Five people with beta thalassemia who had their blood stem cells genetically altered no longer require regular blood transfusions to stay healthy. Their Chinese-made treatment is likely to be cheaper, and perhaps safer and more effective, than its American counterparts.
Developed by CorrectSequence Therapeutics, the therapy employs a novel form of CRISPR base editing designed to change a single letter of DNA with almost no unwanted and potentially dangerous off-target edits. The Shanghai-based company told
Endpoints News
that the first patient treated has now been transfusion-free for nearly two and a half years.
The study of the five patients, published Wednesday in
Nature
, arrives as interest grows among Western drugmakers in experimental therapies made in China. And the new study suggests China will continue to become a bigger competitor even for the most cutting-edge medicines.
“This is a reflection of the tremendous acceleration in the research that’s coming from China — the quality and the quantity,” Mitchell Weiss, chair of the hematology department at St. Jude Children’s Research Hospital who wasn’t involved in the study, told Endpoints. “It doesn’t look like they’re skipping corners.”
Correctseq’s therapy boosts levels of fetal hemoglobin to make up for a deficiency in the adult form of the oxygen-ferrying protein. Two commercial medicines, Casgevy and Zynteglo — made by US companies — do the same thing in different ways. But CRISPR Therapeutics and Vertex Pharmaceuticals charge $2.2 million for Casgevy, and bluebird bio charges $2.8 million for Zynteglo. Neither treatment is approved in China, and the high price tags of those drugs and other multimillion-dollar gene therapies are spurring several startups in the country to develop
more affordable versions
.
“They’re not depending on US technologies,” Weiss said. “They’re doing it themselves because they can now, and because they can probably do it cheaper.”
Correctseq CEO Xiaodun Mou told Endpoints that it was too soon to discuss the price or commercialization of the treatment. But labor, manufacturing, research and clinical trials can all be cheaper and faster in China. Co-founder Jia Chen told Endpoints he believes the therapy will be safer and more effective too. Although it’s hard to make direct comparisons, in addition to fewer off-target edits, the trial results suggest its edited cells engrafted in patients more quickly than they did with the American therapies.
“All of the patients have been clinically cured, because they have been independent of the transfusion for at least one year,” Chen said. “It was thrilling to see all these patients treated. And every time they were released from hospital, we went to meet them, and they always hugged me and cried, because it’s a release for them.”
Weiss was impressed but wants to see more patients treated and followed for at least five years. “A cure means that it lasts, and so a conservative clinician would not say it’s a cure,” he said. “But this promises to be a cure.”
Chen’s background in studying how DNA is naturally repaired in cells helped him quickly realize both the promise and problems of emerging gene editing technologies.
After finishing a PhD at the Chinese Academy of Sciences in 2009, Chen moved to the US for a postdoctoral fellowship at the NIH where he made a
surprising discovery
. When cells attempt to correct a single-strand break in DNA — the kind of damage that arises daily from the wear and tear of life — an enzyme called APOBEC can hijack the process and turn one letter of the genetic code into another.
That mutagenic process might contribute to aging, disease and possibly even evolution. In 2014, Chen moved back to China to start his own lab at ShanghaiTech University. As he continued to study APOBEC, another group of scientists in the US fused the enzyme to Cas9, the molecular scissors of CRISPR. David Liu’s lab at the Broad Institute used a dulled version of those scissors to nick a single strand of DNA at a precise spot, prompting the piggybacked APOBEC enzyme to swoop in and do its work.
Liu called the method
base editing
. It gave scientists a way to precisely fix or introduce genetic typos. It wasn’t perfect though. The enzyme would sometimes latch onto other strands of DNA totally independent of CRISPR. That posed a problem for turning the tool into a medicine.
“We want to really eliminate off-target mutations, because for a therapy, safety is a priority,” Chen said.
Back in Shanghai, his lab was devising a solution. Chen discovered a protein that naturally inhibited APOBEC. The lab tethered the enzyme and its inhibitor together to prevent the base editing tool from working even when it reaches its target site. Then it created a second molecular machine that would follow closely behind, break the tether, release the inhibitor and allow APOBEC to make its edit — but only when both systems are locked in place.
