For people with rare diseases, a single gene therapy treatment could restore normal function and alleviate the burden of ongoing care, as Dr Ian Winburn tells Kennas Fitzsimons

Dr Ian Winburn

Gene therapy is the next generation of medicine that targets the underlying cause of genetic diseases. It has the potential to offer patients a really transformational clinical benefit and improve quality of life.

Thats according to Dr Ian Winburn, Global Medical Lead, Haemophilia, Endocrine and Inborn Errors of Metabolism (IEM), Rare Diseases, Pfizer Biopharmaceuticals Group. Dr Ian Winburn, Global Medical Lead, Haemophilia, Endocrine and IEM, Pfizer Biopharmaceuticals Group, pictured right during his presentation on gene therapy at BioPharma Ambition held in Dublin Castle on March 4. Pic: Conor McCabe Photography.

Formerly a clinician in the UK National Health Service (NHS), Dr Winburn trained in general surgery and completed a PhD on novel drug discovery in renal transplantation before moving into industry 10 years ago, where he worked in the area of inflammation and immunology before leading the European haemophilia team.

Dr Winburn is now working to develop innovative gene therapies with the potential to restore normal function to patients with rare diseases, possibly with just a single treatment, changing the way people manage their disease.

Gene therapy: What is it?Gene therapy uses genes as medicine. It works by introducing functioning copies of missing or defective genes into the body and can target the underlying cause of a disease at the cellular level.

There are various types of gene therapies, such as the gene editing technique, CRISPR (clustered regularly interspaced short palindromic repeats), as well as epigenetic approaches that look at ways in which genes may be turned on or turned off.

Pfizer Rare Disease is focusing on an in-vivo approach that utilises a recombinant adeno-associated virus (AAV) to deliver the gene therapy.

This approach works by targeting the missing or non-functional gene in an individuals DNA and adding a copy of it with a functioning gene that, in turn, produces a functioning protein.

The functioning gene serves as a blueprint for the tissue to create the missing or non-functioning protein that is causing a disease.

Dr Winburn said: Gene therapy is in the branch of genetic medicine, where you can think about approaches that look to add a gene to a host cell, and that gene goes on and codes for a protein. That protein its coding for can replace a missing protein. So, in the example of haemophilia, where theres a missing factor VIII or factor IX clotting factor, that protein that is either missing or is faulty could be essentially administered through a gene therapy. A gene is added to a host cell that codes for the factor VIII or factor IX and therefore replaces that protein.

The functioning gene is delivered directly to the targeted cells by means of a highly specialised viral vector. This vector, effectively, is the package that contains the gene. In simple terms, it can be likened to the cardboard boxes that online retailers use to ship products.

The manufactured vectors are protein shells modelled after viruses in which all infectious viral components have been removed, and a functioning gene is added. Different viral vectors are used to reach specific tissues in the body, such as the liver or muscle.

VectorVector is a great word because vector describes a direction, by definition, and the other way we can think about vector is a vector often carries something. There are a few approaches you can use to develop a vector. We have embraced an AAV vector that has the capacity to deliver the transgene, the gene that is going to be added to the host somatic cell. In the case of haemophilia, it is targeted at the liver, Dr Winburn says.

Rare diseases focusAbout 280 million people worldwide live with a genetic disease, and more than 80 per cent of rare diseases are genetic in origin, according to Pfizer. For people born with rare diseases, the burden of disease management can be huge. Treatment is often ongoing and may be lifelong. Gene therapy could enable patients to live without the need for ongoing treatment. This raises the prospect of relief not only from symptoms but also from the burden of disease management.

Dr Winburn elaborates on the reasons why gene therapy approaches are currently focused specifically on rare diseases that have single-gene alterations.

It tends to be rare genetic diseases that are monogenic in nature Some of the more common diseases are very much multifactorial in origin: there may be a genetic component but there are other aspects to their aetiology rather than these single, monogenic conditions that gene therapy really lends itself to.

The other aspect is that these are areas of huge unmet medical need. Often, there isnt a high standard of care with either medicines or clinical interventions that are ultimately influencing the progression and the symptoms of the disease, he says.

A lot of rare diseases often affect children by the very nature of their being of genetic origin. In some cases, children dont get the opportunity to grow up into adulthood because of these rare diseases. Having the opportunity to develop medicines where there is such a high level of unmet need and, ultimately, impact in a positive way the lives of families and their carers is a huge motivation.

