Abstract: The disclosure provides compositions and methods for for modifying an endogenous cell surface protein (e.g., an endogenous TCR) in a cell (e.g., a T cell) with a CAR or an exogenous protein (e.g., an exogenous intracellular or cell surface protein (e.g., an exogenous TCR)).

Abstract: Methods for editing the genome of cells such as T cells and hematopoietic stem cells are disclosed. The methods include inserting a nucleic acid sequence of an exogenous partial open reading frame (ORF) of an autosomal dominant gene (e.g., CTLA4) into an intronic target region of an endogenous autosomal dominant gene in the cell, wherein the endogenous autosomal dominant gene comprises one or more disease-causing mutations; the exogenous partial ORF of the autosomal dominant gene is free of disease-causing mutations; and insertion of the exogenous partial ORF of the autosomal dominant gene into the intronic target region results in a modified autosomal dominant gene that encodes a protein which is free of disease-causing mutations. Methods for treating haploinsufficiency and methods for increasing gene editing efficiency are also described.

Abstract: The disclosure provides compositions and methods for for modifying an endogenous cell surface protein (e.g., an endogenous TCR) in a cell (e.g., a T cell) with a CAR or an exogenous protein (e.g., an exogenous intracellular or cell surface protein (e.g., an exogenous TCR)).