It was like two-factor authentication for gene editing. Chen christened the technology
transformer base editing
.
Chen co-founded Correctseq with three colleagues in 2020 to develop therapies based on the technology. The following year, the startup quietly raised close to $40 million in a Series A funding round led by Lilly Asia Ventures and Boyu Capital. Mou told Endpoints the company has now raised about $60 million total.
Although Mou is focused on treating patients in China first, she said that the company has filed patent applications across Asia, Africa, Europe and the US and is interested in eventually taking the company’s drugs global. “We want our technologies to benefit more patients,” she said.
Correctseq treated its first patient in October 2023. The first five patients have all been transfusion-free for over a year now. The company has since treated
at least 10 more
and is planning a
Phase 2 trial
that could enroll about 20 more people.
Data from the first five patients came a week after two papers appeared in
The New England Journal of Medicine
describing comparable studies sponsored by
Beam Therapeutics
and
Editas Medicine
, both based in Cambridge, MA. The three companies used different forms of CRISPR to achieve similar results: the elevation of fetal hemoglobin.
Fetal hemoglobin production normally shuts down in infancy due to a protein called BCL11A. Casgevy, the commercialized CRISPR therapy, effectively shuts down that repressor — a double-negative that allows blood cells to make fetal hemoglobin again.
Beam, Correctseq and Editas have taken a slightly different approach that alters the patch of DNA that the repressor protein binds to — the HBG1 and HBG2 promoters. The result, enhanced fetal hemoglobin production, is about the same, but allows BCL11A to carry on with its other roles in the cell.
The ability to produce fewer off-target edits is “an important advance,” said Vijay Sankaran, a physician and blood cell biologist at Boston Children’s Hospital whose research on BCL11A
helped lay the groundwork for Casgevy
. “[It] should provide additional opportunities to target the BCL11A axis in potentially a safer and more effective manner.”
Weiss cautioned that it’s too soon to know if the technical differences in the therapies will make a difference for patients. “Base editing has theoretical safety advantages. But we don’t know if they translate to real safety advantages,” he said. “And the only way to know which method for manipulating the genome is better is to follow these patients out for a long time.”
The patients did not appear to have any side effects related to the base editing treatment, although they all suffered from severe anemia, leukopenia, neutropenia and thrombocytopenia from the chemotherapy conditioning used to wipe out their bone marrow and make room for the engineered cells.
Most companies that are working on new treatments for the two blood diseases have pivoted to a so-called
in vivo
approach that would
edit the patient’s blood cells directly in their body
. If successful, such an infusion could eliminate complex laboratory work and the grueling need for chemotherapy preconditioning.
“It’s our future direction, and my lab is working on that,” Chen said.
Numerous other companies abandoned promising therapies for beta thalassemia and sickle cell disease after Casgevy was approved,
including Editas
, which has shifted its focus to
more common diseases
. But Mou said that Correctseq is committed to its CS-101 program and noted that there are more than 300,000 patients with beta thalassemia in China — three times more than the number with sickle cell disease in the US.
“We definitely want to bring this product to the market,” she said. “We’re expecting that by the time CS-101 enters the market, there will be a more systematic and scientific system to guide us to a more reasonable price.”
Weiss thinks there’s room for more beta thalassemia and sickle cell treatments. But he also believes technology is no longer the limiting factor for gene therapies, as evidenced by Editas’ withdrawal from the field.
“That they’re dead in the water reflects the bigger problem with gene therapy: that it’s not commercially viable,” Weiss said. “Our technology has surpassed our society’s ability to deliver it efficiently.”
If China is able to make gene therapies that are just as safe and effective as US medicines, but offer them at a lower price, it could shake up the system globally.
“I think in the end, we’re going to find that there are going to be many treatments that are going to be similar in their efficacy. It’s the whole package that matters,” Weiss said.
