The first humans will have Crispr deployed like a drug inside their bodies this year, as companies embark on a new stage of the gene-editing revolution that could lead to many more diseases being treated, or even cured, with the technology.
Discovered in 2012, Crispr-Cas9, often shortened to Crispr, allows scientists to make precise changes to DNA at specific points and could transform treatment of genetic diseases. Last year, the first trial used Crispr to edit blood cells that were taken out of and then returned to a body. But this year, it will be injected into the bodies of patients to conduct the edit live, opening the way for the edits of genes in many more kinds of cells.
Crispr was discovered in bacteria, as part of the mechanism that helps them defend against viruses. The Crispr genetic code can guide Cas9 — an enzyme that acts like molecular scissors — to specific locations on the genome, allowing scientists to remove a gene, tweak it to change its function, or regulate genetic activity.
Most scientists worry about the ethical implications of editing inherited genes that can be passed down generations, such as when Chinese scientist He Jiankui sparked controversy when he claimed to have produced the first genetically edited babies using Crispr-Cas9. But many are excited by the opportunity to cure diseases by editing genes that only affect the patient.
Editas Medicine, a Boston-based biotech, will seek to restore patients’ sight using Crispr-Cas9 technology in a person, in vivo, not a Petri dish.
Charlie Albright, chief scientific officer at Editas, said genome-editing was the only way to achieve a “potentially transformational and durable change” for the patients suffering from a rare inherited eye disorder. “It’s a super exciting time to be part of the first in vivo experimental medicines going into the clinic,” he said.
Rival biotech group Intellia Therapeutics plans to seek US approval for its own trial in the second half of 2020. It will use Crispr to attempt to cure amyloidosis, a rare and potentially life-threatening liver condition.
Crispr Therapeutics became the first company to use the gene-editing technology in humans last year, treating two patients with blood disorders. It removed cells from the body to edit — and then returned them. Success in these patients helped the company raise more than $270m in a recent follow-on offering.
Investors are also eager to see how the three listed biotech groups testing Crispr fare as they start to produce trial data in the US. Silvan Türkcan, an analyst at Oppenheimer, said the companies’ share prices had been moving on partnerships and updates that were particularly hard to model for investors, but they would now start acting more like traditional biotech stocks, trading on data readouts.
“We need to see the promise of Crispr — that you can develop a superior product to gene therapy, precisely — holds up,” he said.
Crispr companies have had to overcome hurdles including concerns about safety and intellectual property.
If an edit misses its target, it could disrupt the genome, resulting in mutations and potentially causing cancer. But accuracy rates have improved and Editas obtained FDA approval for its first trials within 30 days, suggesting that the regulator did not require extra time to deliberate.
Crispr technology has also been at the centre of a patent battle between the University of Berkeley, where scientists first discovered it, and the Broad Institute, where it was first used in human cells a year later. But Mr Türkcan said investors had become more certain that the dispute would be solved by cross-licensing, as applied to monoclonal antibodies, which fuelled a previous revolution in biotech.
Investors are starting to distinguish between companies’ strategies. Shares in Crispr Therapeutics climbed the most, up 113 per cent last year, as it has produced the first real results. Editas rose 30 per cent and Intellia was up 7 per cent
Intellia’s work on the liver may have the highest risk, because the virus that carries Crispr has to float around the body once injected and find its target, unlike at Editas where it will be injected into the eye, which has its own separate immune system.
But for John Leonard, Intellia chief executive, the risk is worth it. “The idea of curative therapy is the ultimate objective,” he said. “You can potentially treat a whole series of tumours that are untreatable at this point.”
Intellia’s first patient will potentially experience no benefit, because the trial starts with low doses that will be increased as clinicians monitor for side effects.
Crispr Therapeutics is taking a very different tack. Its clinicians will make edits outside the body and in diseases which are well understood: blood disorders b-cell thalassaemia and sickle cell. Sam Kulkarni, Crispr Therapeutics’ chief executive, said the company was trying to follow the lead of Genentech, which rode the biotech boom to become one of the sector’s largest companies, while many others were sold off for at low prices.
“If it’s ex vivo, we will know exactly what changes we’re making,” he said. “Then as we build the company, our expertise, and our market cap, and can afford to spend more on this, we can do more and more and we can improve the platform to make smaller Cas9, brand new delivery technologies.”
Mr Kulkarni said that 60 per cent of the opportunity was in editing genes outside the body. Crispr Therapeutics, which is working with larger biotech Vertex Pharmaceuticals to pursue many of its treatments, plans to launch a trial every six months, with a whole series ex vivo. Next, will be three trials to treat cancer, including trying to edit immune cells to tackle solid tumours. Then it will attempt to create an artificial pancreas for diabetics, and finally, it will take treatments into humans directly.
Steve Seedhouse, an analyst at Raymond James, said that despite the risk, he preferred Intellia to Crispr Therapeutics partly because it was trying to treat amyloidosis, a disease that is rising in prevalence and a market that is expected to grow at 7.2 per cent a year until 2025, according to research firm Grand View Research.
“Intellia spent a lot of years really developing the delivery technology and optimising the in vivo application of Crispr Cas9, so it may be slow and steady wins the race,” he said.
Beyond these three biotechs, Crispr could end up transforming the entire pharmaceutical industry.
Mr Kulkarni said the sector would become more like “Apple v Samsung”, where biotechs competed on adding generation after generation of features. The ability to tweak the “chassis” of Crispr could transform the business into an “engineering-based competition”, rather than one where companies invest in a biological hypothesis to find a molecule that they can then patent and profit from.
“With Crispr, there is no limit to what we can do,” he said. “We’re almost obligated to open up new avenues and areas . . . We can move faster than pharma.”
Hope for sickle cell
Victoria Gray had been ill for all of her 34 years. Her sickle cell disease, a severe hereditary form of anaemia, caused excruciating pain, forcing her into hospital every few months, and often keeping her bed-ridden at home.
The Mississippi mother of four became depressed, exhausted by her illness and feared death: the average sickle cell patient dies in their 40s.
“I was at the end of my rope and Crispr saved me,” she said.
Ms Gray was the first patient to try the sickle cell treatment from Crispr Therapeutics — and was the second person to be treated with the gene-editing tool in the US.
Sickle cell, with which about 300,000 babies are born a year, is caused by deformed red blood cells which struggle to push through blood vessels, damaging organs.
Last year, Ms Gray’s cells were collected, edited outside of her body and infused back in as part of a stem cell transplant.
The transplant itself can cause serious side effects.
“It was three months of my time,” she said. “They could help me live long and not have to feel so much pain. It helped me a lot with my anxiety and worrying about dying.”
Now, she is planning a birthday party for her son. Her pain has gone, she is recovering her energy and hopes to return to work. Her children do not have sickle cell — but as carriers, they could have children with the disease. Ms Gray hopes that participating in the trial could help many others, including maybe her grandchildren.
“It can save not only lives now but lives in the future,” she said.