Back to the basics of xenohearts

UHeart™ (photo credit United Therapeutics)

As you probably know, on January 7 at the University of Maryland Medical Center in Baltimore  a 57 years old man named David Bennett became the first human to have his heart replaced with that of a CRISPRed pig. But what does make a xenoheart suitable for transplantation?

The backbone of any pig intended for use as an organ donor is the TKO construct, i.e. a triple knockout lacking three genes needed to produce sugar molecules found naturally on the surface of porcine cells.

By disrupting the α-1,3-galactosyl transferase (GGTA1), the enzyme responsible for synthesizing the α-Gal sugar, alongside CMAH and B4GALNT2, interspecies incompatibilities improve substantially.

In a feature published last April Nature Biotechnology explained that, on top of that, it’s useful also to insert a few human genes involved in the immune responses to the transplant, such as genes encoding components of the complement activation pathway (CD46, CD55 and CD59) and regulators of platelet coagulation (thrombomodulin, tissue factor pathway inhibitor and endothelial protein C receptor).

The first xenoheart ever transplanted into a human was developed by Revivicor, a subsidiary of United Therapeutics. It is a “ten-gene” xenoheart with six human transgenes plus a fourth knockout in the porcine growth hormone receptor gene. The latter knockout aims to prevent the organ from getting too large.

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