Death after 8 days of gene therapy, NEJM released the most detailed cause of death based on autopsy reports

Tech 2023-10-14 19:14:24 Source: Network

In October 2022, a 27 year old patient with Duchenne Muscular Dystrophy (DMD) named Terry Horgan unfortunately passed away after receiving CRISPR gene editing therapy delivered by adeno-associated virus type 9 (AAV9) vector. The exact cause of death was not disclosed at the time, but it raised concerns and doubts about the prospects of CRISPR gene editing therapy

In October 2022, a 27 year old patient with Duchenne Muscular Dystrophy (DMD) named Terry Horgan unfortunately passed away after receiving CRISPR gene editing therapy delivered by adeno-associated virus type 9 (AAV9) vector. The exact cause of death was not disclosed at the time, but it raised concerns and doubts about the prospects of CRISPR gene editing therapy.

On September 28, 2023 local time, the New England Journal of Medicine (NEJM) published an article online titled "Death after high-dose rAAV9 gene therapy in patients with Duchenne muscular dystrophy." This is a study on Terry's autopsy report, detailing the cause of Terry's death and suggesting that he may have died from acute respiratory distress syndrome (ARDS) caused by severe congenital immune response.

It is reported that gene editing is an emerging and relatively accurate genetic engineering technology that can modify specific target genes in the genome of organisms. CRISPR/Cas9 is the third generation gene editing technology, following zinc finger endonucleases (ZFNs) and transcriptional activator like effector nucleases (TALEN). Gene editing is one of the means of gene therapy.

Tailored medicine

DMD is an X-linked recessive genetic disease with a clear preference for male onset. Patients typically start onset at the age of 3-5 and may die from respiratory and heart failure by the age of 20-30. DMD is a rare disease, and its incidence rate is about 10% in 100000 male infants. The pathogenic factor is due to a defect in the DMD gene, which leads to abnormal function of dystrophin on the muscle cell membrane, causing damage to muscle cells, progressive necrosis, atrophy, and clinical symptoms and signs of muscle weakness.

Terry was diagnosed with DMD at the age of 5 and a half, and by the age of 18, he had lost his ability to walk independently. DMD has always been a part of my life, "Terry described his relationship with DMD in an article on the official website of the non-profit organization Cure Rare Disease on December 14, 2020.

Terry grew up in a small town and didn't have many interesting things to do. Playing Star Wars with his brother was one of them. I found out that I really like the technology and computers that make daily life easier, "he said. At the age of 8, he made his first computer himself, and a few years later, he made several more. Later, Terry entered Cornell University in the United States to study information science, and after graduation, he stayed at Cornell University to work as an administrative assistant and also as an IT staff member of the "Cure Rare Diseases" organization.

Terry Horgan. Image source: CureRareRelease official website

Since childhood, Terry has been traveling to major hospitals in New York, Philadelphia, and Washington, but most doctors are at a loss. As he grew older, he no longer had the opportunity to participate in clinical trials, to the point where he "gave up hope". The work done by the 'Cure Rare Diseases' organization has reignited hope for me, and soon, I will receive help, "Terry said.

The founder of the organization 'Cure Rare Diseases' is Terry's brother, Richard Horgan. In 2017, as a student at Harvard Business School, he founded this organization to develop targeted therapies for his brother and help rare patients like him.

The team of the "Cure Rare Diseases" organization includes researchers and doctors from institutions such as Yale University, Heidelberg University, and Charles River Laboratories International in the United States. In 2019, they tailored a therapy called CRD-TMH-001 for Terry, which is a new version of CRISPR technology that can reactivate backup genes in Terry cells: delivering Cas9 and transcription activating protein VP64 from Staphylococcus aureus with rAAV9 to regulate the expression of non muscle full length dystrophin subtype (Dp427c).

In August 2022, "Cure Rare Diseases" announced on its official website that the US Food and Drug Administration (FDA) had approved this one participant human clinical trial. It is considered to mark multiple medical milestones: the first personalized CRISPR therapy in history, the first clinical trial of gene editing therapy for DMD, and the first clinical trial of the new version of CRISPR.

