July 15, 2024

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Single-Person Clinical Trial: Spends 16 Million and Dies 8 Days Later

Single-Person Clinical Trial: Spends 16 Million and Dies 8 Days Later – Latest Post-Mortem Report Published by NEJM



Single-Person Clinical Trial: Spends 16 Million and Dies 8 Days Later – Latest Post-Mortem Report Published by NEJM

On September 28, 2023, the New England Journal of Medicine (NEJM) published a “death report” detailing the tragic case of a 27-year-old man who suffered cardiac arrest on the 6th day of participating in a clinical trial and tragically passed away on the 8th day.

Behind this cutting-edge scientific paper lies a five-year effort by a brother to develop a unique “new drug” for his terminally ill sibling. To save his younger brother suffering from a rare disease, he gathered leading global medical experts, secured substantial investments, and conducted a clinical trial with only one participant.

 

Single-Person Clinical Trial: Spends 16 Million and Dies 8 Days Later - Latest Post-Mortem Report Published by NEJM

 

 

In 2018, Richard Horgan, a graduate student at Harvard Business School, stumbled upon a news story about a 6-year-old girl with a life-threatening rare neurological disease. Traditional treatments were proving ineffective, and her life hung in the balance. With relentless efforts from her family, medical experts from top children’s hospitals developed a “customized” treatment drug for the girl in just 10 months, significantly improving her condition. This miraculous event garnered widespread media coverage and was even published in NEJM as a research paper.

While this heartwarming story might seem like an ordinary human interest piece to most, it held profound significance for Richard – his younger brother, Terry Horgan, was also a rare disease patient.

At the age of 5, Terry was diagnosed with Duchenne muscular dystrophy (DMD), a rare genetic muscle disorder with a prevalence of 1 in 3300 in infants and young children, leading to severe disability. Typically, DMD manifests around the ages of 2-3, and by the age of 12-13, patients are often confined to wheelchairs, with an average lifespan of less than 20 years.

DMD results from the inactivation of the dystrophin gene, a protein that protects muscle fiber cell membranes, prevents muscle fatigue after exercise, and blocks pathological calcium ion influx into muscle fibers. However, DMD patients severely lack this protein, leading to severe muscle degeneration, structural disruption, and loss of function in muscle tissue.

While corticosteroids can partially slow down muscle deterioration and disease progression in DMD patients, most experience rapid deterioration. Moreover, corticosteroids come with side effects like diabetes, obesity, and emotional disturbances, significantly affecting patients’ quality of life. Often, patients must rely on conservative treatments like wheelchairs and tracheostomy.

Terry was no exception; he had been taking deflazacort, a potent corticosteroid used to treat DMD, since his diagnosis. However, at the age of 18, he still lost the ability to walk, and his deteriorating cardiopulmonary function constantly threatened his life.

But Terry had something different – a brother who was willing to give everything to help him.

 

 


Seeking a Solution through Genetic Sequencing

As early as 2016, the anti-sense oligonucleotide drug Eteplirsen for DMD had received accelerated approval from the U.S. Food and Drug Administration (FDA). Other experimental treatments directly targeting the causes of DMD were also entering clinical research phases.

However, Terry had no opportunity to benefit from these groundbreaking treatments due to his age, as he was not within the recruitment criteria for these clinical trials.

But Richard didn’t give up. Even before he graduated, he had established a non-profit organization called Cure Rare Disease, focused on saving Terry’s life.

When he saw the miraculous story of the 6-year-old girl being cured, Richard had only one thought: Could his brother also benefit from such a magical “customized treatment”?

Richard initially contacted the doctor who had designed the “customized therapy” for the 6-year-old girl. However, the doctor informed him that the “customized therapy” was an anti-sense oligonucleotide drug that theoretically couldn’t be used for Terry’s case.

Undeterred, Richard reached out to a genetic expert at Yale University, who conducted comprehensive genetic sequencing of Terry’s muscle cells.

A few weeks later, disappointing news arrived from the sequencing laboratory: Terry’s DMD pathogenic mutation involved a deletion of the anti-dystrophin protein promoter and exon 1, making him unsuitable for all currently available treatments.

But there was a glimmer of hope – this mutation could potentially be addressed using the latest gene editing technology, CRISPR.

Richard waited for this sentence. When the sequencing results came back, he had assembled a team of experts from numerous top research institutions specializing in genetic disease treatment. Most of them were volunteering for Cure Rare Disease.

Raising Millions and Crafting a Tailored Treatment Plan

The team proposed a solution to Richard that was similar to the “customized treatment” for the 6-year-old rare disease girl, but with a twist. They transitioned from anti-sense oligonucleotides to CRISPR gene editing.

CRISPR is a natural nucleic acid cleavage tool derived from bacteria, recognized as an efficient gene “scissors.” Furthermore, some modified CRISPR systems can not only cut genes but also control gene expression in a targeted manner – known as “CRISPR activation.”

Richard’s team chose the “CRISPR activation” approach.

Further research revealed that within Terry’s muscle cells, the synthesized anti-dystrophin protein could be categorized into three types: muscular (Dp427m), cortical (Dp427c), and Purkinje (Dp427p1). Of these, only Dp427m had a severe defect, while the other two were intact. Some data indicated that Dp427c might perform similarly to the unaffected muscular type anti-dystrophin protein.

 


Could Dp427c replace Dp427m?

Based on these findings, the team decided to take a daring step and use the latest “CRISPR activation” technology. They employed a common gene therapy vector, the recombinant adeno-associated virus (rAAV) serotype 9, carrying a special RNA segment.

