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Taking a new path?

Over the last few years the field of gene therapy has been a domain of controversies and security issues. But the recent approval of a gene therapy treatment in Europe could be a sign that the technology is heading in a new direction.

In the autumn of 2012 the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) approved the authorization of Glybera for marketing in the European Union. It is intended to treat lipoprotein lipase (LPL) deficiency in patients with severe or multiple pancreatitis attacks. Glybera is consequently the first gene-therapy medicine to be recommended for authorization in the European Union.
However, the process has been far from unproblematic. Over the three years that have passed since the application was filed, it has been analyzed and ruled upon four times by the CHMP and three times at CAT, the Committee for Advanced Therapies. In June 2011 both the CHMP and CAT adopted negative opinions concerning the use of Glybera in the treatment of patients with LPL deficiency. During re-examination, the CAT view was that there was scope for approval of Glybera with additional post-marketing studies, but the CHMP still maintained its negative opinion in October 2011.

“The initial indication for the use of Glybera was very wide, as it included all patients with LPL deficiency. There was data only on a limited number of patients with heterogeneous evidence of metabolic and clinical effects,” says Marisa Papaluca at the European Medicine’s Agency.

Following the initial recommendation to refuse the marketing authorisation for Glybera, the European Commission had asked the EMA to re-evaluate Glybera when used in a more restricted patient population than initially applied for. The new, restricted indication – treatment of adult patients with LPL deficiency who suffer from severe or multiple pancreatitis attacks despite dietary fat restrictions – was according to the EMA much more in line with the available data.The company was requested to conduct a new analysis of all submitted data, to re-evaluate both the metabolic effects of Glybera and the clinical outcomes relevant to the revised therapeutic indication.

Two types of transfers
The method of using gene therapy has been developed over the last couple of decades. The basic concept is straightforward: replacing a defective gene or adding a functional copy. There are two different types of gene transfer interventions that can be performed on humans. The first type is somatic gene transfer, in which the somatic cells of a human are genetically modified. The second type is germ-line gene transfer, in which it is the germ-line cells – that is the gametes, such as egg and sperm cells, as well as precursor cells from which gametes are derived – that are genetically modified.

“The benefit of gene therapy is the possibility of one single operation and then it’s done. It has the potential of putting an end to lifelong medication, side effects, and negative impacts on life quality. Unlike pharmaceuticals, which are often aimed at only treating the symptoms, parts of gene therapy would be able to get to the actual cause of the disease,” says Cecilia Lundberg, Professor of CNS Gene Therapy at the Wallenberg Neuroscience Center, Lund University.

She is currently working with the development of novel viral vector constructs for regulatable and cell-targeted gene therapy in Parkinson’s disease, an area where forward progress is being made, according to professor Lundberg.
“What we can see is that viruses can be injected into the brain without any impact on the patient’s psychological functions. This is an important step forward, since psychiatric side effects in particular can only be tested on humans. Still, we are a long way from being able to cure the actual cause and release a commercial product for medical treatment.”

A field of controversy
Gene therapy medicines are nevertheless regarded as highly complex substances and there are a variety of specific challenges surrounding them. One aspect specific to gene therapy is the question of how to target only the target cells. Other challenges relate, for example, to clinical trial design with gene therapies, immunogenicity aspects and also the long-term safety follow-up of patients.
Over the years, a number of serious setbacks have occurred in the gene transfer field. For example, a study back in 2005 on children with SCID, who were being treated with gene therapy, had to be discontinued since the treatment was found to cause leukemia. Another, even more fateful case, was the death of a boy in 1999 due to an immunological reaction towards the virus that was being used in the gene therapy treatment. Professor Cecilia Lundberg agrees that the field has experienced a lot of problematic issues in the last couple of decades.

“I think that we have learnt a lot and become much more aware of the potential side effects. For the last ten years, there have been many discussions regarding the safety aspect and to try to get to the bottom of what went wrong. The young boy that passed away due to the immunologic reaction is a strong indication for the need for cautiousness and to highlight awareness. The immune system, for instance, is a powerful force in the body. In other words, we must be sure of what we’re doing before anything is initiated.”

In her dissertation Making doable problems within controversial science Hannah Grankvist at Linköping University, has interviewed US and Swedish scientists on their experience of gene transfer research. According to Grankvist’s conclusions, the general view among the interviewees was that gene transfer research was a difficult field to work in.

“Several of them often feel misunderstood. They spend a lot of their time explaining what gene therapy is actually about, partly sincemany people have an idea that the main goal is to try to modify our genes and ‘design our children’. Thus, a persisting problemis trying to convince society about its benefits.”

In recent years the field has focused on large and common diseases such as different types of cancer, HIV and hemophilia. Here, the technology has seen quite a development, both in reducing side effects but also in actually curing patients completely from diseases. According to Hannah Grankvist, it has generally been easier to attract investors for these widespread kind of diseases than for rare ones, such as single monogenic inherited disorders for which gene transfer originally was for.
“The problem is that this results in very little money going to those kinds of disorders. There have even been cases where the parents of a patient have had to pay for a study, which of course raises ethical concerns.”
On the other hand, another controversy or potential dilemma within gene therapy is the possibility of going down a slippery slope towards a society where gene transfer is used for less severe diseases than today and where the line has been moved to include other diseases and medical conditions, like psychological and social-behavioral disorders such as anxiety and obsessive-compulsive disease.
“Concerns are raised that disorders and conditions that at present have no genetic explanation could, due to new knowledge regarding genetic information, be regarded as in originating from genetic defects and therefore be considered as in need of medical treatment,” she says.

Grankvist emphasizes that gene therapy is still in an experimental phase as it is yet accompanied by many technical difficulties. For instance, not all successful trials that involve animal studies are transferable to human trials. It is difficult to develop systems and design vectors, which are the vehicles to which the gene is coupled and which will transport the gene into the cell. Professor Lundberg says that the field has seen a great deal of technical progress, yet highlights the importance of a wider knowledge concerning the actual disorders.
“One of the most important aspects in progressing gene therapy – as it is within all other areas – is to get more knowledge about the diseases. We are already becoming skilled at understanding the tools and applying them for symptom relief, but in order to use them better we need to know what’s causing these diseases,” says Lundberg.

Future possibilities
According to the EMA, the approval of Glybera has demonstrated that Europe has a regulatory pathway in place to bring gene therapies to the market. There are gene therapy products in advanced clinical development for a number of therapeutic indications, such as genetically inherited diseases and certain types of cancer. A number of companies developing gene therapies have come to the Agency for classification as advanced therapy medicinal products (ATMPs), for scientific advice or for orphan designation.
“We are confident that some of these products will make it to the stage of marketing authorisation application in the next five to ten years,” Marisa Papaluca says.

Professor Lundberg agrees that the recent EMA approval marks a breakthrough for the field.
“It’s an indication of this field not being mere science fiction anymore, which is something that we scientists have been convinced about for some time now. What remains to be seen is how it will actually be used, what the financial possibilities will be and if it can compete with already existing drugs on the market,” says Cecilia Lundberg.

Hannah Grankvist hopes that the authorizationmight remove some of the preconceptions of the field, even if she is not convinced that gene therapy will take the role of a revolutionizing medicine.
“I think it could play a big part together with other treatments, and hopefully the research will move towards rare diseases. I do see a huge optimism among researchers. The practical issues and technical problems will all be resolved sooner or later, it’s just a matter of time. And as soon as we see safer vectors, there will also be fewer risks.”

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