Cellular storage material may track CLN2 disease therapy efficacy
Researchers measured effects on disease before, after Brineura treatment
The levels of abnormal storage material inside certain immune cells could be used as a biomarker of disease activity and response to treatment with late infantile Batten disease, or CLN2 disease, a new study shows.
Data showed that over three years of treatment with Brineura (cerliponase alfa) — the only approved disease-modifying therapy for CLN2 disease — the buildups were gradually and significantly reduced, while symptoms didn’t worsen.
“Our take-home point is that the amount of abnormal storage material in [immune cells] can act as an objective marker of response to treatment in children” with CLN2 disease, the researchers wrote in the study, “Buffy Coat Score as a Biomarker of Treatment Response in Neuronal Ceroid Lipofuscinosis Type 2,” which was published in Brain Science.
A type of Batten disease, late infantile Batten is caused by mutations in the gene that provides instructions for making an enzyme called TPP1. Without working TPP1, molecular debris builds up to toxic levels inside lysosomes, the cell’s recycling centers, ultimately killing cells, particularly nerve cells.
This results in the neurological symptoms that characterize the disease, namely seizures and vision loss.
BioMarin Pharmaceutical’s Brineura is an enzyme replacement therapy (ERT) that delivers a lab-made version of the TPP1 enzyme directly into the fluid surrounding the brain.
It’s widely approved for treating CLN2 disease based on clinical trial data showing it can help break down toxic waste and slow progression of motor and language decline. In the U.S., it’s available for children 3 years and older, and to patients of all ages in Europe.
“Assessments of therapeutic effect have been largely limited to clinical observational measures, namely the CLN2 rating scale,” the researchers wrote, calling it “a crude measure of motor and language performance” that doesn’t offer information on patient progress.
They said since “changes in symptoms occur relatively slowly,” it’s often hard to determine “whether the absence of change is due to a slow rate of progression or because the treatment has been effective.”
Effects of Brineura on late infantile Batten disease
This makes for a need for objective biological measures to assess the severity and progression of infantile Batten disease, along with the effectiveness of treatment. This type of biomarker “could act as an adjunct to clinical ratings to support timely decisions regarding modification of treatment,” wrote researchers in the U.K. who evaluated whether abnormal curvilinear storage aggregates in peripheral blood cells could be used as a disease biomarker of late infantile Batten. The presence of these aggregates inside a type of immune cell called lymphocytes is a hallmark of CLN2 disease.
This abnormal storage material can only be visualized with electron microcopy, which uses extremely powerful microscopes to obtain a resolution that can clearly show tiny structures inside cells.
“Electron microscopy is readily available in centers providing [Batten disease] diagnosis. With appropriate setup and regular use … electron microscopy can be applied to routinely obtained peripheral blood samples,” the researchers wrote.
As a proof-of-concept for this idea, they analyzed blood samples from six children with late infantile Batten before Brineura treatment and at yearly intervals after starting it.
The children initiated treatment at a median age of about 4.5 and were on it for a mean of nearly 2.5 years. The researchers specifically analyzed cells in the so-called buffy coat, the immune cell-rich layer that forms following the centrifugation of a blood sample.
Results showed patients’ immune cells contained abnormal storage aggregates and that the number of cells with evidence of this toxic buildup decreased significantly with Brineura.
The percentage of abnormal cells dropped by an average of 3.5% after a year of treatment, 6.5% after two years, and 7.5% after three years.
Moreover, “there was no significant difference in CLN2 scores over the time points in the study,” the researchers wrote, indicating “little to no deterioration in symptoms over a three-year period,” which provided more evidence of the treatment’s effectiveness.
“Our data suggest that the percentage of abnormal storage [aggregates] in CLN2 disease could be of value as an objective, visual marker of therapeutic response and a biomarker of disease activity. By comparison, the CLN2 clinical score is much better suited to the assessment of functional loss rather than any gain or normalization of function,” they said.
The data also suggest Brineura has effects throughout the body, even though it’s administered directly into the brain.
More research is needed on the effects of treatment outside the brain, “both in order to develop noninvasive biomarkers for assessing treatment efficacy and to understand the potential positive effect of ERT on [organ function outside the brain] in the long-term,” the researchers said.