Gene Therapy, DNA's Past, RNA's Future: The Lost Years

(Posted on Thursday, April 4, 2024)

This story is part of a series on the current progression in Regenerative Medicine. In 1999, I defined regenerative medicine as the collection of interventions that restore tissues and organs damaged by disease, injured by trauma, or worn by time to normal function. I include a full spectrum of chemical, gene, and protein-based medicines, cell-based therapies, and biomechanical interventions that achieve that goal.

In this subseries, we focus specifically on gene therapies. We explore the current treatments and examine the advances poised to transform healthcare. Each article in this collection delves into a different aspect of gene therapy’s role within the larger narrative of Regenerative Medicine. 

The inception of gene therapies laid the groundwork for a dramatic shift in medicine. They mark the dawn of a new era in personalized healthcare. 

The 1990s were a crucible for gene therapy, with efforts around the globe pushing boundaries, driven by the audacious vision of curing diseases at their root—the genetic level. This decade saw clinical trials that delivered the first definitive evidence that gene therapy was more than just a science fiction fable. 

Milestones and Discoveries

In 1990, The National Institutes of Health performed one of the first gene therapy treatments. This treatment was given to two young girls. The two girls had a rare and life-threatening disorder called severe combined immunodeficiency (SCID), which was caused by a genetic mutation. SCID leads to a dysfunctional immune system, making patients vulnerable to infections and other health issues. The researchers at the NIH aimed to fix the underlying genetic cause of the girls’ SCID by using gene therapy. 

The treatment for SCID involved extracting blood cells from the patients, modifying them genetically, and then reintroducing the modified cells back into their bodies. Although it was not a complete cure, gene therapy had a significant positive impact on the girls’ health and quality of life. The treatment helped to alleviate some of the debilitating symptoms associated with the disease, strengthened their immune systems, and reduced their vulnerability to infections. This breakthrough was a turning point in gene therapy research and proved the safety and effectiveness of addressing genetic disorders in human patients.

Another milestone was achieved in gene therapy when 4-year-old Ashanthi de Silva became the first person to be successfully treated with this technique. Ashanthi, like the previous cases, was diagnosed with severe combined immunodeficiency (SCID), a condition that severely compromises the immune system.

 The treatment Ashanthi received involved introducing a functional copy of the adenosine deaminase gene into her body using a viral vector. Viral vectors are genetically engineered viruses that deliver therapeutic genes to target cells. This gene therapy treatment used the adeno-associated virus (AAV) as the viral vector.

In Ashanthi’s case, the viral vector transported a functional copy of the adenosine deaminase gene into her body. This allowed her body to produce the missing enzyme, restoring her immune system’s ability to fight infections.

A Fatal Setback for Gene Therapy

Despite the positive trajectory of gene therapy, a tragic setback occurred when 18-year-old Jesse Gelsinger died during a gene therapy trial for metabolic liver disease, shaking the field and prompting a re-evaluation of the safety protocols. 

In 1999, Gelsinger, who had a genetic liver disease called ornithine transcarbamylase deficiency, participated in a gene therapy trial at the University of Pennsylvania. The trial aimed to develop a treatment for infants with severe forms of the disease. Despite having a milder form of the disorder, Gelsinger volunteered for the trial and was given an injection of an adenoviral vector carrying a corrected gene.

Regrettably, he suffered from a severe immune reaction to the viral vector that was used in the gene therapy. This immune response set off a series of events that led to the failure of multiple organs, ultimately resulting in his untimely death just four days after receiving the injection.

The adverse immune reaction Gelsinger experienced highlights a critical challenge in gene therapy research. In his case, the immune response to the adenoviral vector caused an overwhelming inflammatory reaction within his body, leading to systemic complications and organ dysfunction. This severe reaction underscored the importance of carefully assessing and mitigating potential risks associated with viral vectors used in gene therapy.

Still, We Push Forward

The aftermath of Jesse Gelsinger’s death was significant. It resulted in a lawsuit, a government investigation, the suspension of gene therapy trials in the United States for a period, and the implementation of new regulatory processes for gene therapy trials. Gene therapy was still relatively new and uncharted territory. This lack of precedent and experience resulted in a trial-and-error approach that was often confronted with ethical concerns.

Despite the challenges, the 1990s were a decade of innovation and success stories that laid the groundwork for modern gene therapies. One breakthrough in the previous trials was the delivery of genes into the body using genetically engineered viruses called viral vectors that target specific cells for therapeutic gene delivery. Retroviruses and adeno-associated viruses were developed as vectors for efficient and safe gene delivery. 

Despite the challenges, the 1990s were a decade of innovation and success stories that laid the groundwork for modern gene therapies. One breakthrough in the previous trials was the delivery of genes into the body using genetically engineered viruses called viral vectors that target specific cells for therapeutic gene delivery. Retroviruses and adeno-associated viruses were developed as vectors for efficient and safe gene delivery. 

Retroviruses, for instance, integrate their genetic material into the host cell’s DNA, allowing the therapeutic gene to become a permanent part of the cell’s genome. Adeno-associated viruses, on the other hand, can exist in an episomal form within the cell, providing a more transient but effective means of gene delivery. These viral vectors are designed to facilitate targeted gene transfer without causing harm to the host.

A Legacy of the Past & The Promise of the Future

The gene therapies that have emerged over the past decades represent human ingenuity and perseverance. The 1990s were a defining period, marking the transition from theoretical postulation to real-world application. Understanding the context and the nuanced history of gene therapy during this time is crucial for appreciating the present state of the art and preparing for the future.

By revisiting this critical epoch in gene therapy’s development, stakeholders, researchers, and enthusiasts can gain an informed perspective on the field, its progress, and the milestones yet to be reached. The legacy of the 1990s gene therapy will be the treatments developed and the lessons learned, shaping the ethical and regulatory fabric that will uphold the gene therapies of tomorrow.

As we move forward, guided by the legacy of the past and the promise of the future, gene therapy remains a beacon of hope for the countless individuals who may one day benefit from its groundbreaking applications.

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