Dr Winburn adds that rare diseases, collectively, are common. There are approximately 7,000 rare diseases, and the majority of these are of genetic origin. Gene therapy offers a groundbreaking technology to address these genetic diseases that have historically not had particularly strong standards of care or clinical treatment paradigms offered to them.

Gene therapy for haemophiliaPeople with the genetic disorder of haemophilia have insufficient levels of a clotting factor that helps to stop bleeding. Consequently, they bleed for longer than other people. The disease is typically treated through infusions of the missing clotting factor, with patients undergoing regular replacement therapy. Gene therapy could revolutionise this treatment model.

Its really important to put yourself in the position of a parent who has a young child who has haemophilia, Dr Winburn says.

Often, this disorder of coagulation that results in spontaneous bleeding due to the lack of functioning clotting factor first presents as early as the age of two, classically when children are becoming toddlers, when they start bumping into things and they develop bruising and the likes.

That alerts their parents attention to the possibility that there is something wrong with their clotting system and they [undergo] clinical tests and a diagnosis is made. Or, because its a genetic condition, it may run in families and parents are aware of the possibility of their newborn having haemophilia.

But if you are diagnosed, for example, at the age of two, it means that the mainstay of treatment is factor replacement. So, that commonly is an intravenous infusion possibly two to three times a week, possibly once a week, or once every other week, depending on whether its haemophilia A or B and what type of medicine is being prescribed. But its certainly frequent treatments. Again, if you put that back to a parent wholl be doing those infusions from the age of two or three that lifelong need and burden is huge.

While factor replacement enables children to live a full and active life to a degree, children with haemophilia may not necessarily get the opportunity to engage in all the activities children typically partake in as they are growing up, such as contact sports, Dr Winburn says.

There is this ongoing, lifelong burden of treatment. As those boys transition into adulthood, they often take responsibility for that and if they dont get their treatment then they will bleed spontaneously into their joints, they get problems with haemarthropathy, causing damage.

Ultimately, the incidence of joint damage and joint replacement surgeries is incredibly significant in the haemophilia population. And that is often despite optimal prophylaxis, where its being prescribed.

So, when you think about gene therapy, this is a single, one-off treatment with the potential to alleviate the need for regular infusion for a patient.

Not all patients will be eligible for a gene therapy or are being studied in gene therapy trials. This is not going to be something thats available for everybody. But for those that are eligible, and ultimately in disease where a gene therapy has been licensed by the regulator, this really does have the potential to massively impact their lives and give them a sense of normality that they havent necessarily had up until that point in time.

Future expectationsWhile gene therapy holds promise for many people with genetic diseases, it will not be an appropriate solution for every patient. The potential risks and benefits of gene therapy will be fully established through clinical trial programmes and with continued research and evaluation.

Patient safety and suitability are always primary considerations in the development of new treatments as they progress from preclinical and clinical testing through regulatory approval to potential commercial distribution. Dr Winburn stresses that, as regards the development of new gene therapies, patient safety is paramount.

Safety is always at the forefront of our thinking, it is the heart of our clinical trial programmes, it is the heart of all our regulatory work.

It is an ongoing process around evaluating safety, and particularly long-term safety, and there is a critical importance for all patients that ultimately receive a gene therapy to be followed up long-term within registries, within clinical databases, so that we can monitor and evaluate long-term safety. All our trials are designed so that safety outcomes are critically part of it and its something that we are ever watchful of.

For some patients, gene therapy is already a reality. There are currently a few rare diseases for which gene therapies are available as therapeutic options in Europe, and Dr Winburn anticipates that there may be up to 30 approved by 2023.

There is a rare congenital cause of blindness that currently has a gene therapy available and similarly a rare neurological condition that affects children also has a gene therapy available, thats spinal muscular atrophy (SMA). There is also a gene therapy for beta thalassaemia that has recently been approved and is available within Europe. In terms of haemophilia, the first gene therapy is currently under review in Europe.

It may be premature to imagine a scenario whereby gene therapy is used to treat chronic diseases more generally, but in terms of future applications for these emerging technologies it is a case of watch this space.

This is an area where we are definitely in breakthrough technology. At this moment in time, our focus has been on rare diseases. There is, of course, an interest in understanding what is possible with gene therapy in terms of where it could be utilised, Dr Winburn says.

I dont want to provide any false hopes, but I think aspirationally, there is a hope that this could certainly impact many patients and their families in a positive way.

In association with Pfizer Biopharmaceuticals Group.

Continued here:
Gene therapy: The 'next generation' of medicine - Irish Medical Times