麻豆传媒

What is gene therapy?

It is a way to fix a gene defect in a person鈥檚 cells. One way is with a retrovirus. When these viruses infect cells, they are able to transcribe genetic information into the cell鈥檚 DNA. So we genetically engineer the virus to incorporate the gene a person needs. We can then inject the virus directly into their blood or tissue, or collect cells from them, make changes in a lab, and then reinject the corrected cells.

There were some major setbacks 20 years ago. What happened?

There were a few different issues. One was related to immune responses to the virus, which had harmful effects that were not foreseen. Another significant issue was that in trials treating immune deficiency diseases, some children were successfully treated but then developed leukaemia. That was because of the integration of DNA from the virus into the genome of their haematopoietic stem cells 鈥� the cells that give rise to all our blood cells.

So is it safer now?

There have been many changes in the viruses used for gene transfer. Those we use today can make changes to cells that are not actively dividing and interact differently with the host cell鈥檚 DNA. They are more neutral in how and where they make changes 鈥� not accidentally activating neighbouring genes, for instance. All of these things mean that they have a much lower chance of impacting cell behaviour and growth beyond the expression of the specific gene that we have added.

Will gene therapy now become more widespread?

Two gene therapy treatments have recently been approved by the European Medicines Agency. There are hundreds of clinical trials going on now. For instance, the results of a trial disease called SCID were recently published. Years after the treatment, there has been no indication of any cancer in the patients.

Everyone鈥檚 now talking about CRISPR gene editing. Does it change things?

I think it has huge potential, both in terms of innovation and therapeutic opportunities for patients. Gene editing presents the possibility of correcting the gene mutation locally, instead of inserting new information. It could potentially provide more safety for patients. It鈥檚 really opening a new era.

But will CRISPR make the type of genetic engineering that you do, using viruses, unnecessary?

It鈥檚 very early to say. I think we have plenty of space for parallel investigations that would allow us to identify the best options for patients. We will probably end up with multiple modalities, just as we have many different medicines in general.

Were early expectations of gene therapy unrealistic?

There were a lot of expectations 20 years ago, then there was a big drop related to side effects. Now everybody is again climbing to the top of the hill. But whether there is too much or too little enthusiasm doesn鈥檛 change the fact that development of gene therapy as a treatment is a process.

When you introduce something into your body with curative intent, it鈥檚 a drug 鈥� so gene therapies, too, need to be considered as drugs. That means they require clinical development and monitoring, because every drug works best in certain circumstances and has side effects. What is also really important to keep in mind is that we are talking about drugs in an early phase of development.

You recently led a trial using gene therapy to treat a deadly childhood disease. Can you tell me about it?

It is a very severe neurodegenerative disease called metachromatic leukodystrophy (MLD), and it mostly affects young children. It鈥檚 devastating. These children have a normal early infancy and develop normally. Then at some point, often around 18 months old, they start to experience a progressive loss of abilities 鈥� movement, cognitive skills, language, the ability to interact. They become unable to swallow, to talk. You can imagine how intense that can be for their families. Children affected in infancy seldom survive into adolescence.

How did you treat it?

The trial, which I began and is still ongoing at the San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), involves extracting haematopoietic stem cells from the patients鈥� bone marrow and then using retroviruses to insert the missing gene into them.

While the stem cells are being prepared, the patients undergo chemotherapy 鈥� basically to wipe out the remaining haematopoietic cells and clear the way for the corrected cells.

This is a disease affecting neurons. Why do you insert the gene into blood cells?

We used blood cells partly due to their accessibility, but also because we have had more practice working with them. There has been some work with neural stem cells, but it is very early days.

People with MLD cannot produce an enzyme critical for protecting the myelin around their neurons. When the corrected cells reach the brain, they give rise to progeny that deliver the enzyme. The blood cells鈥� ability to do this has made them a particularly potent form of treatment. We are now looking at using this strategy to make changes in the brain in other neurodegenerative disorders.

What are the so far?

Of the nine children in whom the follow-up is at least three years 鈥� long enough to provide an indication 鈥� some have shown no symptoms, despite reaching an age well beyond when we would have expected to see them. Others have had a milder course of the disease.

When you extract cells from the patient, genetic alteration can be done remotely. Will that make gene therapy more accessible?

It is already happening. An initiative has just been launched by David Williams at Dana-Farber/Boston Children鈥檚 to centralise manufacturing of patient haematopoietic stem cells. It will provide training to enable satellite centres to administer gene therapy, so people can remain in their local hospital.

鈥淪ome of the children now show no symptoms of this fatal genetic disease鈥�

This initiative could also be applied to clinical trials. There are already some in which this is being tested. You really need standardisation and coordination of the work for gene therapy to become more widespread.

For many, these clinical trials are their only hope. It must be hard to turn people away.

It鈥檚 very challenging. With MLD, I knew the disease so well, and its devastation, but at the same time was aware of the many unanswered questions about the new therapy. They could only be answered with clinical trials. It has been extremely difficult to say no, but you have to avoid exposing children to risks if they would not stand to benefit. You also have to complete your trials and demonstrate the treatment works 鈥� or else the path to developing a medicine for more people is that much longer.

Whenever you see that your therapy is really affecting the life of a child, you feel that your hard work really had a purpose. That is why we are doing all this.

This article appeared in print under the headline 鈥淪end in the genes鈥