A technique for precisely rewriting the genetic code directly in the body has slashed “bad” cholesterol levels—possibly for life—in three people prone to dangerously high levels of the artery-clogging fat. The feat relied on a blood infusion of a so-called base editor, designed to disable a liver protein, PCSK9, that regulates cholesterol. https://www.science.org/content/article/base-editing-a-new-form-of-gene-therapy-sharply-lowers-bad-cholesterol?
“It is a breakthrough to have shown in humans that in vivo base editing works efficiently in the liver,” says Gerald Schwank, a gene-editing researcher at the University of Zurich who wasn’t involved in the clinical trial, sponsored by the biotech Verve Therapeutics.
Reported on 12 November at the American Heart Association meeting in Philadelphia, the results mark the first time this CRISPR variant has been infused into people to treat a disease. The success is also a proof of principle for using gene editing for a common health problem like high cholesterol rather than a rare disease.
Some clinicians worry, however, that the treatment’s cost could be exorbitant—some approved gene therapies are priced in the millions—and prevent it from reaching many who could be helped. And the short- and long-term safety of base editing remains unclear. Two of the trial’s 10 participants, nearly all born with various gene mutations resulting in high cholesterol levels, had a heart attack or cardiac arrest, in one case possibly related to the treatment. “It worked. But we won’t know for years how safe this is,” says cardiologist Karol Watson of the University of California, Los Angeles.
Traditional gene therapy, which shuttles a therapeutic gene into the body, is becoming more common. CRISPR, too, has chalked up clinical victories. U.S. regulators are poised to approve the gene editor for the blood disorder sickle cell disease, and in small studies, an infusion of CRISPR has been used to shut off a liver protein to treat two genetic diseases.
But CRISPR works by severing both strands of DNA and letting cells themselves imperfectly repair the break. This can result in potentially harmful DNA rearrangements that could flip on a cancer gene. Base editors, a twist on CRISPR invented in 2016 by David Liu’s lab at Harvard University and the Broad Institute, are more precise because they nick just one DNA strand and swap out pairs of the four DNA bases.
In base editing’s first clinical test, researchers last year engineered donated immune cells in a dish to target a teenager’s leukaemia, then infused them to put her disease into remission so she could get a stem cell transplant. In the Verve trial, however, the editing took place inside the body, specifically in the liver, a relatively easy organ to target because it sucks up foreign particles.
The trial subjects have a disease called heterozygous familial hypercholesterolemia (FH), usually caused by a defect in one copy of a gene that encodes a cell surface protein needed by the liver to clear the blood of low-density lipoproteins (LDLs), the “bad” cholesterol. People with FH must take daily statins and other drugs to control their cholesterol levels, but many struggle to keep to the lifelong regimen. Without any treatment, many would suffer heart attacks or strokes by age 50.
However, two patients who already had severely blocked arteries had heart problems after the base editor infusion. One died from cardiac arrest, a case that Verve says a safety board found was unrelated to the Verve infusion. The other person survived a heart attack, but it came just a day after treatment and could have been related. The man, however, had chest pains prior to the trial that he didn’t mention. “Had he reported the symptoms to the investigators, he would not have been enrolled,” Verve CEO Sek Kathiresan says.
Verve plans to test its treatment in a total of about 40 FH patients.
The company hasn’t detailed how much it would charge for the treatment, but Kathiresan has said it will be more affordable than some of the gene therapies with million-dollar price tags.
Less than a year after betting $400 million cash on Hutchmed’s fruquintinib, Japanese pharma major Takeda has secured US FDA approval for the VEGF receptor kinase inhibitor in previously treated metastatic colorectal cancer. https://endpts.com/fda-approves-takedas-fruzaqla-for-metastatic-colorectal-cancer/?
Fruzaqla, as the therapy is called, is the first new “chemotherapy-free treatment option approved for patients in the US regardless of biomarker status in more than a decade,” Teresa Bitetti, president of the global oncology business unit at Takeda, said in a statement.
Takeda expects Fruzaqla to be available for prescribing through certain specialty pharmacies or distributors in about three business days following approval, a spokesperson told Endpoints News. The company is yet to disclose the price.
