration of SQZ engineered RBCs induces tolerance to the delivered materials through endogenoustolerogenic clearance of RBCs during eryptosis in the liver and spleenFor this Phase I SBIR proposalthe overall objectives are to simultaneously induce tolerance to the viral capsid and transgene product and to demonstrate that the SQZ RBC approach induces tolerance to multiple AAV serotypesThe central hypothesis is that SQZ RBCs will prevent in vivo immunity to capsid protein and transgene and that tolerance induced to AAVcapsid protein will prevent immunity to other serotypesOur hypothesis is based on preliminary data demonstrating that treating mice with RBCs SQZ d with the immunodominant epitope of AAVcapsid prevented reactivity to capsid and that the capsid sequence is highly conserved across serotypesThe rationale is that simultaneously inducing tolerance to AAV capsid and transgene will provide strong support for developing a clinically relevant therapy as immunity can develop to either or both componentsIn addition to broadening the applicability of the productdemonstrating that tolerization to AAVinduces tolerance across serotypes will enable quicker formation of strategic partnerships with gene therapy companiesTo induce tolerance simultaneously to AAV capsid protein and transgene product in Aimmice dosed multiple times with luciferase expressing AAV will be treated prophylactically or therapeutically with SQZ RBCs encapsulating luciferase and capsid proteinSerum levels of luciferase and T cell responsiveness to capsid and transgene will be measured to assess tolerization efficacyTo tolerize to multiple serotypes using AAVcapsid in Aimmice dosed multiple times with luciferase expressing AAVor AAVwill be treated prophylactically or therapeutically with RBCs SQZ d with AAVSerum levels of luciferase and T cell responsiveness to AAVcapsid and AAVor AAVcapsid will be measured to assess efficacySuccessful completion of these aims will establish a strong foundation for further preclinical development and the formulation of a human RBC product for future clinical trialsThe proposed research would significantly progress development of a novel tolerance approach that enables better and broader application of gene therapieswhich has the potential to significantly change the course of genetic disease treatment PROJECT NARRATIVET cell mediated immunity and neutralizing antibodies to viral vector gene therapies restrict treatable patient populations and preclude treatable patients from receiving larger and or multiple gene therapy doseswhich can significantly limit therapy efficacy and durabilityDespite attempts to re engineer viral vectors or engineer more potent transgene packagesthe only current solution is to administer non specific immunosuppressants at the time of gene therapy administrationwhich prevents short term immunity to the viral vector but not the transgeneSQZ Biotechnologies is currently developing an alternative approach using our unique cell engineering platform to tolerize the immune system to the viral vector and transgenepreventing immunity to the gene therapy