Abstract: Described herein are systems and methods for treating, inhibiting, or ameliorating X-linked disorders including Wiskott-Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT) in subjects that have been identified or selected as being ones that would benefit from a therapy to treat, inhibit, or ameliorate WAS or XLT. The systems include nuclease and vector donor constructs configured for co-delivery to modify endogenous WAS locus.

Abstract: The present disclosure provides improved compositions for the homology directed repair of the human globin locus for the prevention, treatment, or amelioration of at least one symptom of a hemoglobinopathy.

Abstract: Aspects of the invention described herein concern the incorporation of a FOXP3 cDNA (e.g., full-length human codon-optimized cDNA) into a FOXP3 gene or a non-FOXP3 locus so as to provide constitutive or regulated FOXP3 expression in a primary human CD34+ cells or cells derived from edited CD34+ cells. In some embodiments, guide RNA sequences that are directed to FOXP3, AAVS1, or other candidate loci are used for CRISPR/Cas9-mediated gene regulation, and gene delivery cassettes for HDR based gene-modification are provided.

Abstract: The present application relates to plasma cells and plasma cell precursors that express a macromolecule, such as a protein, protein mimetic or a peptide and compositions comprising these plasma cells or plasma cell precursors. The application further relates to methods of using and making the plasma cells and plasma cell precursors that express the macromolecule. Methods of treatment comprising administering the plasma cells or plasma cell precursors are also contemplated.

Abstract: Disclosed are methods of making a genetically cell that expressed FOXP3 and methods of treatment. In some embodiments, the method comprises providing a first nucleotide sequence, wherein the first nucleotide sequence comprises a coding strand, the coding strand comprising one or more regulatory elements and a FOXP3 gene or portion thereof providing a nuclease and performing a gene editing process on the first nucleotide sequence, which edits said one or more regulatory elements, and optionally edits the FOXP3 gene or portion thereof. Methods of treating a subject suffering from an autoimmune disease and subjects suffering the effects of organ transplantation are also provided.

Abstract: Some embodiments of the compositions and methods disclosed herein include gene-edited, artificial immunoregulatory T cells (airT cells) comprising a constitutively expressed FoxP3 gene product expressed at a level equal to or greater than the level of FoxP3 expression in natural T regulatory (Treg or suppressor T) cells, and a transduced (e.g., artificially engineered by gene editing, viral vector transduction, transfection or other genetic engineering methodologies) T cell receptor (TCR). In some embodiments, the TCR is preferably specific for an antigen associated with an autoimmune, allergic, or other inflammatory condition. Some embodiments include methods for the preparation and/or use of airT cells. Some such embodiments include use of airT cells for the treatment and/or amelioration of a disorder, in which antigen-specific immunosuppression may be beneficial, such as an autoimmune, allergic, or other inflammatory disorder.

Abstract: Some embodiments of the methods and compositions provided herein include preparing modified B cells. In some embodiments, an endogenous beta-2 microglobulin (B2M) gene in a B cell is modified. Some embodiments relate to increasing the resistance of modified B cells to killing by allogeneic immune cells. In some embodiments, the endogenous B2M gene is inactivated increasing the resistance of the modified B cell to killing by allogeneic immune cells. In some embodiments, a replacement MHC-I is inserted into an inactivated endogenous B2M gene increasing the resistance of the modified B cell to killing by allogeneic immune cells. Some embodiments include enriching for successfully modified cells.

Abstract: Disclosed are methods of making a genetically cell that expressed FOXP3 and methods of treatment. In some embodiments, the method can providing a first nucleotide sequence, wherein the first nucleotide sequence comprises a coding strand, the coding strand comprising one or more regulatory elements and a FOXP3 gene or portion thereof providing a nuclease and performing a gene editing process on the first nucleotide sequence, which edits said one or more regulatory elements, and optionally edits the FOXP3 gene or portion thereof. Methods of treating a subject suffering from an autoimmune disease and subjects suffering the effects of organ transplantation are also provided.

Abstract: Aspects of the invention described herein concern the incorporation of a FOXP3 cDNA (e.g., full-length human codon-optimized cDNA) into a FOXP3 gene or a non-FOXP3 locus so as to provide constitutive or regulated FOXP3 expression in a primary human CD34+ cells or cells derived from edited CD34+ cells. In some embodiments, guide RNA sequences that are directed to FOXP3, AAVS1, or other candidate loci are used for CRISPR/Cas9-mediated gene regulation, and gene delivery cassettes for HDR based gene-modification are provided.