Richard said in a press release, "This is just the beginning of the efforts of the 'Cure Rare Diseases' organization to develop more treatments for rare and ultra rare diseases. We look forward to using this method to continue breaking down the barriers in drug development for patients who currently need effective treatment

Terry Horgan (left) and his brother Richard Horgan (right)

Death due to innate immune response to high-dose rAAV

The progress of the experiment is not as optimistic as expected. On the second day after injection therapy, Terry experienced ventricular premature beats, followed by a decrease in platelet count and a continuous increase in the levels of BNP (brain natriuretic peptide) and proBNP (precursor of brain natriuretic peptide), markers of cardiac dysfunction. On the 3rd to 4th day after treatment, Terry experienced asymptomatic hypercapnia and respiratory acidosis, and the condition improved after symptomatic treatment.

On the fifth day after receiving gene therapy, Terry's heart function began to deteriorate, and doctors speculated that he had myocarditis. On the 6th day, Terry developed acute respiratory distress, and a chest X-ray showed acute respiratory distress syndrome (ARDS) and left ventricular systolic dysfunction (LVEF). During this period, doctors attempted to alleviate the condition by increasing the dose of glucocorticoids, using ecuzumab, tocuzumab, and anabolin. During his cardiopulmonary arrest, the doctor performed extracorporeal membrane oxygenation (ECMO) on him.

On the 8th day, Terry died of multiple organ failure and severe hypoxic ischemic nerve damage.

The autopsy results showed that Terry had severe diffuse alveolar injury, with minimal transgenic expression in the liver, and no evidence of AAV9 antibodies or effector T cell responses in the organs. The research team pointed out that these findings suggest that in patients with advanced DMD, high-dose rAAV can cause a strong innate immune response, leading to acute respiratory distress syndrome (ARDS).

The research team believes that Terry developed cytokine mediated capillary leakage syndrome, characterized by pericardial effusion on day 5 and ARDS on day 6, leading to worsening of the existing right ventricular heart failure. Unlike some other DMD patients who participated in rAAV trials, Terry did not develop thrombotic microvascular lesions and did not produce adaptive humoral or cell-mediated immune responses to AAV capsids or transgenic products. Although thrombocytopenia may indicate complement activation in Terry's body, there is no complement deposition in the lungs and heart, indicating that complement mediated thrombotic microvascular disease is not a cause of death.

ARDS related to AAV gene therapy is not common, and other patients who received the same dose of rAAV9 vector therapy did not experience this toxic reaction, indicating that host factors and inherent characteristics of the vector caused an unexpected increase in the lung vector genome level, leading to Terry's death. The research team pointed out that Terry's viral vector genome load is relatively high, possibly due to his lower lean muscle mass. Compared to patients in the same labeled dose study, Terry received a relatively higher vector dose per muscle nucleus.

The research team concluded that Terry, who is 27 years old, is already in the late stage of DMD, which may limit his physiological reserve and reduce his ability to survive under cardiopulmonary stress associated with acute toxicity reactions to gene therapy.

On April 26, 2023, Richard said in a blog post: "Terry is in the final stages of his illness, his time is running out, and he is well aware of the real possibility of his own death. This experiment is his only opportunity to end the disease he has fought for throughout his life. Although the results are devastating for everyone, the driving force behind the development of rare disease science continues

It is reported that since 2020, the FDA has reported 6 deaths from gene therapy, but relevant companies have not provided detailed reports. Terry is the most detailed case of death disclosed so far. According to the official account of "NEJM Medical Frontier", the patient's family issued a statement saying: "By providing knowledge in areas that we know little about at present, we hope that one day we can help other patients receive safe and effective treatment. Regardless of the results, the transparency of clinical trials paves the way for cross team learning and sharing of key knowledge, thus promoting medical innovation."

References:

one https://www.cureraredisease.org/blog-posts/terry-horgans-career-with-duchenne

two https://www.cureraredisease.org/blog-posts/preliminary-findings-from-the-crd-tmh-001-clinical-trial

three https://mp.weixin.qq.com/s/p2DLMqh8Z3T-5Wt9b0mfqQ

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