The death of a six-year-old girl after receiving experimental gene editing therapy at a hospital in Shanghai was never publicly disclosed, and experts say that much greater caution should have been exercised before this first-in-human study, and that red flags during preclinical testing had not been adequately addressed, reports Medscape.
The child’s death has prompted an official investigation, while 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.
A month earlier, clinicians at the Children’s Hospital of Philadelphia and Penn Medicine in Philadelphia had successfully treated KJ 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 this year.
According to the investigation, the girl’s family had paid more than $800 000 towards the development of this treatment for their daughter, who 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 personalised gene editing treatment designed to correct a single DNA base mutation in neurons.
Unlike the treatment used for 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, like the Covid vaccine, might get.
The patient received an infusion on 24 March. She initially developed fever, an expected reaction after AAV administration, before showing signs of severe toxicity, including anuria, excessive thirst consistent with kidney injury, thrombocytopenia, and rapid clinical deterioration.
She was transferred to the ICU, but died a 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 concerns
Experts 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 Centre 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 non-human 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 Centre for Law and the Biosciences at Stanford University in 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.
Before publishing the study, Nature was unaware of any concerns related to the clinical trial.
Medscape article – First-in-Human Gene Editing Trial: What Went Wrong? (Open access)
See more from MedicalBrief archives:
Chinese gene-editing scientist aims to cure Alzheimer’s
Chinese declare that gene-editing scientist is breaking the law
Doubts and outrage over genetically edited babies claims