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Results from the first human clinical trial of an experimental gene-editing therapy for Duchenne muscular dystrophy (DMD) have shown that the treatment edited some of its intended genes but had limited efficacy and triggered a devastating immune response that killed one participant, a boy in China.1 The findings highlight the urgent need to establish safe doses for this type of experimental therapy.
The trial attracted attention on August 5, when Shanghai-based HuidaGene announced that one participant, a young boy, had died about a year earlier. Researchers criticized the company for taking so long to disclose the death, an event that also focused attention on China’s rapidly developing clinical-trial sector.
On August 27, HuidaGene said it wanted to “establish the clinical facts and conduct a comprehensive investigation” before communicating with the wider public. The company said that a manuscript describing the boy’s death and post-mortem findings had been submitted to a journal in January and was now published in Cell.
The boy was one of four children who received the experimental DMD treatment. DMD is a progressive and ultimately fatal genetic disease that primarily affects boys, causing difficulty walking and gradual muscle weakness. It results from mutations in the DMD gene, which is needed to produce dystrophin, a protein that strengthens muscle fibres.
The therapy used an adeno-associated virus (AAV) to deliver a base editor — a type of CRISPR gene-editing technology — into the muscles, with the aim of correcting the mutations. The boy who died and another participant received high doses of AAV; two others were given 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 because of low blood oxygen levels, 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 amounts of AAV to reach muscle cells throughout the body, but this increases the risk of severe immune reactions, including fatal reactions 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,” Woodcock said.
Limits of animal testing
Before 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-lived than those observed in the children. The authors acknowledge that the study involved 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, co-author Hui Yang, a co-founder of HuidaGene, said that testing more animals does not necessarily guarantee that unusual reactions in humans will be predicted, particularly because immune responses vary 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 first reviewed safety data from other high-dose recipients and from the two children who received lower doses. The doses were calculated according to the children’s body weight.
The researchers said that the boy had a higher body-mass index (BMI) than the other children 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, which was the intended target of the treatment. Yang said the boy’s muscles might have been exposed to a higher dose, but it remains unclear whether that caused the severe immune response. The authors suggest that weight-based dosing might not be appropriate.
Rethinking dose selection
Yang said the research team had tried to reduce the risk of severe immune reactions by giving the children immunosuppressants, testing both doses in animals and spacing out treatment between participants while conducting safety reviews. The measures were insufficient in light of the boy’s death, he said.
“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 must be developed. “The most important lesson is that severe systemic immunotoxicity after AAV administration remains difficult to predict.”
Next-generation AAVs that can penetrate muscle more effectively might produce the same editing effects at lower doses, Woodcock said. Alternatively, he added, researchers could consider delivery systems other than AAV.
Source: www.nature.com