Compositions, systems and methods for cell therapy

Abstract

Disclosed herein are compositions and methods for cell therapy comprising an engineered cell. The present invention is directed to a composition for treating a subject having or suspected of having a disease, the composition comprising a modified cell comprising a modified endogenous gene, wherein an endogenous gene or fragment thereof is replaced with a transgene using a CRISPR/Cas9 system to generate the modified endogenous gene, the modified cell having an altered response to a cell signal or stimulus.

1 . A composition for treating a subject having or suspected of having a disease, the composition comprising a modified cell comprising a modified endogenous gene, wherein an endogenous gene or fragment thereof is replaced with a transgene using a CRISPR/Cas9 system to generate the modified endogenous gene, the modified cell having an altered response to a cell signal or stimulus. 
     
     
         2 . The composition of  claim 1 , wherein the altered response to the cell signal or stimulus comprises an activation of the transgene. 
     
     
         3 . The composition of  claim 1  or  2 , wherein the transgene encodes a transcription factor or a therapeutic molecule. 
     
     
         4 . The composition of  claim 3 , wherein the transgene encodes a transcription factor and the activation of the transcription factor activates or downregulates a signaling pathway in response to the cell signal or stimulus as compared to the response to the cell signal or stimulus by the unmodified endogenous gene. 
     
     
         5 . The composition of  claim 4 , wherein the activation of the transcription factor activates an anti-inflammatory response and the unmodified endogenous gene activates an inflammatory response. 
     
     
         6 . The composition of  claim 5 , wherein the coding region of the endogenous gene is replaced with the coding region of a transgene and the coding region of the transgene is operably linked to the promoter of the endogenous gene. 
     
     
         7 . The composition of  claim 6 , wherein the modified cell comprises self-regulated feedback control of anti-cytokine therapy to a subject. 
     
     
         8 . The composition of  claim 1 , wherein the endogenous gene is Cc12 or ADAMTS-5. 
     
     
         9 . The composition of any one of  claims 1  to  8 , wherein the transgene is sTNFR1 or IL-1Ra. 
     
     
         10 . The composition of  claim 3 , wherein the transgene encodes a therapeutic molecule. 
     
     
         11 . The composition of  claim 10 , wherein the modified cell produces therapeutic molecules in response to the cell signal or stimulus. 
     
     
         12 . The composition of  claim 1 , wherein the cell signal or stimulus comprises TNF-a and IL-la. 
     
     
         13 . A composition for treating a subject having or suspected of having a disease or disorder, the composition comprising a modified cell comprising a modified endogenous gene, wherein an endogenous gene or fragment thereof comprises a signal peptide and the signal peptide is deleted or knocked out using a CRISPR/Cas9 system to generate the modified endogenous gene, the modified cell having an altered response to a cell signal or stimulus. 
     
     
         14 . The composition of  claim 13 , wherein the altered response to the cell signal or stimulus comprises a decrease in responsiveness of the modified endogenous gene to the cell signal or stimuli compared to an unmodified endogenous gene. 
     
     
         15 . The composition of  claim 13 , wherein the modified cell is resistant to IL-1 induced inflammation. 
     
     
         16 . The composition of  claim 13 , wherein the endogenous gene is IL lrl. 
     
     
         17 . The composition of  claim 13 , wherein the cell signal or stimulus comprises IL-1. 
     
     
         18 . The composition of  claim 13 , wherein the disease is a chronic disease. 
     
     
         19 . The composition of  claim 18 , wherein the chronic disease is osteoarthritis. 
     
     
         20 . The composition of  claim 13 , wherein the disease is cancer. 
     
     
         21 .- 43 . (canceled)