Why 2014 has been a ‘breakthrough year’ for gene therapy

Rhys Evans’ life could have been very different.

He could have been a ‘bubble boy’, forced to walk around in a protective see-through plastic canopy. You see, he was born with an immune system that barely worked. The slightest infection could have proved fatal. But Rhys is now 14 years old and doing fine.

So how did Rhys avoid living in a bubble?

The simple answer is that Rhys got lucky – his condition was diagnosed when he was a baby. Even more fortunately, doctors at Great Ormond Street Hospital were able to do something about it. They understood that Rhys’s condition was caused by a genetic flaw and they thought that if they could correct this flaw then they could restore his immune system. That is exactly what happened, and why Rhys is now no different to any other young teenager.

Rhys’s treatment is an example of gene therapy, which was the subject of a fascinating lecture that I attended last month. Leonard Seymour, professor of gene therapies in the Department of Oncology at Oxford University, gave four reasons why 2014 has been a breakthrough year for this revolutionary, but controversial, approach.

Four reasons why 2014 has been a breakthrough year for gene therapy

Let me begin by describing these successful trials.

1. Bubble Boy Syndrome

Rhys Evans is not the only boy (it does not affect girls) to have received gene therapy for this syndrome – 20 were given it at about the same time as Rhys. But he was lucky. In the trial, one in four ended up with leukaemia.

This year has seen the results of a new trial. In this, nine boys were treated and eight have been reported as still alive, 16 to 43 months after treatment. The ninth died from an infection already present when he began the gene therapy. Overall, the outcome is hugely promising and suggests that gene therapy could provide a permanent cure for patients who would otherwise receive a bone marrow transplant from a donor, with all the consequent risks of rejection.

2. HIV

HIV is a virus that weakens the immune system by destroying the white blood cells that fight disease and infection. In order to destroy the cells it has to enter them, and it does this via a protein called CCR5, found on the cell surface. Researchers have noticed that about 1% of patients contract HIV and yet come to no harm. The reason is that their cells have a rare genetic mutation which prevents them from displaying the CCR5 protein on their surface.

Now researchers have managed to engineer white blood cells so that they have this same rare mutation. They have injected billions of these genetically modified cells into 12 trial patients, and there is evidence that this procedure is safe and could suppress the virus.

3. Leukaemia

Leukaemia is cancer of the blood, and acute lymphoblastic leukaemia is a particularly severe version that especially affects children and can be fatal within a few months. This year, Novartis, in conjunction with Pennsylvania’s Perelman School of Medicine, reported astonishing results of a new gene therapy: 27 out of 30 paediatric and adult patients experienced complete remission – a stunning success.

How did this happen?

T cells are the ones that roam around the body destroying foreign invaders. In this trial, T cells were taken from the patient, genetically reprogrammed to help them to hunt cancer cells that express the protein CD19 and then re-introduced into the patient’s blood. There they proliferate, they find the cancer cells and they destroy them.

4. Brain Cancer

The polio virus kills cancer cells. However it can also, of course, give you polio.

Researchers at the Preston Robert Tisch Brain Tumor Center of Duke University have genetically modified the polio virus by adding in a piece of genetic code taken from the common cold rhinovirus. The result is that the modified polio virus kills cancer cells, but not normal cells. Testing on humans has shown this approach to be safe, and a clinical trial on five patients started in May 2012.

One of these patients was Stephanie Lipscomb. She had a tumour the size of a tennis ball in her brain. Surgery, radiation therapy and chemotherapy had not worked. She had little hope. Now though, thanks to the polio virus, her tumour has shrunk, she is free of symptoms and is in excellent health. Four of the five patients in the trial are alive and have responded well to the treatment. The fifth died as the tumour grew back. The mechanism of action is not completely understood. While the modified polio virus kills tumour cells, it seems that the body’s own immune system also attacks tumour cells that are infected by the virus.

Correcting mistakes – why gene therapy is revolutionary

As you will have observed, the successful trials I’ve just told you about were all the result of reprogramming the genetic code of cells. Let’s go back to basics.

Each cell in your body contains your full genetic code written in the DNA bases of A which pairs up with T, while C joins to G.

