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Prof Jane Farrar discusses the innovative gene therapy being used to treat rare inherited diseases and the challenges that come with it.
There have been many moments in Prof Jane Farrar’s life so far that led her to her line of work.
As head of the School of Genetics and Microbiology at Trinity College Dublin (TCD), her research is deeply entrenched in the advancement of gene therapy and how it can improve people’s health.
While she was always interested in science at school, one particular moment that steered her towards the work she does now happened when she was a PhD student. She met a child with epidermolysis bullosa, a rare genetic disease that causes extremely fragile, blistering skin.
“His mum said: ‘Tell Jane what you do.’ And this was a boy of 11 at the time, and he said: ‘I fight the pain with my mind.’ That was a great motivator for me because I thought there’s an 11-year-old sitting there and he’s got a genetic condition and there has to be solutions. If we understand the basis of disease, we must be able to find solutions.”
Farrar studied under David Mc Connell and Peter Humphries, who she said were great mentors to her. She added that Mc Connell gave her a great opportunity early in her PhD, telling her to go and learn about retinal degeneration from people around the world – which is exactly what she did.
“What I learned from that experience is that ultimately in science, lots of people are accessible to you and you just have to ask.”
Gene therapy in action
Farrar was incredibly humble as she described the work she does, saying that “it’s much less to do with me and much more to do with the team”.
Half of the team she works with aim to understand the genetic basis of retinal degeneration and sight disorders in Ireland. “Within that, we find really novel findings as well, we’re understanding a lot more globally about the genetic basis of retinal degenerations.”
The other half of the team is involved in designing innovative gene-based therapies for rare, inherited retinal degeneration and common ocular disorders.
‘If we understand the basis of disease, we must be able to find solutions’
– PROF JANE FARRAR
Farrar said the team is focusing on delivering a gene using adeno-associated viruses (AAVs). These are little viruses that act as a mode of transport to bring genetic material to a particular cell.
“We’re using an AAV that’s cut down, it’s got hardly anything in it. It’s really not a virus at all and it can’t make copies of itself,” she explained. “It’s literally just a Trojan horse used as a carrier to carry your piece of DNA into a cell.”
Viruses are commonly used in this way because they have evolved over millions of years to be able to get into cells very effectively. This means that researchers like Farrar and her team can manipulate them in such a way to take out the virus part, put in a human gene instead, and send it into specific cells.
Once in there, that gene – which carries a stretch of DNA – can make “the correct message and encoded protein that is missing in the patient”. This, in turn, can help fight against certain genetic diseases.
A focus on Stargardt disease
Farrar is also part of the Start project, a European training network that aims to diagnose, understand and treat Stargardt disease, a rare genetic eye disease that causes vision loss.
Led by Ghent University’s Prof Elfride De Baere, the project involves 14 partners including TCD. The researchers are investigating many different elements of Stargardt disease, such as the diversity of mutations, different therapeutic strategies and how to simulate the disease model.
“You can take a blood cell or a skin cell from a patient and you can de-differentiate them into stem cells, they’re called induced pluripotent stem cells (iPS cells),” said Farrar.
“You can take these iPS cells from a blood sample or a skin biopsy from a patient and now you can actually make all the different cell types … Not only can you make a cell type, you can grow three-dimensional tissue. So in a little dish, you can grow three-dimensional retina.”
While this is not a perfect retina, Farrar said these retinal ‘organoids’ are essentially the patient’s disease model, meaning they can be compared to a control and even used to test therapeutic strategies.
As well as the research into Stargardt disesase, the focus of the Start project is to train PhD students. Each partner institute gets one PhD student and these students receive training both locally and through secondments in different institutes across Europe.
The project is supported by the EU under the Marie Skłodowska-Curie Innovative Training Networks programme. “None of the work that we do would be possible without funding,” said Farrar.
“Fighting Blindness Ireland, Science Foundation Ireland, Enterprise Ireland, the European Union, the various framework programmes, the Health Research Board, the Irish Research Council – they are essential, nothing can happen without funding.”
Challenges in gene therapy
Because there are so many genes that can mutate to cause some form of disease, a major challenge in gene therapy is the volume of solutions that are needed when looking at diseases at a genetic level.
This means needing a lot more data, a lot more clinical trials, a lot more funding and a lot of time. Farrar also said some specific genes might be tied to incredibly rare diseases with a very small number of patients.
Another challenge is ensuring that the cause of the disease is known. Identifying this can be done through genome sequencing, which has advanced massively in the last 20 years.
In 2003, the cost of sequencing the very first human genome was around $3bn. Today, that cost is down to a few hundred dollars, with one US company striving to get the cost down to $100.
‘For some forms of disease, we need to look at more generic approaches’
– PROF JANE FARRAR
However, Farrar said that even with access to this sequencing technology, there is still a proportion of patients where the cause of disease will remain unclear.
“For some forms of disease, we need to look at more generic approaches, where we’re not necessarily treating precise genes but an overarching approach that will provide benefits.”
While gene therapy has come a long way in recent years, there are still some misconceptions around it. Farrar said many people think that gene therapy means changing our DNA.
“The focus of gene therapy is for adult tissue, so the therapies that we’re currently using are not going to get passed into eggs or sperm, so they’re not going to be passed onto the next generation,” she said.
“It’s actually not that different to any other drug therapy, it’s just a gene therapy. Of course, we have to make sure it’s safe … but that happens in the testing process”
Prof Jane Farrar is speaking at the Fighting Blindness Retina Conference on 3-5 November. Those interested can register for free on the Fighting Blindness website.
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