First-in-Human Gene Editing Trial: What Went Wrong?

The death of a 6-year-old girl after receiving experimental gene editing therapy at a hospital in Shanghai was not publicly disclosed, prompting an official investigation. A report published by Science, produced in collaboration with Retraction Watch and supported by the Science Fund for Investigative Reporting, has drawn comparisons with the 2018 scandal involving Chinese biophysicist He Jiankui, who secretly created the world’s first gene-edited babies.The girl’s death occurred just 1 month before, and clinicians at the Children’s Hospital of Philadelphia and Penn Medicine in Philadelphia successfully treated K.J. Muldoon, an infant with severe carbamoyl phosphate synthetase 1 deficiency, with patient-specific clustered regularly interspaced short palindromic repeats gene editing therapy. This breakthrough received worldwide attention.In contrast, the girl’s death at Xinhua Hospital, was never publicly reported, even though the research team led by neuroscientist Zilong Qiu, PhD, of the Songjiang Research Institute, Shanghai Jiao Tong University School of Medicine in Shanghai, China, published its preclinical findings in Nature earlier this year. The publication and available clinical records also omitted another notable detail. According to the investigation, the girl’s family contributed more than $800,000 to the development of this treatment.Fatal Experimental TreatmentThe girl carried a rare CHD3 gene variant associated with Snijders Blok-Campeau syndrome and had a global developmental delay. She was referred to Xinhua Hospital for personalized gene editing treatment designed to correct a single DNA base mutation in neurons.Unlike the treatment used for the infant, K.J. Muldoon, which delivered the base editor to the liver using lipid nanoparticles, Chinese researchers needed to target the girl’s brain. To accomplish this, they packaged genes encoding base-editing enzymes and guide RNA into adeno-associated viruses (AAVs). Although AAVs have long been used in gene therapy, they can trigger inflammatory reactions at the high doses required for effective treatment.Because only a small proportion of the viral vectors reached their target cells and produced base-editing components, treating enough brain cells required administering hundreds of billions of viral particles. That means many of the viruses will never reach the target, so the strategy is to deliver “hundreds of trillions of viruses — thousands of times more” than a person getting a virus-based vaccine, such as the COVID vaccine, might get.The patient received an infusion on March 24. She initially developed fever, an expected reaction following AAV administration. She subsequently experienced signs of severe toxicity, including anuria, excessive thirst consistent with kidney injury, thrombocytopenia, and rapid clinical deterioration.She was transferred to the ICU and died 1 week later. The hospital’s ethics committee concluded that death was “definitely related” to the experimental treatment and identified thrombotic microangiopathy as the cause.Safety ConcernsExperts interviewed by Science and Retraction Watch believed that the findings should have prompted greater caution before initiating a first-in-human study. Steven Gray of the University of Texas Southwestern Medical Center in Dallas, who develops viruses for gene therapy, said, “This shouldn’t have gone to trial.”According to this investigation, the warning signs identified during preclinical testing were not adequately addressed. Among the nonhuman primates that received the therapy, all four developed moderate-to-severe liver injury, and one also experienced kidney damage.The investigation also raised concerns regarding informed consent. According to the reports, the consent form did not explicitly state that death was a potential risk, despite the treatment representing the first human administration of the therapy.“Death should always be mentioned in a first-in-human trial,” said bioethicist Hank Greely, director of the Center for Law and the Biosciences at Stanford University in Stanford, California.According to the report, the lax oversight of this recent trial and the failure to publicly report the fatality “shows the gap between what is intended and what has been put in place,” said Joy Zhang, a sociologist at the University of Kent in Canterbury, England, who wrote about the pervasive culture of secrecy in Chinese scientific institutions.The investigation also found that the preclinical findings published in Nature did not mention either the participant’s death or certain signs of toxicity observed in animal studies. According to the reports, the girl’s family requested that the findings be retracted.According to this report, Qiu, Shanghai Jiao Tong University, and Xinhua Hospital have not responded to requests for comment from Science and Retraction Watch regarding the undisclosed death of a 6-year-old girl in an experimental gene editing trial. Before publishing the study, Nature was unaware of any concerns related to the clinical trial.This story was translated from Medscape’s French edition.