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Case study: Hope for children with rare neurodegenerative disorder

A rare but devastating disorder

Batten Disease is a rare paediatric form of dementia. Between 30 and 50 children are diagnosed  each year in the UK, but its impacts on those children and their families cannot be understated. Patients often develop normally until around three years of age, but then their motor skills degenerate. By four or five children are unable to walk with difficult to control seizures and loss of vision. By the age of six, patients will be bed bound with seizures, limited or no speech and blindness. Patients rarely live past the age of nine or ten.

The disorder was first recognised in the early 20th Century by Dr Frederik Batten, working at Great Ormond Street Hospital (GOSH). It is one of a group of paediatric neurodegenerative disorders for which there was, until very recently, no treatment and very little hope for patients. 

Professor Paul Gissen is a Deputy Theme Lead for Novel Therapies for Translation in Childhood Diseases theme at the NIHR Great Ormond Street Hospital Biomedical Research Centre (BRC). He explains what is happening at a biomolecular level for patients: “The variant of Batten Disease that we are trying to treat is caused by the mutations in the CLN2 gene, which is responsible for generating an enzyme called TPP1. When the enzyme doesn't work, various chemicals accumulate inside the brain and retinal cells, causing the cells to die out, the brain shrinks and patients lose important functions.”

Replacing the missing enzyme

Professor Gissen led the UK arm of a trial for a new enzyme therapy to replace TPP1 in patients with the CLN2 variant, with a synthetic protein called cerliponase alpha, created by a company called BioMarin. The trial was run in the NIHR Clinical Research Facility, which includes staff time for the nurses, clinical trial coordinators and clinical researchers. 

The challenge in treating any brain disease is the blood brain barrier, which protects the brain and prevents any chemical given orally or by intravenous infusion from reaching neuronal cells and matter. Though some small molecules that can cross the blood brain barrier, enzymes like TPP1 are too large to get across. The study used a special intracerebro-ventricular device was that allows the infusion to be given into a port under the skin on top of the head, with a catheter leading directly into the brain ventricles. 

The trial began in Hamburg toward the end of 2013 and came to the NIHR Great Ormond Street BRC in 2014, where initially four patients were treated. Centres in Rome and Columbus, Ohio joined, and 24 patients were recruited in total, with 23 continuing to complete the trial. 

By mid-2016 the trial showed promising results, which were published in the New England Journal of Medicine. Biomarin submitted documents to register the drug with the FDA in the US and the EMA in Europe, allowing compassionate use of the drug while the paperwork was processed. But the treatment is never over: like a diabetic relying on insulin, enzyme replacement therapy is for life as it is replacing something that the body is missing. 

Professor Gissen continues: “This was a tricky time because we were giving a treatment that was not yet approved and is a very difficult drug to deliver directly to the brain. I got approval from the Great Ormond Street Hospital ethics committee to give the treatment on the ward to new patients on a compassionate use programme because it looked like there were such good results in our trial. The patients didn’t have anything else - there was nothing.

"Thankfully the hospital ethics committee approved us giving the drug off the trial to new patients on the wards. Though the drug was free, the time and infrastructure around it isn’t and we are grateful that GOSH is focused on patient outcomes and agreed that we could do this.”

Once the drug, called cerliponase alfa or Brineura, was approved for use by the FDA and EMA in late 2017, it was continued for the six UK compassionate use patients already receiving it as well as for the trial patients, but not for any new patients. An application to the UK National Institute for Health and Care Excellence followed. Final approval was given in late 2019, so all patients can now receive the treatment on the NHS.

Improving access to the treatment

Great Ormond Street Hospital currently treats 19 patients, each receiving an infusion every two weeks, and takes around four hours. “We observe them for a couple of hours afterwards on the ward,” says Professor Gissen."Treating patients closer to home would be a lot easier for them. At the moment the infusions have to be done in the hospital but we are making inroads to moving to local hospitals.

"Colleagues around the world are amazed that it is our nurses who would deliver the drug," he add. "Elsewhere it is done by doctors or sometimes neurosurgeons because they have to put the needle into the device, which goes straight into the brain. Certainly it could be done in the local hospital but eventually we think it could be done at home.” 

The success of the treatment seems to depend on how early children were on the drug: the longest any UK patient has been on the medicine is six and a half years. Professor Gissen explains: “The child who started the youngest at GOSH was three years and seven months back in November 2014. Now he can still run, he talks in sentences and even though you don’t expect a massive effect on vision because the enzyme doesn't go into the eyes he can still see quite well. I can see that he’s starting to lose vision but he chats and loves his trucks and plays and goes to school. This is amazing.”

The success of this treatment is evident, and another trial is in progress with the UK arm in the NIHR Great Ormond Street BRC for patients who have been diagnosed because a sibling has the disease rather than through the development of symptoms. In 2017 one child was started in the UK pre symptomatically at about 20 months because her sister was diagnosed before her. The younger sibling has never had any deterioration, seizures and is walking normally.

Professor Gissen concludes: “This variant of Batten diseases affects very few children, but the enzyme replacement drug has made a huge huge difference individually to them and their families. Bigger improvement to their lives would be to start them earlier on the treatment and provide care closer to home to reduce travel. We are working on both.”