Gene Therapy, DNA's Past, RNA's Future: The Golden Era


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. 

Imagine being able to eliminate the root cause of diseases by manipulating genes. Thanks to the transformative field of gene therapy, this prospect is no longer just a far-fetched idea but an exciting reality. Gene therapy made significant breakthroughs between 2000 and the 2010s, marking a golden era in medical history. These breakthroughs have opened up new possibilities and treatments for previously incurable genetic disorders, giving hope to millions of people around the world.


Gene Therapy’s Pioneering Milestones


Zinc finger nucleases were officially discovered in the 1990s but were studied in immense detail in the early 2000s. These engineered proteins have been researched for their ability to modify genetic material. Zinc finger nucleases can target and cut specific DNA sequences, allowing for gene insertion, deletion, or replacement. 


This breakthrough gave rise to the possibility of treating several illnesses, including cancer, HIV, and cystic fibrosis. Severe Combined Immunodeficiency Disorder (SCID) is caused by a genetic mutation on the X chromosome that fails to produce a protein essential for developing immune cells. However, this mutation can be corrected using Zinc Finger Nucleases, offering new hope for individuals suffering from SCID.


Retroviral vectors, which deliver a functional copy of a defective gene, were also developed in the late 1990s and explored further in the early 2000s. They are one of the most used vectors for gene therapies. However, clinical trials revealed unexpected adverse effects, leading to setbacks in their progress. 

A Major Setback


In 2000, twenty male patients were involved in gene therapy clinical trials conducted in the UK and France. Five of those twenty participants were diagnosed with leukemia. All the patients who were diagnosed with leukemia had been treated for an inherited immune system disorder known as X-linked severe combined immunodeficiency (SCID-X1).


The issue was that the viral vector used to deliver the therapeutic gene had activated an oncogene, leading to the development of leukemia in the patients. Specifically, the retroviral vector contained a potent enhancer in the long terminal repeat (LTR) region, inadvertently activating the oncogene. 


The leukemia cases in the SCID-X1 trials highlighted the importance of carefully designing gene therapy vectors to avoid unintended activation of oncogenes. This setback led to increased scrutiny and safety measures in gene therapy.


The Humane Genome Project 


The Human Genome Project, completed in 2001, marked a significant milestone in genetics by providing a comprehensive blueprint of human DNA. This endeavor changed the understanding of genetics and propelled gene therapy into a new age. The project facilitated gene therapy by identifying genes for various conditions and diseases, thus enabling the development of targeted treatments based on individual genetic makeup.


Moreover, the knowledge gained from the Human Genome Project facilitated the emergence of precision medicine. This type of medicine uses genome sequencing and data analysis to customize diagnosis and treatment based on an individual’s genetic makeup. This personalized approach to therapy enables more effective and tailored treatments that cater to each patient’s specific genetic profile.


The Biotech Boom of the Early 2000s


As one of the founders of Human Genome Sciences, I take pride in being part of a company that significantly contributed to gene therapy during the early 2000s. Human Genome Sciences built on the groundbreaking work of the Human Genome Project, focusing on using the human DNA sequence to develop protein and antibody drugs for treating diseases such as hepatitis C, lupus, anthrax, and cancer. Our work was focused on providing personalized treatments tailored to specific genetic mutations.


Other gene therapy companies, such as Genzyme Corporation, Sangamo Therapeutics, and Audentes Therapeutics, also emerged and made significant contributions to the field. For instance, Genzyme focused on developing treatments for rare genetic disorders. At the same time, Sangamo specialized in developing genomic therapies based on the zinc finger nuclease technology discussed previously. Audentes, on the other hand, focused on developing gene therapies for rare neuromuscular diseases that provided targeted genetic treatments for debilitating conditions. As a result of the work done by these companies, gene therapy moved toward its first global approval.


The First Approval of Gene Therapy


Gendicine, a groundbreaking gene therapy product, received regulatory approval in China in 2003. Developed by Shenzhen SiBiono GeneTech, it is a cutting-edge treatment for head and neck squamous cell carcinoma, which affects the lining of the throat and mouth. Unlike chemotherapy or radiation, which attack cancerous and healthy cells, Gendicine targets only the tumor cells, minimizing damage to healthy tissues.


Gendicine works by introducing a tumor-suppressing gene directly into the tumor cells. The gene p53 is a natural tumor suppressor that helps regulate cell growth and division. In cancer cells, the p53 gene is often damaged or mutated, allowing the cells to grow and divide uncontrollably. By introducing a healthy copy of the p53 gene into the cancer cells, Gendicine helps restore average cell growth and division, reducing the tumor size. Clinical trials that led to the approval of Gendicine showed promising results—patients who received the treatment experienced reduced tumor size and improved survival rates. 


The Discovery of TALENs


In 2005, a groundbreaking gene-editing technique called transcription activator-like effector nucleases (TALENs) was introduced. TALENs are considered advanced gene modification tools known for their safety and precision. They use a specially designed protein that recognizes and binds to specific DNA sequences, allowing accurate cutting and modification. TALENs are precise in targeting, making them a preferred choice in a wide range of research areas, including stem cell research, cancer therapy, and the development of new treatments for genetic diseases.


During clinical trials in the 2000s, TALENs were used to target genetic disorders such as cystic fibrosis and hemoglobinopathies. For cystic fibrosis treatment, TALENs were used to fix genetic mutations related to the disease. They were also studied to see if they could be combined with other factors to increase the efficiency of CFTR gene integration through homology-directed repair pathways (HDR). In the case of hemoglobinopathies, TALENs were researched as a possible treatment for conditions like sickle cell disease and thalassemia.


Continuing on the Trail


The Human Genome Project, Zinc Finger Nucleases, Retroviral Vectors, and the emergence of biotech companies such as Human Genome Sciences, Genzyme Corporation, Sangamo Therapeutics, and Audentes Therapeutics have all contributed immensely to the progress in gene therapies and regenerative medicine.


With the continued progress and increased safety measures in gene therapy, we have better prospects for developing personalized and effective treatments for genetic disorders. Gene therapy’s future looks bright as the human genome’s intricacies are unveiled. 

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