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A History of Gene Therapy: Exploring Lessons Learned In Light of New Approvals

On May 24, the U.S. Food and Drug Administration (FDA) approved onasemnogene abeparvovec-xioi (Zolgensma), the first gene therapy for pediatric patients with the most severe and common subtype of spinal muscular atrophy (SMA). Characterized by the progressive loss of motor neurons due to a mutation in the survival motor neuron 1 (SMN1) gene, this rare disease is currently the leading genetic cause of infant mortality. Zolgensma has demonstrated significant improvement in treated patients’ ability to reach developmental motor milestones, such as head control and the ability to sit without support, and it signifies a major step forward for this patient population and for the therapeutic field as a whole.

In order for us to continue progressing in this rapidly evolving field, it is important that we understand the key principles and events in gene therapy’s history that have led us to where we are today. By innovating new techniques that sidestep known challenges, we can continue developing life-saving therapies. In this blog, I will outline the major landmarks in the history of gene therapies and how they have contributed to where the field is now and where it is headed in the future.

First & Failed Attempts

Initially suggested by Friedmann and Roblin as a potential treatment for genetic diseases in 1972, the first successful experimental gene therapy treatment in the USA occurred in 1990 in a four-year-old patient named Ashanti DeSilva. DeSilva, who suffered from a type of severe combined immunodeficiency (SCID) called adenosine deaminase (ADA) deficiency, was cured with a retroviral vector containing the functional ADA gene.

However, gene therapy experienced a series of setbacks in the early 90s in which serious adverse events and even the tragic deaths of patients occurred. Jesse Gelsinger was the first patient publicly identified to have died from gene therapy treatment in a clinical trial in 1999. Within four days after administration receiving a recombinant adenoviral vector that contained a corrective ornithine transcarbamylase (OTC) gene, Gelsinger died due to a lethal immune response. His death became a catalyst for new research.

Principles & Initial Approvals

Much of the inherent challenges can be pointed back to the complexity of gene therapy compounds. Gene therapies can use a variety of vector types—such as viruses, nanoparticles, and even naked DNA—to deliver nucleic acid (or cargo), which can either be translated into a functional protein that is missing or absent in the patient, or inhibit the over or ectopic expression of a gene. Having seen both the dangers and potential of gene therapies with the first treated patients, investigators dove into intensive research to improve vector safety in an attempt to give gene therapy a second chance by minimizing the potential of adverse events.

Between 2003 and 2009, researchers modified gamma-retroviral and lentiviral vectors by reducing the risk of activating host genes adjacent to their integration site in an effort to increase their safety. This research led to the generation of self-inactivating (SIN) vectors containing insulator sequences, which prevent vectors from activating oncogenes from their host cells. SIN vectors also proved to be less genotoxic since they carry non-viral physiological promoters that drive the expression of the therapeutic gene in the right cell type, at the right time, and at the right dose. In addition, they demonstrated reductions in the potential for recombination, and thereby, the risk of generating replication competent, pathogenic variants.

With these improvements in vector safety, gene therapy received its first worldwide approval from health agencies in 2003 in China for recombinant human p53 adenovirus (Gendicine) for the treatment of head and neck squamous cell carcinoma (HNSCC). In 2012 alipogene tiparvovec (Glybera) was approved in Europe for a rare blood disorder, and in 2017 voretigene neparvovec-rzyl (Luxturna) for Leber congenital amaurosis, an inherited form of vision loss, was approved in the USA.

Recent Approvals & Future Steps

These approvals paved the way for the next generation of life-saving gene therapies. In 2018, the FDA approved the first-ever RNAi therapeutic, patisiran (ONPATTRO), for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis, a rare form of a genetic polyneuropathy. This approval represented the first of a new class of drugs based on small interfering ribonucleic acids (siRNA), which work by silencing the gene involved in causing the disease. As the first approved treatment for this disease in the USA, gene therapy once again showed its potential for treating genetically-based diseases that can be devastating if left untreated.

Circling back to this past week, the FDA’s approval of Zolgensma for the treatment of infantile-onset SMA only further demonstrates how rapidly the field is progressing. By using an adeno-associated virus vector to deliver a fully functional copy of human SMN gene into the target motor neuron cells, Zolgensma is one example of how precisely gene therapies can work and effectively save lives. This targeted ability of gene therapy harbors tremendous potential for treating high-need patient populations like those affected by rare diseases, since 80% of rare diseases are genetically based.

With all of this momentum behind it, gene therapy is only expected to continue progressing. The FDA expects to approve 10-20 gene and cell therapies every year from 2025 on, which as they have stated signifies “a turning point in the development of these technologies and their application to human health.” As this exciting therapeutic field continues to evolve and offer first-ever treatments, the BioAgilytix team looks forward to helping write the next chapters of gene therapy history, which we anticipate to be rich in therapeutic breakthroughs and lives saved.

As the number of gene therapy products in development continues to increase, BioAgilytix continues to keep pace with the evolving and shifting bioanalytical services needed to support their development and validation. Contact our scientists today to learn how we can supply the bioanalysis your gene therapy project needs.

Illustrated DNA Research Molecule