Blood-brain and blood-eye barriers
Brineura®, an enzyme replacement therapy for CLN2 Batten disease, has been available since 2019 under a Managed Access Agreement (MAA). It is administered directly into the brain every two weeks to replace the missing enzyme and has been shown to restore enzyme activity and slow the progression. However, the brain and the eye are protected by the blood-brain barrier and blood-retina barrier respectively meaning the enzyme infused into the brain cannot reach the eye. As a result, children whose other symptoms are being controlled are still losing their eyesight.
A potential study
After the brain infusions, there is a small amount of Brineura® left over in the vial. The clinical team at GOSH were interested in investigating whether Brineura® could save eyesight if administered into the retina.
BioMarin gave permission for this investigation to be carried out using the left-over samples so there was no extra cost for the drug. A huge BDFA and CLN2 community-led fundraising campaign raised over £200,000 to cover the clinical costs to make this clinical trial possible, and the BDFA would like to thank everyone who took part in raising the money.
The initial trial
The first stage of any trial is to ascertain whether a potential drug is safe for the patient to take. For this study a small quantity of Brineura® was injected into the retina of the right eye every two months, the left eye acted as a control. These injections took place under general anaesthetic on days the children were attending the hospital for their regular infusions. Eight patients aged 5-9 years of age were initially enrolled onto the trial, all of them were receiving Brineura® infusions and were experiencing vision loss.
Potential to save sight
The data were recently reported in the Nature portfolio journal, Eye. Most of the children had advanced eye disease and did not show any differences between the treated and untreated eye but did show that it was safe to inject the drug. Three of the children had less advanced eye disease and they showed a modest reduction in rate of change in the retina, allowing them to keep more sight in the treated eye in comparison to the untreated eye. Further work will be needed to determine whether starting this therapy earlier will have more clinical benefit in preventing sight loss.
Professor Paul Gissen, honorary Consultant in Paediatric Metabolic Diseases at GOSH and the UCL GOS ICH said:
“This work is a real team approach. Our Batten’s patients are generally looked after by the metabolic team at GOSH and there has been a sad history of these children going blind.
When Brineura® was developed for the brain infusion, it was a great step forward. I supported the Managed Access Agreement, but we were still seeing these children lose their sight.
By working with colleagues in ophthalmology, we proposed ideas, and developed a programme with Rob Henderson that we could deliver with his team at GOSH."
Has this been licensed?
The drug is being given on ‘compassionate use’ basis. This is a special status for treatments that have not been authorised for use in this way but where there is no alternative treatment, and the condition is life-threatening. All compassionate use programmes are very closely monitored for safety, and the patients on the programme have been very carefully selected.
Other eye trials
This is not the only study looking into saving the sight of CLN2 children. There is another looking into Brineura® injections into the retina in the USA which is currently active but not recruiting (https://clinicaltrials.gov/study/NCT05152914).
A second study started in 2023 is using gene therapy to replace the missing TPP1 gene in the eye. It is also active but not recruiting at the moment (https://clinicaltrials.gov/study/NCT05791864).