The present disclosure provides for transgenic swine, comprising one or more nucleotide sequences encoding one or more HLA I polypeptides and/or one or more HLA II polypeptides inserted into one or more native SLA loci of the swine genome, methods of making and methods of using.

The present disclosure also provides for improved methods of making human immune system mice.

The present invention relates to a transgenic cloned pig for xenotransplantation in which porcine endogenous retrovirus (RUN) EnvC is negative, α1,3-galactosyltransferase (GGTA1), CMP-N-acetylneuraminic acid hydroxylase (CMAH), isoglobotrihexosylceramide synthase (iGb3s), and beta-I,4-N-acetyl-galactosaminyl transferase2 (β4GalNT2) are knocked out, and human CD46 and thrombomodulin (TBM) genes are expressed, and to a method of preparing the transgenic cloned pig. The transgenic cloned pig according to the present invention may overcome hyperacute and antigen-antibody mediated immune rejection reaction, immune rejection reaction due to blood coagulation, and immune rejection reaction due to complement activity, without causing transfer of porcine endogenous retrovirus that occurs in xenotransplantation. Therefore, the transgenic cloned pig according to the present invention may be usefully utilized as a donor animal for xenotransplantation of organs and cells.

The present disclosure is directed to transgenic animals (e.g., transgenic porcine animals) comprising multiple genetic modifications that advantageously render these animals suitable donors for xenotransplanation. The present disclosure extends to organs, organ fragments, tissues and cells derived from these animals and their therapeutic use. The present disclosure further extends to methods of making such animals. In certain embodiments, the transgenic animals (e.g., transgenic porcine animals) have reduced expression of the growth hormone receptor (GHR) gene or have impaired function of the GHR protein.

The present invention relates to novel strains of pig that are highly suitable for xenotransplantation. The first novel pig strain lacks functional porcine endogenous retroviruses so is suitable as a donor for tissue and/or cell xenotransplantation into a human recipient. These pigs can also be used as a foundation pig for further manipulation, for example, by gene editing of xenoantigens to produce a second novel strain of pig that is not only free of infectious porcine retroviruses but is also free of the main xenoantigens responsible for hyperacute organ rejection. These pigs can be used for whole organ, tissue and/or cell transplantation into a human recipient. The present invention also relates to methods for selecting pigs that lack infectious porcine endogenous retroviruses, and their use for tissue and/or cell xenotransplantation into humans, and to methods of gene editing of xenoantigens of the selected pigs to further enhance the immunological quality of the donor organs, tissues and/or cells to avoid xenotransplant rejection.

Genetically modified cells, tissues, and organs for treating or preventing diseases are disclosed. Also disclosed are methods of making the genetically modified cells and non-human animals.

The invention provides for transgenic donor animals (e.g., pigs) whose cells, tissues and organs have a better long-term survival when transplanted into a human patient. The transgenic donor animal carries one or more human transgenes which is expressed only when the endogenous gene of the donor animal is knocked out shortly before a graft is harvested for transplantation. This “genetic switch” allows the donor animal to remain healthy during the majority of its lifetime, while still allowing expression of the human transgene for optimal transplant tolerance in a human recipient. The transgene may encode a cytokine receptor, an adhesion molecule, or a complement regulatory protein.

The present invention relates, in part, to methods of treating a subject with a condition that would benefit from an increased immune response comprising administering to the subject a therapeutically effective amount of an agent that inhibits PTPN2. The present invention also provides methods and compositions for perturbing gene expression in hematopoietic cell lineages.

This document provides methods and materials involved in reducing cardiac xenograft rejection. For example, methods and materials for preparing transgenic pigs expressing reduced or no endogenous Sd.sup.a or SDa-like glycans derived from the porcine β1,4 N-acetyl-galactosaminyl transferase 2 (B4GALNT2) glycosyltransferase and/or reduced or no endogenous α-Gal antigens, methods and materials for modifying the xenograft recipient's immunological response to non-Gal antigens (e.g. CD46, CD59, CD9, PROCR, and ANXA2) to reduce cardiac xenograft rejection, and methods and materials for monitoring the progress of xenotransplant immunologic rejection are provided.

Genetically modified cells, tissues, and organs for treating or preventing diseases are disclosed. Also disclosed are methods of making the genetically modified cells and non-human animals.

A biological product for clinical xenotransplantation into a human and a method of preparing biological product for clinical xenotransplantation into a human involving producing a non-wild type, biologically engineered swine having a biologically engineered genome such that the swine does not express one or more extracellular surface glycan epitopes, is free of certain pathogens, is reared according to a bioburden-reducing procedure in a closed designated pathogen free herd, wherein the biological product is harvested following the swine being euthanized and the product is aseptically removed from the swine, the biological product is processed involving sterilization and storing the product in a sterile container, and the product does not contain one or more extracellular surface glycans, is free of certain designated pathogens, is biologically active and comprises live cells and tissues capable of vascularizing after xenotransplantation.