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Levels of fatty molecules called glycerophosphodiesters, or GPDs, are elevated in the blood and other body fluids of people with juvenile Batten disease – and may be a useful biomarker for diagnosing or treating the inherited disorder – new research has revealed. study.

This finding “raises the possibility of using these biomarkers as a blood diagnostic test or as a measure of efficacy for disease-modifying treatments,” the researchers wrote.

The study, “Glycerophosphoinositol is elevated in blood samples from CLN3 Pigs Δex7-8, Cln3 Δex7-8 mice and individuals with CLN3was published in Overview of biomarkers. The work was funded by the Forebatten Foundation, a US-based non-profit organization that supports research into juvenile Batten disease.

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In search of a biomarker for Batten

Juvenile Batten disease, also called CLN3 disease, is caused by mutations in the CLN3 gene, which provides instructions for making a protein of the same name.

Although the function of the CLN3 protein has long remained unclear, a recent study has demonstrated that it is needed to help cells process GPDs, which are produced when fats used to make cell membranes are broken down. Without functional CLN3, GPDs accumulate to toxic levels in cellular compartments called lysosomes.

Now, a team of American scientists, including researchers from Amicus Therapeutics, have conducted a series of experiments aimed at identifying molecules that could serve as a biomarker of juvenile Batten.

Using a pig model of Batten disease, the team analyzed the levels of more than 700 fats and other small molecules in blood samples. Of these hundreds of molecules, the team noted that four GPDs were typically elevated in pigs with Batten disease.

Specifically, a GPD called glycerophosphoinositol (GPI) showed a pronounced increase in pigs with Batten disease. More modest increases were noted for three other GPD molecules, namely glycerophosphoserine (GPS), glycerophosphocholine (GPC), and glycerophosphoethanolamine (GPE). The researchers noted that the increase in these levels was “remarkably stable over time” in Batten pigs.

Analyzes of the fluid around the pigs’ brain and spinal cord – called cerebrospinal fluid, or CSF – also showed elevated levels of GPI, but not the other three GPDs.

The researchers then measured the levels of these GPDs in blood samples taken from a Batten mouse model. Levels of GPI and GPE, but not the other two molecules, were elevated in mice with Batten disease. The researchers noted that the elevations were more variable over time in mice than in pigs.

“Collectively, the patterns observed across species and time points suggest that glycerophosphodiester species may be closely linked to CLN3 disease. [development] and therefore could be useful as clinical biomarkers of disease state,” the scientists wrote.

To confirm whether these findings translated to humans, the researchers analyzed blood samples collected as part of an earlier natural history study. This included samples from 22 people affected by juvenile Batten disease, 15 carriers of the disease – individuals with a CLN3 mutation who do not have Batten disease themselves, but can pass the mutated gene to their biological children – and six people who did not have Batten and were not carriers.

The results showed that GPI and GPE were significantly elevated in the juvenile Batten disease group, with GPI showing the clearest pattern.

To investigate the usefulness of these molecules as a biomarker, the researchers calculated the area under the receptor operating characteristic curve, or AUC. It is a statistical test that assesses how well a given parameter – in this case, GPD levels – can distinguish between two groups. Here, these two groups were people with or without juvenile Batten disease.

AUC values ​​can range from 0.5 to 1, with higher values ​​reflecting better ability to differentiate. The results showed that the GPI had an AUC value of 0.9848 when comparing individuals with juvenile Batten to non-carrier controls.

“GPE and GPI may have utility as biomarkers of CLN3 disease status. GPI, in particular, shows consistent elevations in a diverse cohort of individuals with CLN3, as well as in several animal models of the disease,” the researchers concluded.

“These findings raise the possibility of using these biomarkers as a blood diagnostic test (eg, newborn screening) or as a measure of efficacy for disease-modifying therapies,” they added.

Notably, in carriers, mean blood levels of GPI were significantly higher than in non-carriers, but significantly lower than in people with juvenile Batten disease. Since carriers have no noticeable symptoms, but may have mildly impaired CLN3 protein function, these findings are consistent with the recent report that this protein helps treat GPI and other GPDs.

“Our observation that heterozygous carriers show intermediate elevations in serum GPI suggests a dose-response relationship in which GPI levels are closely related to functional CLN3 protein levels,” the researchers wrote.