Abstract: Described herein are systems and methods for treating, inhibiting, or ameliorating X-linked disorders including Wiskott-Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT) in subjects that have been identified or selected as being ones that would benefit from a therapy to treat, inhibit, or ameliorate WAS or XLT. The systems include nuclease and vector donor constructs configured for co-delivery to modify endogenous WAS locus.

Abstract: The present disclosure provides improved genome editing compositions and methods for editing a human Wiskott-Aldrich syndrome gene. The disclosure further provides genome edited cells for the prevention, treatment, or amelioration of at least one symptom of WAS, including but not limited to, an immune system disorder, thrombocytopenia, eczema, X-linked thrombocytopenia (XLT), or X-linked neutropenia (XLN).

Abstract: The present disclosure provides improved genome editing compositions and methods for editing a human BTK gene. The disclosure further provides genome edited cells for the prevention, treatment, or amelioration of at least one symptom of X-linked agammaglobulinemia (XLA).

Abstract: The present application relates to, inter alia, compositions including proteins for expression in host cells to render them resistant to rapamycin. The application further relates to methods of using the proteins, cells, and compositions disclosed therein for modulating cell signaling and for selective expansion of cells.

Abstract: Described herein are compositions, systems, and methods for treating, inhibiting, or ameliorating X-linked hyper IgM syndrome (X-HIGM) in subjects that have been identified or selected as being ones that would benefit from a therapy to treat, inhibit, or ameliorate X-HIGM. The systems include nuclease and vector donor constructs configured for co-delivery to modify endogenous CD40LG locus.

Abstract: Some embodiments of the methods and compositions provided herein relate to modifying hemoglobin loci, such as hemoglobin-related mutations including sickle cell mutations. Some embodiments relate to modification of a sickle cell mutation through introduction of a phosphodiester DNA strand break at the site of the sickle cell mutation.

Abstract: Aspects of the invention described herein concern targeting of a FOXP3 cDNA, e.g., full-length human-codon optimized, into a FOXP3 locus or a non-FOXP3 locus so as to provide constitutive or regulated FOXP3 expression in a primary human lymphocyte. The compositions and materials described herein provide specificity for CRISPR/Cas-mediated gene regulation of murine, non-human primates or human FOXP3. Guide RNA sequences are used to target the FOXP3, AAVS1, and other candidate loci for CRISPR/Cas-mediated gene regulation, and gene delivery cassettes for HDR based gene-modification are provided. The alternative compositions described herein can be delivered in the form of Ribonucleoprotein (RNP) and may be used to target human and/or non-human primate FOXP3. Reagents are comprised of novel guide RNA sequences and can generate high frequency of on-target cleavage in combination with a Cas protein and novel gene delivery cassettes including FOXP3 cDNA+/?other cis linked gene products.

Abstract: Methods, compositions, and systems for treating subject(s) in need of plasma Factor VIII, particularly a subject having preexisting anti-FVIII inhibitory antibodies, are provided. The methods involve administering to the subject a therapeutically effective amount of an inflammation suppressor, a therapeutically effective amount of a CD8+ T cell depleting agent, and a therapeutically effective amount of a composition comprising a lentiviral vector (LV) comprising an optimized FVIII expression cassette expressibly linked to a megakaryocyte-specific promoter. Such methods, compositions, and systems are useful to treat subjects with blood clotting disorder(s), such as hemophilia A.

Abstract: The present disclosure provides improved genome editing compositions and methods for editing a human BTK gene. The disclosure further provides genome edited cells for the prevention, treatment, or amelioration of at least one symptom of X-linked agammaglobulinemia (XLA).

Abstract: The present disclosure provides improved compositions for the homology directed repair of the human globin locus for the prevention, treatment, or amelioration of at least one symptom of a hemoglobinopathy.

Abstract: Aspects of the invention described herein concern the incorporation of a FOXP3 cDNA (e.g., full-length human codon-optimized cDNA) into a FOXP3 gene or a non-FOXP3 locus so as to provide constitutive or regulated FOXP3 expression in a primary human CD34+ cells or cells derived from edited CD34+ cells. In some embodiments, guide RNA sequences that are directed to FOXP3, AAVS1, or other candidate loci are used for CRISPR/Cas9-mediated gene regulation, and gene delivery cassettes for HDR based gene-modification are provided.