The drug, which is given as oral capsules, is designed to block all three VEGF receptor kinases. In two Phase III trials, it improved both overall survival and progression-free survival for colorectal cancer patients when added to best supportive care. The FDA granted it priority review, and handed the decision almost three weeks before the PDUFA deadline.
Takeda estimates that around 153,000 new cases of colorectal cancer will be diagnosed in 2023, with 70% of patients expected to experience metastatic disease. They tend to face limited options, in part because of the “highly heterogeneous” nature of the disease, the company added.
The drug is now under review by the EMA, and in September it was filed with Japanese regulators.
It’s flu season. At state health departments and academic medical centres, and at the US Centers for Disease Control and Prevention (CDC), epidemiologists are intently watching two sets of data: the number of flu cases and the number of Americans taking flu shots.
So far, the balance between them looks good. In most of the US, the occurrence of illnesses that look like the flu—ones that cause a fever and sore throat but haven’t been confirmed by a lab test—is low. Out of the viral samples taken from sick people and sent to labs for confirmation, only 2 percent have turned out to be flu. And at this point, more than 142 million Americans have taken the shot, using up most of the 156 to 170 million that manufacturers predicted they would deliver this fall. https://www.wired.com/story/the-long-quest-for-a-universal-flu-vaccine-finally-takes-its-first-steps/?
But there’s one more piece of data that will let analysts know how this flu season will unroll: whether the vaccine actually works. Last year, for instance, the shot was 54 percent effective. The year before, it prevented illness in only 36 percent of those who took it. Since 2009, the vaccine’s effectiveness has been as high as 60 percent and as low as 19 percent.
This variability speaks to the biggest challenge of fighting the flu: Its restless, endless mutation. Every year, vaccine makers in each hemisphere build a new formula based on whatever is circulating. But they can never be confident that the strain they pick in a lab as that year’s target will look the same after six more months in the wild—or whether something entirely new will pull ahead of the pack.
So every summer, as the northern hemisphere’s flu season approaches, public health people fretfully anticipate the data. Will manufacturers deliver the shot in time? Will enough people take it? How effective will it be? And every year, as they watch the numbers settle, at least some of them long for something that could short-circuit the waiting: a vaccine that works no matter how the virus changes and that could be produced far enough in advance to prevent a fall vaccination crunch.
That goal is known as a universal influenza vaccine. For immunologists, it has been an end-of-the-rainbow phantasm for more than a decade. Recently, though, the pursuit of a better flu shot has notched promising achievements. A vaccine candidate developed by the US National Institutes of Health has entered its second Phase 1 clinical trial (which tests whether a compound is safe for humans). Other candidates developed by Moderna, based on the mRNA technology that allowed rapid development of Covid vaccines, are in Phase 1/2 and also Phase 3 trials (which test for efficacy). And novel constructs developed by teams at Mount Sinai School of Medicine and the University of Pennsylvania have delivered promising results in mice. They are all feats of engineering and imagination, deploying the latest virological tools against an ancient foe.
To understand why improving the vaccine is so crucial, it’s important to consider the flu’s public health burden. Just in the US, the CDC estimates that it sickens up to 41 million people each year and kills anywhere from 12,000 to 52,000 depending on the severity of the season. Globally, there are up to 1 billion cases and 650,000 deaths a year, according to the World Health Organization. And that’s with current flu shots controlling the disease’s impact—though public health planners acknowledge that the vaccines are largely a rich-country phenomenon and are much less available in emerging economies.
Drugmakers create fresh flu vaccine formulas each year, matching them to the circulating flu strains detected by a worldwide surveillance network led by the WHO. But getting from strain detection to a finished formula isn’t quick. “If we are making a vaccine for 2023, we have to follow a [strain] recommendation made in February 2023,” says Peter Palese, a professor of microbiology at the Icahn School of Medicine at Mount Sinai and one of the deans of universal flu vaccine research. “By the time the vaccine is made, manufactured by industry, and distributed to CVS [pharmacies] and paediatricians, there is a gap of six to eight months, which is used by the virus to change.”
Lalita Panicker is Consulting Editor, Views and Editor, Insight, Hindustan Times, New Delhi