A gene is a sequence of these base pairs. Like the sequence of words in a recipe book, it instructs the making of proteins, which in turn determine the function of a cell. The instructions are delivered by messenger RNA, which first copies the DNA in a process called transcription, and then informs the creation of proteins in a process called translation.

So the protein that is created, and thus the function of the cell, is determined by the underlying sequence of DNA and this is where problems can arise. There might be a mistake in the DNA. A base pair might be lost, or an extra one inserted. Instead of an A there might be a C. If this underlying recipe is wrong, then the cell will not function as it should, and that leads to disease.

As Professor Seymour explained, the great attraction of gene therapy is that it goes right to the cause of disease by correcting these DNA mutations.

Ever since Watson and Crick discovered the double helix in 1953, and Holley, Nirenberg and Khorana won the 1968 Nobel Prize for explaining how this is translated into proteins, there have been high hopes for gene therapy. After all we had, for the first time, the code for life. Surely it was just a question of correcting any mistakes?

But the field of gene therapy has struggled to the point where some have doubted it altogether.

How gene therapy overcame a serious setback

As I said, gene therapy has struggled in the decades since it was discovered. One of the most serious setbacks was the 1999 case of 18-year old Jesse Gelsinger.

Gelsinger suffered from a rare disease of the liver caused by a genetic mutation. In a trial run by the University of Pennsylvania, he was injected with a type of virus called an adenoviral vector that carried the correct gene, which should have resolved his condition. Instead he suffered a massive immune reaction and died within four days.

As this tragic outcome demonstrated, the challenge of gene therapy is to introduce new genes into the cells of the body without causing collateral damage. The ‘delivery mechanism’ is crucial. Since the birth of gene therapy, researchers have been using ‘nature’s way’. Viruses naturally invade the body, and so the most popular approach has been to engineer these so that they have the correct gene and let them find their way into cells. This, though, has two disadvantages. The virus can only carry a limited amount of DNA, and it may provoke an immune reaction either making the patient sick or killing the same cells that have been corrected by the virus.

So researchers have needed to refine gene delivery systems. They have turned to other natural vectors like plasmids or synthetically engineered versions called virosomes. These do not trigger an immune response, but are not so effective at delivering their cargo of genes into the cell. A more direct approach has been to use a needle to inject the genetic material directly to the target site. This has proved to be a successful way of treating some forms of blindness.

Another approach takes cells from the patient or a well-matched donor, genetically engineers them in the laboratory and then re-infuses them into the body. This has recorded success, for instance in a trial on patients suffering from a severe brain disease called adrenoleukodystrophy.

Finally there is CRISPR, which has this year generated great excitement. Using a naturally occurring protein derived from bacteria, CRISPR can be directed to cut and edit DNA within cells, effectively performing the necessary repair in situ without using a virus. It has been already been used in trials to alter blood stem cells so that they cannot be recognised by the HIV virus.

The basis of the biotechnology revolution

Gene therapy is conceptually attractive because it goes right to the root cause of a disease and performs what should be a permanent correction. But its appeal also lies in its range, because the underlying cause of so many diseases is a genetic flaw. An estimated 4000 diseases, including cystic fibrosis, Huntington’s, and haemophilia are caused by a single DNA mutation. More common diseases like diabetes and cancer are caused by multiple mutations. The principle, though, is the same: if we can correct the genes, the cells should start to function normally, beating the disease.

Genetics is really the basis of the biotechnology revolution. By allowing us to understand why living organisms function as they do, it gives a chance of altering those functions, principally to improve human health. And Professor Seymour left us with a fascinating thought…

Regenerative medicine promises to replace failing body parts, by growing them from stem cells. Thanks to 2012 Nobel Prize winners Sir John Gurdon and Shinya Yamanaka, we can now reverse adult cells, to turn them back into pluripotent stem cells that could then differentiate into any type of functioning cell. However these induced pluripotent stem cells will still have your own DNA, including your own genetic mutations.

But if we could use gene therapy to correct them, then these stem cells could turn into flawless functioning cells, and flawless body tissue!

With all the excitement that gene therapy has generated this past year, I will be keeping a close eye on the companies in this field to see how this story plays out.

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