April 13, 2024

Gene therapy, DNA past, RNA future: a time of promise

This story is part of a series on the current evolution of 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 out by time to function normally again. I include a full spectrum of chemical, genetic, and protein-based medicines, cellular therapies, and biomechanical interventions that achieve this goal.

In this subseries, we focus specifically on gene therapies. We explore current treatments and examine advances aimed at transforming health care. Each article in this collection investigates a different aspect of gene therapy’s role in the broader narrative of Regenerative Medicine.

The history of gene therapy is full of ingenuity, imagination and exploration. The 1960s and 1980s, in particular, were a time of significant progress, marked by fundamental breakthroughs and discoveries. During this period, there was a better understanding of the nature of genes and their potential to cure disease.

Today, gene therapy is at the forefront of genetic research and the possibilities for its use are endless. With continued research and development, gene therapy can transform countless lives.

Development of gene therapy concepts

In the 1960s, the possibility of curing genetic diseases through the introduction of therapeutic DNA sequences was explored. This idea gained momentum after a discovery in 1961. This research demonstrated that messenger RNA, known as mRNA, is crucial in transcribing genetic information from DNA to protein factories within cells.

This discovery resulted from an exhaustive study of the T4 bacteriophage, a virus that infects bacteria. It turned out that the virus’s DNA was transcribed into mRNA, a template for synthesizing new viral particles. This mechanism of transcription and translation is today known as the central dogma of molecular biology.

Furthermore, in 1961, Lorraine Kraus successfully incorporated functional DNA into a mammalian cell. She genetically altered the hemoglobin of cells taken from the bone marrow of a patient with sickle cell anemia. This was done by incubating the patient’s cells with DNA extracted from a donor with normal hemoglobin in tissue culture. Shortly afterwards, these concepts were applied in practice.

Applying new gene therapy concepts

In 1972, two young sisters from West Germany were among the first individuals to receive a pioneering gene therapy treatment for a rare genetic disease called hyperargininemia. This hereditary condition is caused by a deficiency of the enzyme arginase, leading to the accumulation of arginine in the bloodstream. Any buildup of arginine can cause brain damage, epilepsy, and other neurological and muscle problems. Treatment was administered as a last resort to save the children’s lives.

Gene therapy attempted to address the missing enzyme in the sisters’ bodies by introducing a modified enzyme. Unfortunately, the therapy was unsuccessful and the sisters did not respond to treatment. However, this early form of gene therapy highlighted the potential of genetic intervention in treating inherited diseases. It paved the way for further investigation and the development of concepts proposed years earlier, although not everyone agreed with this approach full steam ahead.

Around this time, an influential paper was published on the potential of gene therapy for treating human genetic diseases. The authors suggested that DNA sequences could be incorporated into patients’ cells for an innovative treatment. However, they warned that scientific understanding of gene therapies was incomplete and needed to be addressed, making it a challenging and risky treatment option.

Genetic Engineering and Retroviruses

Soon after this attempt, the field of genetic engineering flourished and provided some new tools that could be applied to gene therapies. One of these new tools were retroviruses. These viruses were a much more efficient way of transferring genes.

Richard Mulligan, a researcher at the Massachusetts Institute of Technology, developed the first retroviral vector suitable for gene therapy. In 1983, collaborating with his colleagues, Mulligan genetically modified a mouse leukemia retrovirus. The retrovirus has been modified to provide the desired DNA without reproducing in humans. A selective marker, a DNA fragment from the bacterium Escherichia coli, was added to the new vector. This marker helps identify the number of genes a cell acquired during gene transfer. Mulligan and his colleagues have published work on these retroviruses, how to use them to introduce selectable genes into tissues, and how to transfer genes efficiently. These discoveries have allowed the field to rapidly progress with new trials and cases.

Building on Success

In the late 1980s, French Anderson led a groundbreaking experiment to treat patients with ADA-SCID, a serious genetic disorder that compromises the immune system. Anderson’s experiment involved inserting a working copy of the defective gene into the patient’s cells using a virus as a carrier. This technique marked the first successful clinical demonstration that gene therapy could be used to treat genetic diseases. Anderson’s pioneering work opened up new therapeutic possibilities for treating genetic diseases and made him the “father of gene therapy.”

After that came the publication of the results of the “first human gene therapy trial.” This was a significant milestone in gene therapy research. The assay described involved using a retrovirus to deliver a working copy of the missing or defective gene into the patient’s cells. This technique allowed the insertion of corrected genes into the patient’s cells, creating a new source of functional proteins that could combat the genetic disease. The trial demonstrated the feasibility of retroviral gene delivery in humans, paving the way for further progress in gene therapy research and new avenues for treating genetic diseases.

The success of these early experiments led to the explosive progression of gene therapy research.

A time of promise hits a snag

From 1960 to 1980, there was much research and development in gene therapy, a significant achievement in genetic medicine. During these two decades, notable advances in scientific understanding were made, such as decoding mRNA and carrying out the first human trials. This period marked a time of true promise.

The following decade was not so kind to gene therapy. In the 1990s, the field faced many challenges and setbacks that threatened to stifle progress. Despite these challenges, the spirit of innovation and improvement that defined the early years of gene therapy has never wavered, and we continue to build on its rich legacy.

To learn more about regenerative medicine, read more stories at www.williamhaseltine.com

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