A half-decade after a scientist’s reckless experiment with human embryos put a stop to much of China’s clinical work on CRISPR gene editing, local researchers are once again performing human studies of the technology.
At least three Chinese biotech companies have recently begun tests of CRISPR treatments for blood, eye and liver diseases, with more on the way. Although most are pursuing the same set of well-trodden targets as their US counterparts, they are moving at rapid speed and with a fraction of the funding of their Western peers.
Shanghai-based YolTech Therapeutics, for example, began preliminary clinical tests of its gene editing therapy for a liver disease called hereditary transthyretin amyloidosis in December — a mere 16 months after raising $17 million in its first major financing. A formal Phase 1 trial was cleared by Chinese regulators in March.
“In China, you have to move fast and make decisions without having the full or comprehensive data,” YolTech chief technology officer Zi Jun Emma Wang told Endpoints News.
Following the embryo fiasco of late 2018, there were broad calls for increased vigilance of gene editing experiments happening outside the mainstay labs of Boston. And while the Chinese studies have largely escaped notice, there are indications that things are different this time. YolTech’s therapy, for example, is based on a similar treatment for the same disease being developed by Cambridge, MA-based Intellia Therapeutics.
Zi Jun Emma Wang“That gave a lot of confidence for Chinese companies, not just from the science perspective, but from the government and investors,” Wang said. “That’s why we are not really pushing forward a highly differentiated program as the first one.”
While they may have similarities with approaches being used in the US, some appear to be moving ahead of their American counterparts.
Another Chinese company, CorrectSequence Therapeutics, has developed its own twist on CRISPR base editing, which changes one letter of DNA into another. In just three years and with roughly $45 million, the company had already treated four patients with the blood disease beta thalassemia by the time its US competitor Beam Therapeutics had dosed its first patient with a similar therapy for sickle cell disease.
Others are testing versions of CRISPR not yet tried elsewhere. Last fall, HuidaGene Therapeutics, a startup based in Shanghai and New Jersey, began a trial in China of a therapy that uses CRISPR to edit short-lived RNA molecules instead of permanently changing DNA.
It’s the first time the technology has been tested in people, but HuidaGene’s target is a familiar one: lowering levels of the blood vessel-forming protein VEGF as an alternative to chronic treatments for age-related macular degeneration.
Zipping ahead and falling behind
Although CRISPR gene editing was invented in American and European labs, with Jennifer Doudna and Emmanuelle Charpentier’s breakthrough of programmable DNA edits published in 2012, Chinese scientists were the first to push the tests of the technology out of the petri dish and into the clinic.
Chinese doctors zipped ahead of their global counterparts when they used the gene editor to make experimental CAR-T cell therapies for cancer patients in 2016. Although considered the lowest hanging fruit for CRISPR — since the immune cells were removed from a patient’s body, engineered in the lab, and then reinfused — it took another three years before the leading American team, led by Carl June at the University of Pennsylvania, began a similar study.
China’s lead came to an abrupt halt when rogue researcher He Jiankui, a previously little-known researcher in Shenzhen, crossed a longstanding red line and used the technology to alter the DNA of human embryos, which were then implanted and carried to term. When the birth of those babies was revealed in late 2018, it caused an international outcry.
Yuxuan Wu“It had very bad effects on the development of Chinese gene editing,” said Yuxuan Wu, who co-founded the biotech startup BRL Medicine in Shanghai to develop CRISPR cell therapies for inherited blood diseases. “Every hospital refused to collaborate with us. So we struggled for about one to two years.”
Outside of China, the CRISPR baby scandal briefly fueled a cottage industry of bioethicists and scientists condemning He’s experiment and calling for efforts to prevent it from happening again. Endpoints contacted more than a dozen American and European gene editing scientists and bioethicists to ask about the new work going on in China. Almost all of them either declined to comment or said they were unfamiliar with these companies and their programs.