After injecting rAAV into the body, the virus began infecting various cells, including skeletal muscle cells, and the specific RNA segment in the virus would “target” the Dp427c promoter location, activating this protein that was otherwise scarcely expressed in muscle cells.

In this way, a large quantity of functional Dp427c was synthesized to replace the defective Dp427m, thereby improving muscle development and survival.

Why is this called “customized treatment”? This approach required sequencing the patient’s pathogenic genes and creating drugs tailored to the test results. In other words, the drugs developed for Terry’s extremely rare genetic mutation could not be used for other DMD patients.

This marked the first time CRISPR technology had been introduced into customized treatment for rare diseases.

The plan was nearly complete, but the next question was about funding.

Although the top medical experts involved were volunteering for Richard’s non-profit organization, it didn’t mean that developing a new treatment was without costs. According to the team’s estimates, the cost of this “customized” CRISPR therapy for a single patient usually ranged between 2 to 3 million dollars.

To secure the treatment for his brother, Richard embarked on a fundraising campaign, promising that Cure Rare Disease would remain a non-profit organization, and a portion of the funds raised would go toward developing treatments for other rare diseases. Ultimately,

he managed to raise 2.3 million dollars.

 


Single-Person Clinical Trial

In August 2022, the FDA granted Cure Rare Disease’s CRISPR gene therapy “Investigational New Drug” status, which meant that Terry could officially receive treatment, but only in the form of a clinical trial.

On October 4, 2022, Terry received an injection of rAAV carrying CRISPR tools customized for him, and the infusion appeared to be successful.

It seemed like everything was moving in a positive direction. However, on the second day after the injection, Terry exhibited signs of ventricular premature beats and reduced platelet count. Simultaneously, levels of B-type natriuretic peptide, transaminases, and creatine kinase gradually increased. On the fifth day after the injection, Terry experienced typical symptoms of myocarditis, and on the sixth day, he developed acute respiratory distress syndrome and heart failure.

On the eighth day after the injection, doctors pronounced Terry’s death.

Subsequently, Richard, through Cure Rare Disease, announced Terry’s passing and expressed his willingness to allow his brother’s autopsy to investigate the ultimate cause of death.

On September 28, 2023, NEJM published Terry’s “death report.” The autopsy results indicated that rAAV’s entry into Terry’s body triggered a strong cellular immune response, leading to the release of a large number of inflammatory factors, ultimately resulting in Terry’s death from rAAV-related capillary leak syndrome.

In reality, rAAV, used as a viral vector for gene therapy, has long been the subject of safety controversies. Because adenovirus infections are too common in the natural world (one of the pathogens causing the common cold is an adenovirus), many people have antibodies against AAV or cross-reacting antibodies. This means that performing gene therapy on patients with pre-existing anti-AAV antibodies carries a risk of loss of efficacy and even severe immune adverse reactions.

The report suggested that Terry experienced more severe congenital immune reactions compared to other patients receiving similar or higher doses of rAAV. Additionally, Terry received a dosage calculated based on his body weight, but due to muscle atrophy, his muscle mass was lower, potentially resulting in a relatively higher drug dose.

Terry’s story shook researchers in the field of gene therapy and once again raised alarm bells about safety issues. However, it must be acknowledged that CRISPR gene therapy remains the last ray of hope for many patients with rare and terminal illnesses.

As the Cure Rare Disease website states: “Our story is not over; there are thousands of Terrys waiting for a chance to fight back.”

 

 

 

Single-Person Clinical Trial: Spends 16 Million and Dies 8 Days Later – Latest Post-Mortem Report Published by NEJM

References:
[1]https://www.statnews.com/2018/10/22/a-tailor-made-therapy-may-have-halted-a-rare-disease/
[2]Kim J, Hu C, Moufawad El Achkar C, et al. Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. N Engl J Med. 2019;381(17):1644-1652. doi: 10.1056/NEJMoa1813279
[3]U.S. Food and Drug Administration. FDA Approves First Gene Therapy for Treatment of Certain Patients with Duchenne Muscular Dystrophy. https://libyw.ucas.ac.cn/https/JLxYOF7vHLognBx5pv7oBzUKl6PAE3q/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy
[4]Ervasti JM, Ohlendieck K, Kahl SD, et al. Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Nature. 1990;345(6273):315-9. doi: 10.1038/345315a0
[5]https://giving.broadinstitute.org/muscle-detectives
[6]Mali P, Aach J, Stranges PB, et al. CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nat Biotechnol. 2013;31(9):833-8. doi: 10.1038/nbt.2675
[7]Qi LS, Larson MH, Gilbert LA, et al. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell. 2013;152(5):1173-83. doi: 10.1016/j.cell.2013.02.022
[8]Cohen N, Muntoni F. Multiple pathogenetic mechanisms in X linked dilated cardiomyopathy. Heart. 2004;90(8):835-41. doi: 10.1136/hrt.2003.023390
[9]https://cen.acs.org/business/Custom-CRISPR-therapies-closer-be-closer-than-you-think/97/web/2019/10
[10]https://www.forbes.com/profile/richard-horgan/?sh=4b7c31464cee
[11]Lek A, Wong B, Keeler A, et al. Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne’s Muscular Dystrophy. N Engl J Med. 2023;389(13):1203-1210. doi: 10.1056/NEJMoa2307798
[12]Lek A, Atas E, Hesterlee SE, et al. Meeting Report: 2022 Muscular Dystrophy Association Summit on ‘Safety and Challenges in Gene Transfer Therapy.’ J Neuromuscul Dis. 2023;10(3):327–36.

 

(source:internet, reference only)


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