Gene Therapy, DNA's Past, RNA's Future: A Time Of Promise

(Posted on Tuesday, April 2, 2024)

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’s history is filled with ingenuity, imagination, and exploration. The 1960s through the 1980s, in particular, were a time of significant progress, marked by breakthroughs and fundamental discoveries. During this period, there was an improved understanding of the nature of genes and their potential for curing diseases.

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 disorders by introducing 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 bacteriophage T4, a virus that infects bacteria. The virus’s DNA was found to be transcribed into mRNA, a template for synthesizing new virus particles. This mechanism of transcription and translation is now known as the central dogma of molecular biology.

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

Applying Novel 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 disorder called hyperargininemia. This inherited condition is caused by a deficiency of the arginase enzyme, leading to arginine accumulation in the bloodstream. Any accumulation of arginine can cause brain damage, epilepsy, and other neurological and muscular problems. The treatment was given as a last resort to save the children’s lives.

The gene therapy attempted to address the missing enzyme in the sisters’ bodies by introducing a modified enzyme. Unfortunately, the therapy did not succeed, and the sisters did not respond to the treatment. However, this early form of gene therapy highlighted the potential of genetic intervention in treating inherited ailments. It paved the way for further investigation and development of the concepts proposed years before, though not everyone was on board with this full-steam-ahead approach. 

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

Genetic Engineering and Retroviruses

Hot on the heels of this attempt, the field of genetic engineering blossomed and provided some novel tools that could be applied to gene therapies. One of these novel tools was retroviruses. These viruses were a much more efficient way to transfer genes. 

Richard Mulligan, a Massachusetts Institute of Technology researcher, 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 deliver desired DNA without reproducing itself in humans. A selective marker, a DNA fragment from Escherichia coli bacteria, has been added to the new vector. This marker helps identify the number of genes that a cell has acquired during gene transfer. Mulligan and his colleagues published works on these retroviruses, how to use them to introduce selectable genes into tissues, and how to efficiently transfer genes. These discoveries allowed the field to progress rapidly with new trials and cases.

Building on Success

During the very late 1980s, French Anderson conducted a groundbreaking experiment to treat patients with ADA-SCID, a severe 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 disorders. Anderson’s pioneering work unlocked new therapeutic possibilities for treating genetic diseases and made him the “father of gene therapy.” 

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

These early experiments’ success led to gene therapy research’s explosive progression. 

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, remarkable strides in scientific understanding were made, such as decoding mRNA and conducting the first trials on humans. This period marked a time of real 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 never wavered, and we continue to build on its rich legacy.

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