An understanding of viral vectors begins with an understanding of viruses and the way they behave once inside the host. Once a virus enters a host’s body, it travels along the surfaces of cells until its proteins begin to bind with receptors on the cells. The virus and the cells then fuse, allowing the DNA or RNA inside the virus to enter the cells, where it begins to reproduce. Unless the immune system can check the action of the virus, it will infect the host and spread.
One metaphor for a viral vector is a letter sent in an envelope from one person to another. When snail mail ruled, one person would write a letter (the genetic material), stick it in an envelope (the viral capsid), and mail it to someone who would open the envelope (bind with receptors) and read the letter (enter the cells).
Another way to envision it is to think back to the days of floppy disks. The floppy disk acted as the virus, with the data on the disk acting as the genetic material. One person prepped the disk and gave it to another who put the disk (viral capsid) into the drive and uploaded the data (genetic material).
The delivery of information (genetic material) was made frighteningly simple and very effective through the use of the envelope or disk (viral vector). Today, the use of viral vectors is integral to our ability to cure genetic diseases that never had so much as an effective treatment in the past.
Vectors & Viruses
A viral vector is a virus that is used to deliver genetic material to a host. It is the equivalent of an envelope or floppy disk. There are four types of viral vectors (adeno-associated viral, adenoviral, lentiviral, retroviral). Each one can deliver the desired genetic material. The specific type of viral vector chosen will be the one that works best with the cells involved.
Most recently, Lyfgenia has used a lentiviral vector to treat patients aged twelve or older with sickle cell disease and a history of vaso-occlusive events. A lentivirus was chosen as the viral vector (delivery method) because a lentiviral vector is a retrovirus and can deliver genes to dividing and nondividing cells.
For sickle cell disease, the lentiviral vector enters the nondividing cell and modifies the HSPCs that are crucial for producing red blood cells. The result: the patient’s body now produces healthy red blood cells on its own. Another type of viral vector might have been chosen, but the lentiviral vector achieves the desired result.
What Piqued My Interest?
When I started writing about gene therapy for several clients in the biotech industry, I was thrown into the world of viral vectors in all their varieties. Ditto for gene editing, clinical trials, and rare diseases. It was my job to make the science behind the different aspects of the various treatments, products, and processes understandable to people without a biotech background.
As I spoke to people in the industry, it struck me that all of the news was uniformly encouraging. The consensus was that we were on the cusp of breakthroughs and technologies that would save lives and change the world. While I saw many of these clients achieve significant advances, it nagged at me that there was such assurance with things that had never been tried outside the lab. I’d previously written a lot about advances in other branches of science and hadn’t seen anything that went so smoothly. I decided I needed to know more about the history of gene therapy to give a balanced picture of the work in progress – which led me to Jesse Gelsinger.
Who Is Jesse Gelsinger?
Jesse Gelsinger is the first person to die due to participation in gene therapy research. He was born with ornithine transcarbamoylase (OTC) deficiency, a rare metabolic disorder that causes one’s body to retain ammonia. Usually, a person with OTC dies before the age of five, but because Jesse had a partial deficiency, he was able to control his ammonia levels with a low-protein diet and drugs. This made him an ideal candidate for the treatment developed by Dr. James Watson, director of the Institute for Human Gene Therapy at the University of Pennsylvania. Jesse was eighteen at the time and eager not only to be well himself but also to be part of something that could help other, younger people.
On Sept. 13, 1999, Gelsinger was given an infusion of corrective OTC gene encased in a dose of attenuated cold virus, a recombinant adenoviral vector; it was injected into his hepatic artery. Gelsinger experienced a severe immune reaction to the vector — the gene’s delivery vehicle — and died 4 days after receiving the injection. Many issues about informed consent and rigor in clinical trial procedures were brought to light. The bottom line was that Gelsinger died from an immune reaction to the viral vector itself. Human gene therapy trials in the U.S. came to an immediate halt, and all trials today are designed with Jesse Gelsinger’s experience firmly in mind.
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