Open thread: CRISPR-Cas9

2017-08-22

in Science

CRISPR-Cas9 is a powerful new gene editing technique with the promise of widespread applications in research, medicine, and industry — as well as to provoke political and moral controversy.

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. August 22, 2017 at 5:35 pm

CRISPR-Cas9 editing has been developed from a bacterial defence system that shreds the DNA of invading viruses. CRISPR stands for “clustered regularly interspaced short palindromic repeats”. These are short strings of RNA, a molecule similar to DNA, each designed to fix onto a particular segment of a virus’s DNA. Cas9 is an enzyme which, guided by CRISPRs, cuts the DNA at the specified point.

Modifying this arrangement for the purposes of genetic engineering is simple, at least in theory. Since DNA and RNA work in essentially the same ways in all living organisms, designing appropriately customised CRISPR guide molecules can induce Cas9 to cut any cell’s DNA wherever the designers choose, eliminating undesirable sequences of genetic “letters”. Since cells will then try to repair this sort of damage, genetic engineers can, by providing corrected versions of the DNA that has been deleted for use as templates which a cell can copy, encourage the repair mechanism to fix the problem in the way they had intended.

The hope was that, by being given such templates, embryos could be purged of nascent genetic disease. That hope appeared fulfilled, at least in part. By the end of the experiment, 72% of the embryos were free of mutant versions of MYBPC3, an improvement on the 50% that would have escaped HCM had no editing taken place.

In achieving this, Dr Ma and her colleagues overcame two problems often encountered by practitioners of CRISPR-Cas9 editing. One is that the guidance system may go awry, with the CRISPR molecules leading the enzyme to parts of the genome that are similar, but not quite identical, to the intended target. Happily, they found no evidence of such off-target editing.

A second problem is that, even if the edits happen in the right places, they might not reach every cell. Many previous experiments, including some on embryos, have led to mosaicism, a condition in which the result of the editing process is an individual composed of a mixture of modified and unmodified cells. If the aim of an edit is to fix a genetic disease, such mosaicism risks nullifying the effect.

. October 1, 2017 at 9:01 pm

The technology along these lines that has got furthest is called CAR-T, where CAR stands for “Chimeric antigen receptor”. These CARs are produced by splicing together the gene for an antibody that recognises a tumour antigen and the gene for a receptor that sits on the surface of the T-cells; put this new gene into a T-cell and it will be precisely targeted at the tumour. The small clinical trials undertaken to date suggest that this could be extremely effective. A trial of 31 patients with acute lymphoblastic leukaemia brought a complete, and unprecedented, remission in 93% of cases. A CAR-T therapy called Kymriah (tisagenlecleucel), made by the Swiss firm Novartis to treat B-cell acute lymphoblastic leukaemia, was approved for use in America on August 30th.

There are two main limitations to CAR-T. One is that so far the T-cells have been programmed to target a molecule, CD19, which is only common to the surface of a few blood cancers. The other is that CAR-T has been known to trigger immune reactions which can prove fatal. Neither problem is obviously insoluble. Editing genes has been made much easier by a new technology known as CRISPR-Cas9, which has already been used to improve the way that CAR-T cells are engineered in mice. It may well eventually allow the receptors used in such therapies to be personalised to the specifics of the patient’s cancer. And more precision, as well as experience, should lead to immune responses less likely to run away with themselves.

What such advances will not do, though, is make such treatments cheaper. Novartis’s new therapy costs $475,000. Genome-editing treatments seem likely to be the most expensive cancer treatments the world has yet seen. And that is saying quite a lot, since many of the newer cancer treatments are eye-wateringly pricey (see chart).

. November 14, 2017 at 7:27 pm

Gene editing takes another step forward

It can now edit individual genetic letters

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