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The accidental discovery worth billions of dollars and a Nobel Prize

As is so often the case with scientific breakthroughs, the discovery of genetic scissors came about by accident. The potential in such technologies has not only attracted the interest of investors – with 25 biotech companies raising $4.5bn in the last quarter – but also the major pharmaceutical companies. The result is rapid growth in the M&A market in advanced-therapies – as Big Pharma believes this innovative technology offers a way to continue growing, while the patents on more and more of their most lucrative drugs expire.

So how did this billion dollar accidental discovery come about? During a study of Streptococcus pyogenes, a type of bacteria responsible for tonsillitis, scarlet fever and a variety of other diseases, Emmanuelle Charpentier stumbled across a previously unknown molecule called tracrRNA. She found that tracrRNA is part of bacteria’s ancient immune system, CRISPR/Cas, which disarms viruses by cleaving their DNA.

After publishing her discovery in 2011, she collaborated with RNA specialist Jennifer Doudna and together they recreated bacteria’s genetic scissors in a test tube before reprogramming them. In their natural form, the scissors recognise DNA from viruses, but Charpentier and Doudna proved that they could be controlled to cut any DNA molecule at a predetermined site. These genetic scissors, named CRISPR-Cas9, allow DNA to be inserted, deleted or rearranged in the genome.

Although Charpentier and Doudna recently won the Nobel Prize in Chemistry for their discovery, they have long been putting the technology to good use in the companies they have set up.

For example, CRISPR Therapeutics, co-founded by Charpentier in 2013, has developed a therapy called CTX001 for treating beta thalassemia and sickle cell disease. These conditions require lifetime treatment that result in regular transfusions, painful symptoms and chronic hospitalisations. Both diseases result in reduced life expectancy.

In most people, levels of fetal haemoglobin (HbF) begin to decline in the months preceding birth, while levels of adult haemoglobin (HbA) increase. Since only HbA contains the component of haemoglobin defective in patients with beta thalassemia or sickle cell disease, CTX001 isolates the patient’s own blood stem cells, editing them with CRISPR/Cas9 to increase HbF expression, then returns them to the patient.

In September, the European Medicines Agency (EMA) granted Priority Medicines (PRIME) designation to CTX001. This is a regulatory mechanism that provides early support to developers of promising medicines to speed up development and evaluations so these medicines can reach patients faster.

The market has been quick to recognise the potential in treatments such as CTX001 and, as a result, CRISPR Therapeutics now has a market cap of $6.5bn, having grown by more than 500 per cent since its IPO four years ago.

But CRISPR/Cas9 is just one of many types of genetic scissor available – others have built on the work of Charpentier and Doudna, creating technology that is arguably superior. For example, Precision BioSciences developed ARCUS, which is significantly smaller than other gene-editing technologies, with a length of only 364 amino acids. This makes it easier to deliver to specific tissues and cells. ARCUS also uses a naturally occurring gene-editing enzyme – the homing endonuclease I-CreI – which evolved in nature to make a single, highly specific DNA edit before using its built-in safety switch to shut itself off. The built-in safety switch reduces the risk of additional, off-target DNA edits, a significant limitation of other gene-editing technologies.

One of the uses of ARCUS is in CAR-T cell therapies, a relatively new approach to treating cancer. Most of the first-generation CAR-T therapies use the autologous approach, which involves taking a patient’s T-cells and modifying them to recognise and attack cancer cells. The problem with this method is that a new therapy must be created for each patient, delaying the start of the treatment and giving the cancer time to spread.

However, allogeneic CAR-T therapies use pre-prepared off-the-shelf T-cells from healthy donors, which can be used to treat cancer almost from the point of discovery, increasing the chance of tackling the disease before it has a chance to take hold.

Another company that has built on the work of Charpentier and Doudna to produce a potentially superior genome-editing technology is LogicBio.

In traditional gene therapy, the corrective genes do not integrate with the patient’s chromosomes, but float inside the nucleus. This means the corrective gene is not carried through to successive generations when cells divide and the therapeutic effect is diluted over time — especially in children, whose cells divide rapidly as they grow, and in tissues such as the liver, where cells also divide and regenerate in adults.

LogicBio’s GeneRide platform harnesses the cell’s natural DNA repair process to integrate the corrective gene into the patient’s chromosome at a precise spot. The gene then persists as an integral part of the patient’s DNA as cells divide.

It is clear to see why the potential in these advanced-therapies has caught the attention of Big Pharma and lead to a boom in the M&A market. Bristol Myers Squibb’s $13B purchase of MyoKardia for a 60 per cent premium to its share price just the latest in a long line of deals. When a company splashes out this much money, you can be sure that nothing is left to accident.

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