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Results from the first human clinical trial of an experimental gene-editing therapy for Duchenne muscular dystrophy (DMD) show that the treatment edited some of its intended genetic targets, but had limited efficacy and triggered a devastating immune reaction that killed one participant.1 The findings highlight the urgent need to establish safer doses for this type of treatment, which was developed by HuidaGene, a biotechnology company based in Shanghai, China.
The trial drew attention on August 5, when HuidaGene announced that one participant, a young boy, had died about a year earlier. Researchers criticized the company for waiting so long to disclose the death. On August 27, HuidaGene said it had wanted to “establish the clinical facts and conduct a comprehensive investigation” before informing the wider public. The company said a manuscript describing the boy’s death and post-mortem findings had been submitted to a journal in January and is now published in Cell in January 2019.
A fatal immune reaction
The boy was one of four children who received the experimental DMD treatment. DMD is a progressive and ultimately fatal genetic disorder that primarily affects boys, causing difficulty walking and gradually worsening muscle weakness. It results from mutations in the DMD gene, which is needed to produce dystrophin, a protein that helps strengthen muscle fibres.
The therapy used an adeno-associated virus (AAV) to deliver a base editor, a type of CRISPR gene-editing technology, into muscle cells in an attempt to correct the mutations. The boy who died and one other participant received high doses of AAV, while two boys received lower doses.
According to the authors, the boy developed sudden, severe abdominal pain within 24 hours of treatment, followed by a fever that responded only partially to treatment. His condition then deteriorated rapidly. His skin became discoloured as oxygen levels in his blood fell, and he developed a slow, irregular heartbeat. His heart eventually stopped, and doctors were unable to revive him. An autopsy concluded that he had died from treatment-related acute respiratory distress syndrome.
Ian Woodcock, a paediatric neurologist and researcher at the Murdoch Children’s Research Institute in Melbourne, Australia, said the boy’s rapid decline suggested a reaction to the dose he received. Gene therapy generally requires large quantities of AAV to reach muscle cells throughout the body, but higher doses increase the risk of severe immune reactions, including death. Similar reactions have been reported in this and other DMD gene-therapy trials.2,3 “Even though AAV doesn’t cause disease in humans, this amount of foreign invasion actually triggers the immune system,” he said.
Limits of animal testing
Before beginning the human trial, the researchers conducted a safety study in cynomolgus monkeys. They observed no adverse effects at either the high or low dose. However, the monkeys’ immune responses were weaker and shorter-lasting than those observed in humans. The authors acknowledge that the study included only four animals and therefore could not detect rare effects such as the severe immune reaction that killed the boy.
Asked whether more animals should have been tested, Hui Yang, a co-founder of HuidaGene and a co-author of the study, said that testing more animals does not guarantee that unusual reactions in humans will be predicted, particularly because immune responses differ between species.
The boy who died was the second participant to receive the high dose. The authors said the trial’s safety review committee had examined safety data from the first high-dose recipient and the two lower-dose recipients before approving his treatment. The doses were calculated according to the boys’ body weights.
The researchers said the boy had a higher body-mass index (BMI) and therefore received a higher dose than the other participant in the high-dose group. A higher BMI does not necessarily indicate that he had more muscle tissue, which was the target of the treatment. Yang said the boy’s muscles might have been exposed to more of the therapy than those of the other participants, but it remains unclear whether this caused the severe immune reaction. The authors suggest that dosing based solely on body weight might not be appropriate.
Seeking safer delivery methods
Yang said the research team attempted to reduce the risk of severe immune reactions by giving the boys immunosuppressive drugs, testing both doses in animals and spacing out treatment between participants so that safety data could be reviewed. However, he said those precautions were insufficient in light of the boy’s death.
“Therefore, the assumptions underlying dose selection, the role of body composition, and the predictive value of preclinical studies need to be reconsidered,” Yang said. He added that stronger independent safety monitoring and methods for reducing the effective dose are needed. “The most important lesson is that severe systemic immunotoxicity after AAV administration remains difficult to predict.”
Next-generation AAVs that penetrate muscle more effectively could produce the same gene-editing effects at lower doses, Woodcock said. Researchers could also consider delivery systems other than AAV, he added.
Source: www.nature.com
