Background
The CLN2 gene, which is found on chromosome 11, produces an enzyme called tripeptidyl peptidase 1 the purpose of which is to break down proteins. The enzyme is insufficiently active in CLN2 disease and as a result those unbroken down proteins settle in the brain tissues. Developmental delay begins around the end of age 2. Children develop seizures and begin to gradually lose the ability to walk and speak. Brief, involuntary jerks in a muscle or muscle group (called myoclonic jerks) typically begin around age 4-5. By age 6 most children are completely dependent on their caregivers, and many will require a feeding tube. Most children with CLN2 disease die between the ages of 8–12 years. Until recently, the only treatment options for children with CLN2 were treatments that relieved symptoms of the condition, or palliative care in the final stages of the disease.
BioMarin
BioMarin undertook research and developed an enzyme replacement therapy trademarked as Brineura®.
Brineura®
The drug, which is called cerliponase alfa or Brineura®, has been approved by the MHRA following successful clinical trials at Great Ormond Street Hospital in collaboration with other centres around the world.
How does it work?
When cerliponase alfa is put into the brain, the cells in the brain take it up and convert it into a replacement enzyme which does the same job as TPP1.
Why does it not work for other forms of Batten disease?
Each type of Batten disease is the result of a different gene malfunctioning. Some malfunctions affect the body’s ability to produce different proteins; some affect the cell walls; and some we don’t know about at the moment. Each gene malfunction causes waste materials to build up in the cells, so that the results are very similar – but they all do it through different routes.
Only CLN2 is caused by the lack of TPP1, and cerliponase alfa can only compensate for this enzyme, not for anything else.
Is it a cure?
Brineura® is not a cure, and it cannot reverse any damage that has already been done, but it does dramatically slow down the course of the disease. The earlier the treatment starts, the more damage it can prevent. It can also be given to siblings of children with NCL2 who test positive for the disease but haven’t yet developed any symptoms, to get as much benefit as possible.
How is the treatment given?
The brain is protected by the blood-brain barrier, which blocks many substances, including certain medications like cerliponase alfa, from reaching the brain. To deliver this medication directly into the cerebrospinal fluid (CSF) surrounding the brain, a specialised device is implanted through the skull into the brain’s ventricles. This device allows regular intracerebroventricular administration. After surgical implantation, the device is infused every other week, with each session lasting about four and a half hours.
Currently, cerliponase alfa can only be administered in a hospital setting. Infusion days begin early, with children typically arriving by 8:30 am. After check-in, initial health checks are performed, including measurements of blood pressure, heart rate, oxygen saturation, respiration and temperature. These observations ensure the children are fit for the infusion and are repeated hourly throughout the day.
To deliver the drug, the area above the device is cleaned and accessed by inserting a port needle. A sample of CSF is removed for infection monitoring. The infusion set is then attached to the port needle and secured with sticky tape and the drug infusion started.
Once complete, the infusion set, and port needle are removed. The children are monitored for a further 30-60 minutes. If vital parameters are normal, then the children can go home.
This process typically finishes around 4pm making the infusion an all-day process.
Are there side effects or other drawbacks?
The most common side effects are fever (pyrexia), hypersensitivity, and device-related infections.
A major drawback is that vision loss continues to progress despite treatment. While the brain is treated, the cells in the eye continue to deteriorate, and eventually, children receiving Brineura® may lose their sight.
How many hospitals make it available?
Currently, Brineura® is available at the following sites:
- GOSH
- Manchester
- Birmingham
- Bristol
- Cardiff
- Newcastle
- Belfast