Gene therapy: finally a viable option

Most genetic diseases are the result of a mutation that means a particular protein is made incorrectly, or not made at all. The idea of gene therapy is to infect cells – just how a virus would – with a small amount of DNA containing a replacement copy of the affected gene which slips into the cell’s genome and starts making the missing protein. The principle is elegant, but many challenges stand between the theory and successful use of gene therapy with real patients. In the last few years a number of advances have been made that have the potential to make gene therapy – something the medical community almost gave up on a decade ago – a powerful tool which could treat or even cure tons of diseases. What could be cooler than using the very tools viruses like HIV have painstakingly evolved to infect us with for our own benefit?

Genes are strings of bases within your DNA that contain the code to make different proteins. If a mutation occurs in the gene and changes the sequence of letters, it can change which protein subunits the cell uses to make the protein. This creates a mutant protein which may not function corrrectly, ot may stop the protein being created at all

That’s right: I made a GIF: Genes are strings of bases within your DNA that contain the code to make different proteins. If a mutation occurs in the gene and changes the sequence of letters, it can change which protein subunits the cell uses to make the protein. This creates a mutant protein which may not function corrrectly, ot may stop the protein being created at all

How does gene therapy work?

Small pieces of DNA containing whatever sequence is missing or mutated in the individual are made in a laboratory and then used to infect a patient’s cells. In principle this is exactly what a virus does, and most attempts at gene therapy so far have actually used viruses to penetrate their target cells, having cut out the dastardly viral genes and replaced them with therapeutic ones. The viral genes get the DNA into the cell and inserts itself somewhere on a host chromosome. The cell machinery then uses this new DNA to make the correct copy of the protein they are missing. When these cells divide, their progeny will also contain the new DNA. Gene therapy can also be used to target cancer cells, adding genes that stop them dividing, or decreasing their lifespan.

There are many challenges associated with gene therapy:

Humans have spent a long time developing defences against viral infection, so actually getting the DNA into the body and to wherever its needed without the immune system kicking the crap out of it is a problem in itself. Furthermore, most of the cells in your body are senescent, meaning they won’t divide into other cells – they will live for a certain amount of time performing whatever function they have and then eventually expire. The dead cells are replaced by the smaller populations of stem cells which keep on dividing to up the numbers of the grunt workers. While different types of cells live for different lengths of time (years for neurons, hours for neurtrophils), infecting the grunts with new DNA is only short term solution in most cell types: the therapy will only last if the infection gets reproduced by the stem cells, which can be hard to find and target. If these cells aren’t infected, a patient might have to undergo gene therapy over and over again to keep all the new cells infected. It is also usually necessary to infect large numbers of cells to see any real benefit to the patient.

On top of these challenges, gene therapy also comes with some serious risks. Although we can control what DNA we add into cells, we can’t control where in the genome the virus inserts itself: the sequence can end up in the middle of another gene resulting in its disruption or inacitvation; it can insert somewhere that alters the shape of the chromosome and destabilizes it, leading to a cascade of other mutations; finally, the gene promoter sequences (parts of the virus genome that signal to the cell to make the protein of the therapeutic gene it is associated with) can affect the regulation of other genes.  This last issue is what nearly killed gene therapy: In the late 1990’s and early 2000’s a number of clinical trials were underway testing gene therapy as a treatment for several serious diseases. Although the therapy worked, several test subjects developed leukaemia. It later transpied that this was the result of powerful viral promoters switching on nearby genes that controlled cell proliferation. While the cancers were treated and the test subjects have in some cases exceeded their formerly short life expectancies thanks to the positive effects of gene therapy, the associated risks were evidently too great to continue.

Recently, advances in various medical fields have made gene therapy a real possibility once more. The most important of these is the replacement of the older viral vectors with new more manageable ones. These newer vectors are associated with less powerful promoters, and some even include killswitches – vulnerability to certain treatments that could kill all the cells with the virus and leave the rest unharmed. Conversely, new techniques can prologue the lives of infected cells compared to uninfected ones. This is mostly a direct result of these cells functioning correctly thanks to the working copy of the gene that the other cells are missing, but in one trial tackling glioblastoma an increased resistance to an alkylating agent was added to the gene therapy payload, which meant that subsequent treatment with alkylating chemotherapy left more of the therapeutically infected cells alive than the uninfected. Both means result in the same end: a larger proportion of the cell population contain the corrected gene compared to those with the pathological  or absent copy.

