Gene therapy setback again: Two children die after receiving experimental therapy

Two letters sent to patient groups by Audentes Therapeutics on June 23 showed that two children with rare neuromuscular disease died after receiving clinical trials for high-dose gene therapy, according to pharmaceutical media STAT. The gene therapy, called AT132, is designed to treat X-chromosome chain myocardyopathy, a deadly disease caused by a single genetic mutation.

Gene therapy setback again: Two children die after receiving experimental therapy


A total of 17 children with a rare neuromuscular disease were reported to have received AT132 gene therapy from Audentes Therapeutics, one of whom died of septicaemia on 6 May after receiving high-dose treatment (3 x 1014 vg/kg, or 3 x 1014 genome copies/kg of weight). Two other patients who were also given high-dose drugs subsequently experienced serious side effects, one of whom died on 23 June. The patient developed sexual liver dysfunction after treatment, traditional treatment was ineffective, and soon the condition worsened, eventually dying of bacterial infection and sepsis.

This is reminiscent of one of the earliest and most famous deaths in the field of gene therapy: in 1999, Jesse Gelsinger, an 18-year-old boy, died after a clinical trial of urea cycle disorder after receiving a trial for adenovirus gene therapy. At that time, adenoviruses were used as vectors to insert genes into the patient’s cells to replace the parts that were lost or dysfunctiond, causing disease. But the immune response triggered by the toxicity of adenoviruses themselves overloaded Jesse’s immune system and died of multiple organ failure, an accident that sent the public into a panic over gene therapy and brought the entire gene therapy industry to a standstill.

Gene therapy did not re-emerge until the more secure carrier, adeno-related virus AAVs, was discovered. AAVs are safer than adenoviruses, and the newly discovered AAV8, AAV9 are 10-100 times more powerful than adenoviruses. It is reported that about 42 companies and nearly 100 drug development projects use AAVs vectors for gene therapy. The carrier used by Audentes Therapeutics in this fatal accident is AAV8, which previously performed well in treating younger neuromuscular disease patients.

Natalie Holles, chief executive of Audentes Therapeutics, said three of the 17 patients with serious side effects were older and heavier. Because the dose of treatment was based on weight, which meant they received a higher viral load, and they all had a history of liver disease, but of the six patients who received low-dose treatment (1 x 1014 vg/kg), none had serious liver problems. Gene therapy for neuromuscular diseases is known to require a particularly high dose of AAVs, which can only allow enough viral vectors to penetrate the blood-brain barrier to reach the nervous system. The high dose used by Audentes is one of the largest doses tested in gene therapy.

Halls promised a thorough investigation into both cases. But she also said it should not be too early to draw conclusions about the safety of gene therapy.

James Wilson, a pioneer in gene therapy and one of the aDVs developers, expressed concern about the high-dose vectors used in treatments several years ago. In February 2018, Wilson published a paper showing that AAV can trigger severe toxic reactions in monkeys and pigs at high doses, with one experimental monkey having to be euthanized for liver failure, and he called on researchers to conduct more genetic testing. “I’m concerned that the field is moving too fast to make people less cautious and could make Jesse ▪ Gail Singer happen again,” Wilson’s co-author, Gao Guangping, a professor at the University of Massachusetts School of Medicine, said in a 2019 interview with Chemical and Engineering News.

Some experts urged caution in the case before more information emerges. “It’s too early to say exactly what this death is,” said Katherine High, co-founder of Spark Therapeutics and a visiting professor at Rockefeller University. She referred to a 2019 death in which patients died in a gene therapy trial for rheumatoid arthritis, but the cause appeared to be the result of an infection caused by arthritis drugs, not a carrier of gene therapy. That’s one of the reasons I think it’s wrong to theoretically deduce without seeing the data. Hay said.

“We don’t know much about the biology of this treatment in delivering AAVs to the human body,” said Glenn Pierce, vice president of medicine at the World Hemophilia Federation and a consultant to several gene therapy companies. This unfortunate event may be a wake-up call for basic research to support clinical development, as the adage for gene therapy is increasing. “

Audentes was acquired by Japan’s Astellas Pharma in December 2019 for $3 billion. AT132 had intended to submit a treatment plan this year, expected to be approved by the FDA by the end of the year, but the program was suspended after the patient’s death.