A new wave of hope

This story is part of a series about current advances in regenerative medicine. In 1999, I defined regenerative medicine as the set of interventions that restore tissues and organs damaged by disease, injured by trauma, or worn down 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 sub-series we focus specifically on gene therapies. We explore current treatments and explore the advances that are poised to transform healthcare. Each article in this collection delves into a different aspect of gene therapy’s role within the larger story of regenerative medicine.

Gene therapy represents the frontier of hope in the fight against genetic disorders and promises to rewrite the rules for how we tackle some of the most persistent and challenging diseases known to man. Over the past decade, we have witnessed a transformation from speculative science to a reality where genetic disorders are treated not only in theory, but also in the lives of patients.

A new wave of gene therapy trials and approvals

Gene therapy has made significant progress in the 2010s, culminating in multiple clinical trial approvals for gene therapy products in 38 countries. The work done during these tests led to formal regulatory approval for the use of gene therapies in several countries, some of the most significant of these were from 2012 to 2017.

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

In 2017, three FDA approvals were a game changer for the medical industry. The first was Kymriaha new way to treat acute lymphocytic 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 delivering a standard copy of the RPE65 gene directly to the eye. Finally, the FDA has approved Yescartathe first CAR T-cell therapy, in 2017 for the treatment of 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 such as Zolgensma offer hope for people with genetic conditions that have until recently been difficult or impossible to treat.

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

The CRISPR revolution

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

Technological development has significantly reduced the barriers to entry for genetic research and therapy, making it more accessible and affordable. With the ability to tailor 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 untreatable diseases.

Every challenge is an open door

Although 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 overcome many of these challenges, with more to open. The biggest challenges in the field Complexity in delivering treatments, persistent safety issues and fearsome immune responses have been the problems.

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

The immune system may recognize AAVs as foreign particles and launch a full-scale attack against them, resulting in a reduced therapeutic effect or system-wide immune response. In some cases, this immune response is so severe that it has even led to death, as was the case in the untimely death of Terry Horgan, a 27-year-old man with Duchenne muscular dystrophy, after a CRISPR-based investigational 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 an early-stage safety trial. He received high-dose gene editing therapy tailored to his unique condition. This trial used an adeno-associated virus as a vector to introduce the CRISPR tool into his body.

In Horgan’s case, the viral vector caused an unexpected and severe immune response, which led to organ failure and ultimately his death. This incident has put the spotlight on the use of these vectors, prompting intense scrutiny by the medical community and reinforcing the discourse on the safety of gene therapy.

Horgan’s experience draws parallels to the 1999 case of Jesse Gelsinger, the first person publicly identified as having died during a gene therapy clinical trial. He appears both familiar and ominous. There are similarities in the unexpected immune responses elicited by gene therapy vectors, underlying the need for renewed vigilance in early trials. Yet the difference lies in the progress made in the twenty years between these tragedies, a period marked by leaps in genetic understanding and technological advances.

Charting a course for transformation

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

This is an opportune time for the medical community and others to delve into the enormous 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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