Jesse Gelsinger, 18, had a rare metabolic disorder called ornithine transcarbamylase deficiency syndrome, or OTCD, in which ammonia builds up to lethal levels in the blood. He managed the condition with a low-protein diet and a regimen of nearly 50 pills a day.
In 1999, Gelsinger volunteered to participate in a gene therapy trial with the hope of helping others with the same disease. However, a few days later, he became the first person to die as a result of a gene therapy experiment.
The potential OTCD treatment was to inject a genetically modified and weakened adenovirus vector into the patient’s liver, and to introduce the normal ornithine aminome thyltransferase gene (OTC gene) into the patient’s liver chromosomal DNA, to restore the liver’s ability to metabolize ammonia.
Gelsinger received this modified virus.
However, he had an intense inflammatory response and developed a dangerous blood-clotting disorder, followed by kidney, liver, and lung failure. Four days after receiving the shot, Gelsinger was declared brain dead.
Gelsinger’s family sued the University of Pennsylvania, which had developed the program.
The tragedy shocked the drug development community, and immediately cooled the research boom in gene therapy. The entire gene therapy industry began to crumble: investors withdrew their funds, startups went bankrupt, the heads of R&D projects were stripped of their titles, and gene therapy centers were shut down.
Gelsinger’s story is well known in the field of gene therapy. The tragedy brought gene therapy development to a near standstill for the next 18 years. Mainly because Gelsinger’s accidental death made many developers believe there were many unknown and uncontrollable serious risk factors in gene therapy, as if shooting in the darkness where the target cannot be seen.
More Deaths Caused by Gene Therapy
Some 18 years after Gelsinger’s death, a gene therapy for an eye illness was approved by the FDA. In 2017, Spark Therapeutics’ Luxturna, a treatment for a rare genetic retinal disease, was approved for people who have a mutated RPE65 gene. Luxturna uses a modified virus to deliver a healthy copy of the gene directly to a patient’s retinal cells through eye surgery. It only required local injection and had little effect on the body. That’s one of the reasons it could succeed on the market. This treatment re-spark interest in the field of gene therapy.
In 2019, the FDA approved Novartis’ Zolgensma (onasemnogene abeparvovec-xioi), a gene replacement therapy indicated for the treatment of spinal muscular atrophy in pediatric patients. Later that year, the company got in trouble for not informing the FDA and the European Medicines Agency (EMA) about toxic effects of the intravenous formulation of the drug observed in laboratory animals until seven months later. The company lost an accelerated assessment of the drug by the EMA over the data manipulation issue.
In 2019, in an animal trial of a gene therapy developed by Solid for the treatment of Duchenne muscular dystrophy, three monkeys and three piglets all suffered severe toxicity and eventually died. The company was later placed under a clinical research hold in 2019 after one of its human participants suffered an adverse reaction, though that hold was lifted in 2020.
In 2020, Astellas Pharma acknowledged that a fourth boy died in the troubled Phase I/II trial through which its Astellas Gene Therapies (formerly Audentes Therapeutics) has been evaluating its adeno-associated virus gene therapy candidate AT132 in patients with the muscular disease X-linked Myotubular Myopathy. The company had lowered the dose of the treatment after the first three deaths led to an FDA clinical hold on the trial.
What Is a Gene?
Genes (DNA) are the most delicate and complex structures in the human body. They exist in the nucleus of the human body’s cells to ensure the normal functioning of the structure and function of the human body; in addition, genes also determine characteristics such as height, gender, appearance, hair color, skin color, blood type, sex, etc.
Scientists have now found that humans have at least 20,000 to 23,000 genes. If the DNA in the 50 trillion cells of the human body is stretched and connected together, its length is equivalent to 16 times the distance from the earth to the sun. How can such a small nucleus fit such a length? The DNA twists further on top of the double helix, becoming supercoiled, like an old-fashioned telephone wire when twisted.
The outside of DNA is coated with proteins to form chromosomes. There are 23 pairs of chromosomes in each somatic cell of a normal person, and a chromosome contains hundreds to thousands of genes, that is, each chromosome is a highly coiled and compressed shape of genes.
The discovery of DNA is one of the most important and well-known scientific stories of the 20th century. In 1953, American biochemist James Dewey Watson and British physicist Francis Crick published in the journal Nature that they discovered the DNA of two strands of nucleotides, paired as a double helix form, encoding the genetic information of all living things.
Since then, genetic testing technology has flourished, ushering in a new era in biomedicine. For example, the somewhat-controversial PCR nucleic acid test we used in the COVID-19 epidemic is a genetic test.
Unfortunately, the gene therapies that have followed have traveled a bumpy road marked by adverse reactions and even death.
Gene Therapy: A Pandora’s Box
The concept of gene therapy is very attractive: The target gene is introduced into the human body to correct an incorrect gene and cure a disease. However, the structure of genes isn’t as simple as that of proteins. Genes are a very central and important substance in the nucleus. Gene therapies target the problem gene that needs to be corrected but can damage other genes when it is off the target.
The consequence of serious off-targets, several cases of death, is a warning.
The human genetic sequence is very important. It’s perhaps the most critical aspect of human physiology. It can’t be changed casually. Genes control all individual organisms and all important physiological processes such as protein synthesis, cell division, reproduction, and so on. Genes can reproduce themselves precisely and faithfully, ensuring the stability of a life’s characteristics.
Modern medicine is still far from able to anticipate the full spectrum of biochemical consequences from pharmaceutical treatments. Acetaminophen was around for more than 100 years before we discovered that pregnant mothers who took the drug were more likely to have children with behavioral issues. That inability to foresee side effects is potentially magnified when it comes to genetic alterations.
The 2020 Nobel Prize in Chemistry has been awarded to two scientists for their contributions to the discovery of a gene-editing method called CRISPR-Cas9. This is a technique that allows precise modification of nucleotide fragments and has been described as “God’s scalpel.”
However, this “God’s scalpel” can’t be used casually.
Chinese scientist He Jiankui tried to use gene-editing technology to open “Pandora’s Box,” causing an uproar in the scientific community around the world. He Jiankui rashly edited a baby’s genes in the name of helping the offspring of AIDS patients. His unethical and immoral acts got him imprisoned and cost him his career.
As biotechnology advances, there is an ever-greater need to rational rather than blindly advancing in the name of profits and technological superiority, even if it’s done under the guise of medical treatment. While we all want a better life, we need to be more cautious when it comes to the development of certain technologies that touch the microscopic level of matter in the human body. We have no idea what could happen as these genetic changes are inherited or how they will interact or interfere with other biological processes. Who knows what we will discover 100 years from now.
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