Gene Therapy, DNA's Past, RNA's Future: A New Wave Of Hope

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. 

Gene therapy represents the frontier of hope in combating genetic disorders, promising to rewrite the rulebook on how we address some of the most persistent and challenging diseases known to humankind. Over the last ten years, we have witnessed a transformation from speculative science to a reality where genetic disorders are treated not just in theory but in patients’ lives. 


A New Wave of Gene Therapy Trials and Approvals

Gene therapy made significant strides throughout the 2010s, culminating in multiple regulatory trial approvals for gene therapy products across 38 countries. The work done in these trials led to formal regulatory approval for the use of gene therapies in a variety of countries, some of the most significant of these were from 2012 to 2017.


In 2012, Glybera became the first-ever gene therapy approved in the European Union. This therapy treats lipoprotein lipase deficiency by compensating for the missing or ineffective enzyme. Similarly, Strimvelis, approved in 2016, has been used to treat ADA-SCID. This rare genetic disorder severely compromises the immune system in children. This therapy corrects the gene responsible for the disease.


In 2017, three FDA approvals were game-changers for the medical field. The first was Kymriah, a new way of treating acute lymphoblastic leukemia by genetically modifying the patient’s T-cells to attack cancer cells. The second approval was for Luxturna, which treats a genetic form of blindness by directly providing a standard copy of the RPE65 gene to the eye. Lastly, the FDA approved Yescarta, the first CAR T-cell therapy, in 2017 to treat large B-cell lymphoma.


Zolgensma, approved in 2019, is a gene therapy for spinal muscular atrophy (SMA), which causes muscle wasting. This therapy introduces a new, functional copy of the human SMN gene into a patient’s motor neuron cells, providing a one-time treatment for this lifelong disease. Gene therapies like Zolgensma offer hope for people who have genetic disorders that have been difficult or impossible to treat until recently.


While these approvals were happening, CRISPR-Cas9 became synonymous with a new era in gene editing.


The CRISPR Revolution


During the mid-2010s, the genetic research and therapy field experienced a seismic shift with the introduction of the CRISPR-Cas9 system. This tool has dramatically changed gene editing, allowing for precise and efficient modification of genes in living organisms. Unlike traditional gene-editing methods, the CRISPR system enables accurate targeting of specific genes with unprecedented speed and precision.


Technology development has significantly reduced the barriers to entry for genetic research and therapy, making it more accessible and affordable. With the capability to customize treatments with unprecedented specificity, new therapies can be tested and developed with greater accuracy and efficiency. This has paved the way for more effective genetic research and treatment, potentially leading to cures for previously thought untreatable diseases.


Every Challenge is an Open Door


While gene therapy has seen notable successes and approvals, there have also been setbacks in recent years. In science, every challenge is an open door, and gene therapy has walked through many of these, with more to open. The biggest challenges in the field have been the complexities in delivering treatments, persistent safety concerns, and daunting immune responses. 


Adeno-associated viruses (AAVs) are one of the most commonly used gene therapy vectors. However, high doses of AAVs can cause potential side effects, such as inflammation and liver damage. While these side effects are usually manageable, they can lead to more severe complications.


The immune system may recognize AAVs as foreign particles and launch a full attack against them, resulting in a reduced therapeutic effect or a system-wide immune response. In some cases, this immune response is so severe it has even resulted in death, such was the case in the untimely passing of Terry Horgan, a 27-year-old man with Duchenne muscular dystrophy, following an investigational CRISPR-based treatment.


A Death in a Gene Therapy Trial


Terry Horgan’s story is both brave and tragic. In October 2022, he was the only participant in an early-stage safety trial. He was given a high dosage of gene-editing therapy tailored to his unique condition. This trial used an adeno-associated virus as the vector to introduce the CRISPR tool into his body.


In Horgan’s case, the viral vector precipitated an unexpected and severe immune response, leading to organ failure and, ultimately, his death. This incident has thrust the use of these vectors into the limelight, prompting intense scrutiny from the medical community and invigorating the discourse on gene therapy safety.


Drawing parallels with the 1999 case of Jesse Gelsinger, the first person publicly identified to have died in a clinical trial for gene therapy, Horgan’s experience emerges both familiar and foreboding. Similarities can be seen in the unexpected immune reactions elicited by gene therapy vectors, underlying the need for revamped vigilance in early trials. Yet, the divergence lies in the progress made over the two decades separating these tragedies, a period marked by leaps in genetic understanding and technological advances. 


Charting a Course for Transformation


Gene therapy has transitioned from the margins to the epicenter of medical science. The innovations of the early 21st century are now yielding concrete treatments for diseases once considered incurable. Conditions such as inherited blindness, spinal muscular atrophy, and various forms of blood cancer now benefit from FDA-approved gene therapies.


Now is an opportune moment for the medical community and others to delve into the vast potential of gene therapy. After all, we are not just the products of our genes but the architects of our genetic health.

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© William A. Haseltine, PhD. All Rights Reserved.