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A urine test, called urine proteome, found higher expression of specific proteins in people with different subtypes of Batten disease, according to a study.

These proteins may be useful as readily accessible biomarkers of disease progression and response to treatment, its researchers wrote. They could also be potential therapeutic targets.

The study, “Urinary proteomic analysis of patients with neuronal ceroid lipofuscinosis, ”Was published in the journal iScience.

Batten disease, also known as neuronal ceroid lipofuscinosis (NCL), is a group of genetic disorders characterized by seizures and progressive loss of visual, motor and cognitive abilities.

The disease is caused by mutations in genes that affect the function of lysosomes, structures that break down and remove cell waste, resulting in the toxic buildup of certain molecules in tissues.

Late infantile Batten disease, or CLN2, results from a mutation in the TPP1 gene that causes deficiency or dysfunction of the lysosomal protein TPP1.

The only approved treatment for any form of Batten is TPP1 replacement therapy Brineura (cerliponase alfa), which treats CLN2 disease. New biomarkers are needed to aid in the development of therapies.

Proteomic analysis can detect variations in the levels of different proteins in individuals with a disease, compared to healthy individuals. Researchers at University College London used proteome analysis of urine samples from patients with CLN2, as well as animal models of CLN5 and CLN6 disease, to identify and validate candidate biomarkers for these three forms. disease.

The researchers then studied the proteins identified in patients with CLN2, CLN5 and CLN6 disease, as well as biomarkers identified in previous studies to validate the results.

Compared to four healthy controls of the same age, urine samples from two CLN2 patients showed a two-fold or more increase in 61 proteins, and a two-fold or more reduction in 11 proteins.

Urine from three CLN5 sheep and 13 CLN6 sheep also showed marked differences in protein expression profiles, compared to healthy sheep.

In samples from CLN2 patients, a total of nine candidate biomarkers were identified, including five lysosomal proteins. In CLN5 and CLN6 sheep, four potential biomarkers were identified for CLN5 and CLN6, and one for CLN6 only.

Targeted proteomic analysis was then used to confirm the observed differences in the expression of the candidate protein in a separate group of nine CLN2 patients and 13 healthy controls. The proteins identified in CLN5 and CLN6 sheep were analyzed in comparison with urine samples from two patients with CLN5 and two with CLN6.

Three candidate proteins – BHMT1, LAMP1 and TPP1 – were significantly altered in CLN2 patients. TPP1, which is deficient in CLN2, was lower in patient samples, as expected. The mean expression of the other two proteins, BHMT1 and LAMP1, were 17.8 and 3.4 times higher, respectively.

The changes observed in TPP1 and BHMT1 were specific to CLN2, making BHMT1 a potential new biomarker for CLN2.

Of the five candidate proteins identified in the CLN5 and CLN6 sheep models, two were not detectable in human urine samples. The other three showed no difference in expression in this comparison.

A broader analysis of new and previously identified candidate biomarkers included patients with CLN1, CLN3 and CLN7. Groups of patients were identified on the basis of their protein expression profiles. Three candidates – LAMP1, PAM and GOT1 – were most significantly modified between patients and healthy controls. TPP1 was also reduced in all Batten subtypes compared to controls.

In CLN2 patients in particular, the expression of BHMT1 was six times higher and that of TPP1 was up to nine times lower than that of other Batten subtypes.

Compared to controls, the mean expression of the lysosomal proteins LAMP1 and HEXA was three times higher, and GOT1 expression six times higher, in all types of Batten disease.

“[W]We used a two-phase proteomic discovery and validation strategy to identify and confirm altered urinary proteins in patients with CNS, “the researchers wrote, adding that” it would be possible to include these proteins during follow-up. the effect of future new systemic treatments. “

This study has some limitations, the researchers added, namely the small number of patients included and the use of animal models for proteomic discovery that could not be validated in humans.

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