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Advances in gene therapy could help cure a cruel childhood illness

Most viruses make people sick. But we're learning to use them to deliver cures to complex diseases

Yewande Pearse


LA Biomed

You don’t usually want to be infected by a virus. In most cases, they'll make you very ill by invading living cells, hijacking their machinery to multiply and then bursting from those cells to infect the ones around it. But by manipulating particular types of viruses to carry genes of interest rather than their own, scientists can introduce a vital gene into the body of a person who is missing it.

That's the cutting edge of research into Batten disease, the rare childhood brain disease I studied for my PhD. An inherited disease that affects about 1 in 100,000 children worldwide but represents the most common cause of pediatric neurodegenerative disease, Batten disease is incredibly cruel. Named after Frederick Eustace Batten, a British neurologist and pediatrician who first discovered it in 1903, the disease is caused by genetic mutations that affect the cells' ability to get rid of metabolic waste. However, how this actually leads to disease is a mystery.

Without notice, an otherwise "healthy" child with the illness starts to lose vision between ages five and 10. It rapidly worsens. Other symptoms include personality changes such as becoming aggressive, other behavioral issues, and learning delays.

Seizures, sometimes violent, usually start around age nine and are followed by a gradual loss of movement and speech, initially appearing as clumsiness, unsteadiness, and Parkinson-like symptoms. Eventually, kids with Batten disease become blind, bedridden, and physically and mentally debilitated. They require 24-hour care until they die, usually in their early 20s.

The first time I heard about Batten disease, I was doing a masters in neuroscience. It was winter, the heat was on full blast, and I was sitting in a stuffy lecture theater thinking about whether it was jacket potato day at the cafeteria. Standing in the way of me and my potato was a lecture on rare childhood diseases. However, the professor giving the lecture was so incredibly passionate about his work that I soon forgot about lunch. I never forgot about Batten disease though, and when presented with an opportunity to study it years later, I couldn't turn away.

For years, there has been no effective way to treat this horrible disease. Most treatments have been symptom-orientated as part of an overall palliative care approach. For example, doctors often prescribe anticonvulsant drugs to control the seizures, and other medications to help alleviate psychiatric symptoms like hallucinations. To treat the underlying causes of disease, one promising candidate is gene therapy, which supplies cells that are missing or replaces defective genes with normal, working ones.

Although scientists have made incredible progress in terms of working out how to do this theoretically, some genetic diseases are more challenging to treat using gene therapy than others. Few studies have attempted to directly address the genetic defect behind Batten disease by using gene therapy, mainly because it becomes more complicated to target a mutation when, as in Batten, the faulty gene makes a protein that sits in the membrane of a cell rather than floating freely within it. And getting it wrong could be worse than taking no action: previous studies have raised concerns that the over-expression of the gene, CLN3, would cause more harm than good because it is normally expressed at very low levels that are tricky to match.

But a study last year pushed the boundaries of what's possible, presenting the possibility that gene therapy could ultimately save lives devastated by a Batten diagnosis.

In 2016, a paper by University of Nebraska pharmacology grad student Megan Bosch and colleagues hypothesised that if the CLN3 gene that is missing in Batten disease can be replaced in cells at the right level, the devastating symptoms that result from its absence will be alleviated.

To assess the idea, scientists genetically modified mice to remove the CLN3 gene, mimicking how Batten disease works in humans. The animals were injected with viruses containing the gene replacement at one month of age, and researchers assessed their behavior over the next five months as compared to untreated and control mice. Researchers used mice who already showed disease symptoms, rather than injecting them at birth, because children who may eventually receive the therapy are unlikely to be diagnosed before they become symptomatic.

The key part of the study is that they used two different forms of a virus to deliver the gene. In one virus, they expressed the CLN3 gene at a level three to eight times greater than the in the other. It was in mice where a lower level of expression was observed that neurons, which are usually severely affected, were infected by the virus at higher levels – and the mice appeared to suffer less from the disease. Researchers were able to show the importance of the level of CLN3 expression once the gene was delivered to the cells.

Taken together, this study identified a promoter – which turns on gene expression – that can turn on human CLN3 at a level that restores normal movement and decreases pathology in the brain of mice with Batten disease. These scientists showed for the first time that this type of gene therapy can help alleviate symptoms, a critical first step toward a viable treatment for Batten disease and its relatives.

This paper is so promising that the pharmaceutical company Abeona Therapeutics is preparing to launch a clinical trial in the next 12-24 months with the aim of reversing the genetic errors responsible for juvenile Batten disease.

One Batten disease story that will stick with me forever is the story of two parents who had what they thought was a perfectly healthy little girl, until they noticed that she was struggling to see clearly. After years of trying to get to the bottom of their daughter's vision loss, they received a misdiagnosis of Macular dystrophy, a rare eye disorder that causes blindness. The mother told me about how she was just about able to make peace with the fact that her daughter would have to go through life blind only to find out that this was only the beginning.

Imagine the devastation that followed when the parents learned she had an incurable disease. It's like being hit by a truck, getting up, then having it reverse and strike again at double the speed. No child, or parents, should have to endure this. And it's looking increasingly like, in the future, nobody will have to.