SLIGHTLY over a decade ago, being diagnosed with a human immunodeficiency virus (HIV) infection was a death sentence awaiting its time.
After years of research into understanding how HIV replicates itself and causes disease have resulted in practices to prevent its spread as well as drugs that can prevent the infection from turning into the disease we know as AIDS — Acquired Immunodeficiency Syndrome.
Even so, these drugs are not believed to be a cure, but merely a means of keeping HIV in check and preventing the onset and progression to AIDS. Make no mistake — HIV is still a lethal killer.
Recently, the New England Journal of Medicine published an article reporting that HIV had been repurposed as a delivery vehicle for gene therapy to treat cerebral adrenoleukodystrophy (ALD).
What does that even mean? Let us start from the beginning. What is gene therapy in the first place? But why would we need therapeutic genes and how does it work? The total genetic make-up of every living organism is called a genome and is made up of a chemical called DNA. The genome can be further divided into segments called genes — these are basically the instruction sets that are used by our cells to produce specific molecules such as proteins.
For genetic diseases, there are errors in these instructions that can result in the product molecule not being synthesised, or being produced with flaws that makeit dysfunctional.
If the patient were to receive the correct gene to compensate or override the flaw, this would in theory, rectify the problem. The concept of treating genetic diseases in such a way was proposed as early as 1972 and is known as gene therapy. But how can the problem gene be corrected in practice? In other words, how can the functional gene be delivered to the genome as a repair or replacement geneto treat such diseases?
As an example, I will use thalassemia, a disease where the haemoglobin proteins that carry oxygen in the red blood cells are not able to form properly because of a defect in the gene called beta-globin.
To rectify the problem, a copy of the beta-globin gene is inserted into a virus. These therapeutic gene carrying viruses are then mixed with a type of cells called stem cells from the patient. Stem cells are the body’s cells that have not yet become specific cell types like those for blood or skin. Once the viruses have delivered their load into these cells, it is hoped that the cells can then multiply and evolve into cells that have the correct gene. But you might ask, why use a virus?
Viruses are not quite alive in the way we understand other living organisms to be — they are not able to self sustain and reproduce. In order to reproduce or replicate, they hijack the cellular system of their infected host. They do this by integrating their genomes (DNA) into the host’s genome and forcing the host cells to make more viruses. The virus is thus a natural vehicle for delivering externally sourced DNA into a cell.Due to this capability, scientists had figured out a way to use viruses as a means of DNA delivery. HIV belongs to a class of viruses called lentiviruses and as we know, they are able to invade human cells. This makes HIV an ideal vehicle to be used for transporting and integrating the DNA it is carrying into a human cell, such as what would be required in gene therapy. (The use of the term DNA as the genome for lentiviruses is not scientifically accurate but will suffice for this discussion.)
You might argue that HIV is a dangerous killer virus that can result in AIDS and the eventual death of the human host. However, in this case, the virus has been disabled and “reprogrammed” to deliver the therapeutic gene that will in turn correct the genetic defect.
One analogy is to imagine a missile containing a nuclear warhead; the missile itself is simply the delivery vehicle for the warhead. If the nuclear warhead were to be replaced with cloud-seeding chemicals, the missile could then be used to deliver those chemicals to bring potential relief to drought stricken regions, thus changing its ultimate application from a destructive one to one that benefits humans. This is similar to how scientists have used the AIDS-causing virus.
Over the years, several trials for gene therapy have been approved by the United States Federal Drug Administration (FDA). The gene therapy treatment for ALD is a breakthrough in several ways. ALD is a degenerative brain disease. The brain has a protective barrier that makes it very difficult for drugs to pass through to deliver therapeutic effects. Gene therapy is able to circumvent this. Gene therapy had also been tried previously using other types of viruses — the results appeared to have unintended consequences. The patients receiving the gene therapy developed a form of blood cancer called leukaemia. It seemed that the delivery of the gene had introduced other defects into the genome that in turn led to cancer. However, using the AIDS virus did not seem to cause this side effect. In a way, a feared killer has been reformed to save lives instead of being the harbinger of death.
I have discussed one type of gene therapy; research is also being carried out using methods that can repair or “edit” problem genes. This type of gene therapy can basically repair the defective genes on site in the genome without providing a replacement or supplementary genes. I should also add a disclaimer that, obviously, gene therapy is much more complex than the rather simplified way I have portrayed it.
Gene therapy is no longer the pipe-dream of idealistic scientists — the first such treatment was approved for use by the FDA in August 2017; the most recent approval was on Oct 18. With many in the trial phases, it is likely that we will see even more such treatments in the near future. They may soon be available for thepublic worldwide.
To my knowledge, gene therapy trials have not been conducted in Malaysia. Nevertheless, we must prepare ourselves for what is perhaps inevitable. Such treatments will one day reach our shores, maybe even as soon as next year. Are we ready for the socio-economic implications such therapies will bring about? Do we have adequate regulations to protect patients and institutions when deploying such applications?
Preparing for such an eventuality will require changes in how we finance health care and manage the social impact such revolutions bring about. Gene therapy drugs will be expensive — they may cost tens of thousands of ringgit per dose, perhaps even more. How will this impact our health care system? Will we face a situation where life-saving treatments are available but yet lives are lost due to prohibitive costs? Gene therapy use and research will also have deep ethical implications. Trials can go catastrophically wrong. Legislation must be in place to protect and provide a code of conduct for patients as well as the institutions, clinicians and researchers involved. It is not a future that we can avoid. We must make the necessary preparations to provide the best outcomes.
The writer is a bioinformatician and molecular biologist with the Faculty of Science and Technology and a Senior Research Fellow at the Institute of Systems Biology, Universiti Kebangsaan Malaysia. Email him at firdaus@mfrlab.org