“It’s very hard to get reliable information on what’s happening in China,” said Krishanu Saha, a gene editing researcher at the University of Wisconsin in Madison and co-director of the Global Observatory for Genome Editing, which was tasked with tracking developments in the wake of the CRISPR baby scandal. “It’s something we should pay more attention to.”
A quiet resurgence
As the field has advanced, Wu’s interests have changed, too. He began to view altering cells outside the body, known as ex vivo editing, as impractical. “The process is very complicated and expensive, especially for patients in China,” he said.
Wu founded his second startup, YolTech, in 2021 to focus on editing genes directly inside the body. He believes such in vivo editing therapies will be cheaper and easier to make and administer — thanks in part to the popularization of lipid nanoparticle production used in the Pfizer/BioNTech and Moderna vaccines for Covid.
As coronavirus fears and restrictions eased, interest in gene editing studies renewed in China. He Jiankui, who was sentenced to three years in prison for “illegal medical practices,” has also returned to the lab — and recently tweeted that he is getting back into embryo editing.
When contacted by email, He blamed the biotech funding downturn of 2022 to 2023 for the slowdown of clinical CRISPR research in China, rather than his own actions. And he confirmed that he is working on embryo editing again.
“I believe that society will eventually accept embryo gene editing, therefore, I have proposed a research project, using embryo gene editing to prevent Alzheimer’s disease. However, we will only use defected embryos that are not suitable for transplantation,” He wrote.
He’s work is an uncomfortable subject for the crop of new Chinese gene editing biotechs, which insist that they are not interested in editing embryos or germ cells. And it raises questions about the meaningfulness of China’s regulatory changes.
“China has imposed a great deal of additional regulation post-He Jiankui, and it looks good on paper,” said Hank Greely, a bioethicist at Stanford University. “But it is easier to make laws modeled after things other countries have done and create things that look like [institutional review boards] than it is to create a culture that gives any power to them.”
Moving faster, with less money
Wang, who worked at the Boston gene editing companies Beam Therapeutics and Tessera Therapeutics before Wu recruited her to YolTech, said that the cheaper labor and lab space in China helps companies do more with less. YolTech began its first clinical test just over two years after its founding with a little more than $32 million raised in Series A financing.
Comparisons to US startups, which have had to work out the kinks of a new technology, aren’t straightforward. But Intellia, which is working on multiple drugs, had spent about $600 million over six years by the time it began testing its first therapy in people. And Verve Therapeutics spent roughly $200 million over four years before beginning the first tests of its cholesterol-lowering therapy.
YolTech started dosing its therapy in December, and several unique factors helped accelerate it into the clinic, including the country’s investigator-initiated trial system that allows companies to test drugs in people before regulators OK a formal test. It also got a government-subsidized manufacturing facility in “ready-to-move-in condition,” Wang said.
“We got a lot of help or attention for being the first in vivo gene editing program in China. You can imagine a lot of suppliers, vendors, or CROs moved their priorities for us,” she added.
The company is planning a second therapy, with its own version of base editing, that edits PCSK9 to lower cholesterol — the same focus of Verve’s lead program. YolTech is blunt about piggybacking on diseases already tested by American companies, and worried Chinese regulators would delay a trial with too many new variables. But it’s also likely led to a low profile for the companies.
Erik Sontheimer“So far, these companies have generally been doing things that are very comparable to what first-wave companies are already doing and presenting publicly,” said Erik Sontheimer, a gene editing scientist at UMass Chan Medical School. “If one of them comes up with something that’s really new, that will go further in terms of making people sit up and pay attention.”
Wang and Wu said that they don’t view YolTech as a direct competitor to Intellia or Verve. The Chinese market is large and shouldn’t have to wait for US companies to make a drug and hope it reaches China and Asia, they said.
“That’s one of the biggest motivations of why YolTech was founded,” Wang added. “But I wouldn’t be surprised if we ended up getting approved in China earlier than Intellia.”