Crispr: Bad News For Gene Editing

Summary

• New data concerning chromothripsis may affect the long-term outlook of companies such as Crispr Therapeutics.
• The long-term impact on health of gene editing may not be known until around 2040.
• Given the uncertain outlook, investors may be wise to re-evaluate their positions in companies employing DNA double strand breaks to edit the genome.

Meletios Verras/iStock via Getty Images

Author's Note, 09/19: Unfortunately, I misread the data concerning the number of patients who experienced adverse events, so any reference to side effects has been deleted.

Preamble

I’m sure there are many investors in ARK funds who receive their daily bulletin detailing ARK’s buys and sells. Some of those ARK (ARKG) followers may also be Crispr Therapeutics (NASDAQ:CRSP) stock holders and are perhaps heartened to see that ARKG has been enthusiastically adding to their position over the last couple of months. This is understandable given that it was reported as recently as June of this year that ARK funds were "surging" as a result of recent positive reports of successful human trials. However, since around July, investors may be mystified as to the reason the stock is, slowly, but surely, falling. Of course, no one can pinpoint all the myriad possible reasons for this, however one contributory factor may be chromothripsis.

Background

From the diagram below, one could be forgiven for thinking that with Crispr’s technology, gene editing is a relatively straightforward and safe procedure. As you may note, the technology allows for DNA double strand breaks (DSB), and then amendments are made to correct the target malady. However, despite the undoubted sophistication of the technology, recent studies suggest that these DSBs can lead to a host of chromosomal abnormalities.

Source: Crispr Therapeutics presentation

What could go wrong?

One of the research projects led by Mitchell L. Leibowitz suggests that: “a catastrophic mutational process called chromothripsis is a previously unappreciated consequence of CRISPR-Cas9“. For those unfamiliar with chromothripsis, it is an extensive chromosome rearrangement restricted to one or a few chromosomes that can cause human congenital disease and cancer. For the layman, Fyodor Urnov, a research professor at Berkley, describes chromothripsis as being similar to rearranging a section of a jigsaw in random order with no regard for whether the resulting image makes any sense.

It is accepted that chromothripsis is very common in cancer, and it is well established that it leads to tumor suppressor loss and dysregulation of genes with known cancer links. Indeed, a study published last year showed that chromothripis was present in 49% of the cancers studied.

May I say at the outset that I am not suggesting that gene editing treatment will lead to cancer, since there is at present zero evidence that this is the case. Nevertheless, there is a rising number of voices, including the CRISPR Journal, urging caution given the lack of information on the long-term safety of genome editing and recent evidence showing the presence of chromothripsis in edited cells has added to these concerns. To this end, CRISPR are enrolling subjects who have previously received CTX001 sickle cell treatment into a long term follow up study that is expected to be completed in 2039.

As far as I am aware, in addition to Crispr Therapeutics, Intellia (NTLA), Editas Medicine Inc (EDIT), Caribou Bioscience (CRBU) and Graphite Bio (GRPH) use DSB techniques. Whereas, Beam Therapeutics (BEAM) does not use DSB, the company use single strand editing technology.

How does chromothripsis occur?

The mechanism by which chromothripsis occurs has not been completely explained, although a micronuclei model is the one which has gained the greatest traction amongst the scientific community. In short, mashed up DNA becomes separated from the main nucleus and forms a separate micronucleus, which then, over time, becomes reincorporated into the main nucleus. This mashed up DNA then contributes to the cell becoming carcinogenic.

Chromothripsis can be generated by a single catastrophic event during the life history of a cell. Such a catastrophic event includes gene editing. The Leibowitz research proposes that the Cas9 process cuts the targeted chromosome into two sections: one with a centromere (“centric”) and one without (“acentric”). During mitosis, the centric chromosome fragments then form the main nucleus of the cell and the acentric chromosome fragment forms a micronucleus, as highlighted by the red arrow in the diagram. It is hypothesised that if the DSB is not repaired before mitosis, the acentric fragment forms a micronucleus as shown. In other words, this is a timing event that is very difficult to overcome.

Source: Leibowitz research paper

What is the size of the problem?

The Leibowitz study reports that micronucleation occurs in approximately 4% of the cells edited via Cas9. Furthermore, there is concerning evidence that prove that the original errors produced by the editing may be magnified in following generations of the affected cell.

As to remedies for this issue, Leibowitz proposes that single strand editing technology may minimize the possibility of chromothripsis.

How serious is the issue?

Of course, typically, faulty cells are either recognised by the immune system and destroyed or undergo programmed cell death; otherwise known as apoptosis. It has to be said that the frequency of micronuclei formation in healthy tissue is unclear, but in cultured fibroblasts a micronucleus is formed in about 1 out of every 100 divisions.

Also, as far as I am aware, oncogenic cell production involving Cas9 has not been seen in animal studies, nor in people who have participated in clinical trials. In fact, no studies produced by the companies I mentioned previously have described the formation of micronuclei, which supports the assertion in the study that this consequence was previously unknown. Companies such as Crispr Therapeutics have reported that patients are cured of their disease, however, critically, long-term follow up data are unavailable at this time.

Indeed, another study led by Mitchell Weiss of St. Jude Children’s Research Hospital and David Pellman of the Dana–Farber Cancer Institute and Harvard Medical School, suggest; “So far, none of the companies leading the clinical development of CRISPR-based therapies appears to have considered the issue; its clinical implications, if any, remain unclear”. In the report, Pellman goes further by theorising that Cas9 has “an on-target effect. You cannot make this go away by making the cutting more specific”.

To sum up

This new information concerning chromothripsis is not a small matter, it may seriously impact those companies employing DSB technology. One can easily imagine the FDA restricting the use of these treatments to only the most severely impaired patients until long-term data become available. This being the case, investors may wish to carefully consider their investments in the companies mentioned in light of this information.

Analyst’s Disclosure: I/we have no stock, option or similar derivative position in any of the companies mentioned, and no plans to initiate any such positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.