Xenografts – here’s where we stand

Surgeon Jayme Locke and immunologist Megan Sykes

David Bennett, the first patient transplanted with a genetically edited pig heart, died on March 8 last year, two months after the surgery, presumably from a latent pig virus (a problem that does not seem hard to solve with more stringent protocols and screening, as Linda Scobie explained to me a few months ago). Since then, experimental transplants have continued in brain-dead patients who had donated their bodies to research. After xenokidneys with a single genetic modification transplanted in late 2021, in the summer of 2022 it was the turn of ten edits xenohearts. The state of the art now is that the potential of the approach still appears high, as does the morale of specialists.

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Next-Gen CRISPR – pasting whole genes without cutting

PASTE is a three-part CRISPR tool invented at the MIT McGovern Institute for Brain Research. It’s composed of a modified CRISPR-Cas9 (it’s called nickase because it nicks a single DNA strand instead of cutting both) and two effectors: RT stands for reverse transcriptase (just like in prime editing) while LSR means large serine recombinase.

This brand-new molecular machine writes the genome in three steps. Step 1: the nickase finds the desired site. Step 2: the reverse transcriptase inserts a landing pad. Step 3: the recombinase lands there and delivers its large DNA cargo. The aim is to replace whole genes, when fixing mutations is not enough (one example is cystic fibrosis). Here are the links to learn more:

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Happy 10th Birthday CRISPR!

The seminal paper by Doudna & Charpentier was published online at the end of June 2012. The printed issue came out a few weeks later, on August 17 (don’t try to buy it, Science VOLUME 337|ISSUE 6096 is out of stock). No wonder the gene-editing community is in the mood for celebration these days. If you are too, don’t miss the chance to read these articles on CRISPR’s ten-year anniversary!

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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?

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CRISPR children, how are they?

Credit: Stefano Navarrini, Innovative Genomics Institute, Anna Meldolesi

Lulu and Nana are three years old. Amy is the name Nature Biotechnology uses to refer to the third CRISPR baby, born in late spring-early summer 2019. Their health is a closely held secret, that Vivien Marx has investigated for the journal’s December issue. “A full understanding of the health risks faced by the children due to their edited genomes may lie beyond the reach of current technology”, she writes. Despite or maybe because of that, the news feature is well worth reading. Below are a few points:

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Base-editing comes of age and more SCD news

Alexis Komor and Nicole Gaudelli developed based editing when they were postdoc in David Liu’s laboratory at Harvard. Credit: The CRISPR Journal

The first Investigational New Drug (IND) application for base-editing technology has been cleared by the Food and Drug Administration. BEAM-101, developed by Beam Therapeutics, is an ex vivo base-editing product candidate, meaning that it uses a modified form of CRISPR capable of making single base changes without double-stranded DNA cleavage.

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Xenotransplantation: time to go deeper

Photo credit: Joe Carrotta

And so it happened. “In a first, surgeons attached a pig kidney to a human, and it worked,” as the New York Times puts it. Data are scarce, however, and all the info we have is from the general media. The kidney came from a GalSafe pig, which is the only one FDA approved so far. But scientists from several companies have already developed pigs much more engineered than that (with three or four porcine genes knocked-out instead of one, and human gene additions). To get an updated picture, we highly recommend this article published in Nature Biotechnology last April.

The ever-expanding CRISPR toolbox

Credit: Mon Oo Yee/Innovative Genomics Institute

The list of the latest additions since the beginning of September is impressive. They are called CasMINI (see Molecular Cell), Cas7-11 (see Nature), OMEGAs (see Science), and come respectively from Stanford University (Stanley Qi Lab), MIT (McGovern Institute), and the Broad Institute (Zhang Lab). CasMINI is half the size of Cas9 and could be much easier to deliver. Cas7-11 is the Cas9 of RNA. OMEGAs are a new class of widespread RNA-guided enzymes, thought to be the ancestors of CRISPR.

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