A Revolution Delayed: Viral Vectors in Gene Therapy
With the world in thrall to a deadly viral pandemic, it can be hard to picture a world where viruses are thought of as our saviours. Yet, mere decades ago, stories of viruses swooping in to eradicate diseases and revolutionise medicine lit up the world. For years it was thought that viral gene therapy was the revolution that never was. It may appear to some that their initial promise has since faded: leaving behind nothing but a bitter taste in our mouths. But the long, tumultuous history of viral gene therapy has taught us lessons that may yet light our way towards a safer future.
It started in 1972 with a speculative paper in the journal Science that suggested the possibility of using viruses as ‘vectors’, or, put simply, vehicles, to deliver DNA fragments of our choice into human cells. Viruses, as it had become apparent, had mastered the black art of gene editing far before we did. Forged in the fires of natural selection, they are experts at enslaving our cells to suit their purposes. Some argued that we could bend them to our will; that we could simply add fresh bits of DNA to their genomes, and they would do all the heavy lifting of getting it into our cells to do our bidding.
And so it proved. Close to two decades of toil later, in 1990, a four-year-old girl with a debilitating defect in her immune system was successfully treated with a retroviral vector, a gene therapy method that helped her body produce a crucial enzyme. It sparked a decade of feverish excitement over gene therapy, with new clinical trials being approved left and right, and headlines prophesying a new age of medicine. We were on the precipice of greatness.
And then disaster struck.
His name was Jesse Gelsinger. He suffered from a rare metabolic disorder that researchers tried to remedy with a gene on an adenoviral vector. Tragically, the virus triggered a severe immune response, killing him in days.
That tragedy, coupled with a 2008 case involving four patients contracting leukemia following retroviral gene therapy, dealt a seemingly mortal blow to the field of gene therapy.
Slowly but surely, however, the scientific community learned from its failures. It soon came to light that adenoviral vectors elicited particularly strong immune responses, explaining Jesse’s death. Retroviral vectors, such as the ones involved in the 2008 study, are associated with a phenomenon called ‘insertional mutagenesis’. Retroviruses insert their genomes into random locations in our chromosomes, and some of them, by chance, insert themselves into or around some of our genes, including, potentially, anti-cancer safeguards called tumour suppressors, causing mutations and paving the way for a tumour to take root.
Biologists have found workarounds to these issues by developing new vectors, based on different viruses. The vectors that dominate the field of gene therapy today are based on adeno-associated viruses (AAVs). They’re non-replicating, non-pathogenic viruses that our immune system tends to ignore. They can also infect a wide variety of cells, and AAV-delivered DNA persists in cells for a long time, making them more suited to long-term use. They represent a significant improvement over adenoviruses, but they come with their fair share of flaws. For instance, much like retroviral vectors, the use of AAV vectors is often associated with chromosomal integration, bringing with it the risk of insertional mutagenesis (although this risk appears to be far lower than with retroviruses). Perhaps more importantly, they are prohibitively small. They can only take in upto 5,000 bases of DNA, barely enough for a single gene, or two, at most. While that’s enough to be useful in certain contexts, scientists prefer a greater degree of flexibility.
Enter the herpes simplex virus (HSV-1, to be specific). The causative agent of oral herpes has attracted quite a lot of interest as a potential vector backbone. It has a much bigger trunk, with a capacity of close to 50,000 bases, it’s infamous for its ability to sneak past our immune system undetected, and, crucially, the DNA it delivers into cells forms what’s known as an ‘episome’; a stable, circularised DNA molecule that doesn’t get into our chromosomes, greatly reducing the risks of insertional mutagenesis. Its propensity to cause disease is an obvious point of concern, but that’s being dealt with as well, with engineers working to strip out the parts of it associated with disease phenotypes.
To be sure, several kinks remain to be worked out. Precious few human gene therapeutics have received the regulatory green light anywhere in the world, and there is certainly work to be done with regard to safety and efficiency. But, with the lessons we’ve learned, and with the rise of gene editing techniques like the much-heralded CRISPR-Cas system, there might just be light at the end of the tunnel.