There have also been advances in how to evade the immune system long enough for DNA delivery to the target cells. The bloodstream is full of enzymes designed to break down free floating DNA, and as a result it only survives unprotected in the blood for a few minutes. Attempts to conceal the DNA by attaching it to polythene glycol which make it look bigger and less ‘virusey’ had partial success, but failed when it came to delivering the DNA to specific cell populations that need it. Recently, a better solution has been put forward: magnetic nanoparticles. Complexing the genetic payload with an iron nanoparticle provides the same benefits as polythene glycol in terms of disguising the DNA, but has the added benefit that it can be directed to target regions of the body simply by holding a magnet over the desired region! Once injected near the site of the tumour, magnetofection results in far greater uptake by the tumour and less dispersal to other parts of the body where the gene may actually be damaging. A further benefit of using magnetic nanoparticles is that their well established tolerance by the body, as shown by the years for which they have been used as a contrast material in MRI imaging. Another upshot of this is that their magnetism can be used to track their movements around the body with high precision.

Two recent trials have finally made safe, successful gene therapy a reality: the first was a reinvigorated attempt to treat Severe Combined Imunodeficiency (SCID). This is an autoimune condition in which a defective gene prevents white blood cells from getting rid of toxins. The toxic build up kills the cells, leaving the sufferer without a functional immune system. SCID is sometimes referred to as ‘bubble boy’ disease in reference to sufferer David Vetter, whose treatment was to live in a sterile plastic bubble for 12 years. SCID was one of the first diseases where Gene Therapy was trialled as a cure, and one of the tragic incidents where while the therapy did appear successful, it resulted in a number of test subjects contracting leukaemia. Last year, with the use of new lenti-viral vectors with more malleable regulatory regions a new trial has tentatively reported the same efficacy against autoimmune issues as the earlier trials, but so far without any sign of leukaemia. Another condition which has recently been treated safely and effectively by gene therapy is Choroideremia: a rare and progressive form of blindness. The condition is caused by the deletion of the REP1 gene which is necessary for the survival of retinal cells. From birth onwards the cells gradually die off, leading to blindness. In a new trial, a viral vector which doesn’t insert into the host genome, but rather sits by itself in the cell body – happily making proteins without risking interrupting any other genes – completely prevented further progression of blindness in trial subjects. Although it could not replace dead cells, those in the process of dying were revived, leading to vision improvements in some patients. Vectors which don’t integrate into the host genome are not passed on through cell division, but because retinal cells are very long lived the disease is still treated effectively. This is very good news for the potential treatment of other diseases affecting slowly dividing cells such as brain and liver diseases.

Gene therapy is a tool with many uses, but still with many risks. The threat of cancer is still very real for any trial that inserts a virus randomly into the genome. As such, for the meantime, therapy is limited to diseases severe enough that the cancer risk is worthwhile, but gradually we are improving its scope and safety. With the huge majority of diseases we see today having some genetic basis, the amount of good gene therapy can do is practically limitless.

Will this eventually allow us to splice ourselves silly with viral vectors conferring telekinesis etc, like in Bioshock?

No. Okay, maybe.


Progress in Retinal and Eye Research: Clinical Applications of Retinal Gene Therapy, Lipinski et al 2013

Blood: Immune Reconstitution and Preliminary Saftey Analysis of 9 Patients Treated With Somatic Gene Therapy for X-Linked SCID With a Self-Inactivating Gammaretroviral VectorHacein-Bey-Abina et al, 2013

The Journal of Gene Medicine: Gene Therapy Clinical Trials Worldwide to 2012 – An Update, Ginn et al 2013

Oncotarget: Targeting Cancer Gene Therapy with Magnetic Nanoparticles Charles Li, Linda Li, and Andrew C. Keates 2012

American Society of Gene and Cell Therapy: Solving the Problem of γ-Retroviral Vectors Containing Long Terminal Repeats Derek A Persons and Christopher Baum 2011


3 thoughts on “Gene therapy: finally a viable option

  1. I’ve read through this more than once since you stopped by my blog and I still can’t get over the home made animated gif for the post, great job.

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