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A review of approved therapies in the United States found that tamoxifen, an oral cancer therapy, is able to effectively reduce the build-up of a fatty molecule called globotriaosylceramide, or Gb3, in cell models of two forms of the Batten disease. It worked without compromising cell survival, one study showed.

This study found that Gb3 levels are abnormally increased in cell and mouse models of these two types of Batten, specifically neuronal ceroid lipofuscinosis type 3 – known as CLN3 – and type 7, called CLN7.

Additionally, tamoxifen has been shown to reduce neuroinflammation and improve motor coordination in a mouse model of CLN7 disease, the researchers said.

According to the scientists, these results highlight Gb3 as a new biomarker for CLN3 and CLN7 diseases and suggest that tamoxifen could be a potential treatment for these forms of Batten.

The study, “Reuse of tamoxifen improves CLN3 and CLN7 disease phenotype, ”Was published in the journal EMBO Molecular Medicine.

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Batten’s disease is the most common group of pediatric neurodegenerative disorders. It is associated with the toxic build-up of lipofuscins – fatty and protein deposits – inside lysosomes. Lysosomes are small structures inside cells that break down waste and unused protein into smaller components to throw away or recycle.

The accumulation of lipofuscins primarily affects the central nervous system, made up of the brain and spinal cord, and the retina, the light-sensitive inner wall of the eye.

While the genetic cause of each type of Batten disease is well established, “the functional understanding of proteins remains elusive, making it difficult to target therapeutic drugs by intelligent design,” the investigators wrote.

Today, an international team of researchers has discovered a new biomarker for diseases CLN3 and CLN7, which has made it possible to perform a therapeutic reorientation test. This subsequently identified a potential new treatment for these conditions.

The reuse of compounds already approved – and therefore tested for safety – for one health problem for use in the treatment of another disease or syndrome allows to accelerate the development of a safe and effective treatment, while reducing the risks. costs. This is particularly relevant for rare diseases, where pharmaceutical investments are limited.

CLN3 disease, also known as juvenile Batten disease, is the most common form of Batten and usually develops between 5 and 10 years of age. , but one of the most widespread in southern and Mediterranean Europe.

Both forms are caused by mutations in genes that provide instructions to produce proteins located on the surface of lysosomes.

To identify a potential disease biomarker that could be used to screen for potential therapies for CLN3 and CLN7 diseases, the researchers first analyzed the levels of several fatty molecules – which could potentially contribute to lipofuscin formation – in models cellular diseases.

These models also included cells derived from patients grown in the laboratory, such as fibroblasts, the most common cell type in the tissue that surrounds and supports organs, and neural progenitor cells.

They found that among the molecules tested, Gb3 was the most significantly increased, showing twice the levels in the CLN3 and CLN7 models compared to healthy cells. Gb3 accumulates in cell membranes and inside lysosomes. Of note, Gb3 is known to play a role in the development of Fabry disease, another type of lysosomal storage disorder.

A significant accumulation of Gb3 was also observed in brain tissue, particularly in nerve cells, mouse models of both diseases, compared to healthy mice. This build-up started earlier in the CLN7 model, resembling its earlier disease onset compared to CLN3 disease.

Further analyzes suggested that Gb3 is not only a side effect of lysosomal dysfunction, since suppression of the activity of the Gb3-producing enzyme reduced the accumulation of SCMAS, a characteristic component of storage associated with disease in CLN3 and CLN7 diseases.

Notably, no abnormal level of Gb3 was found in a cellular model of CLN6 disease, also known as the late infantile variant of Batten.

These results demonstrate the storage of Gb3 as a biomarker for CLN3 and CLN7 diseases.

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urinary protein

The team then evaluated whether any of the 1,280 compounds approved in the United States could reduce the accumulation of Gb3 in the lysosomes of cell models of these conditions.

Screening showed that tamoxifen treatment resulted in the most potent reduction in Gb3 levels in both models, without compromising cell survival. It also reduced the build-up of SCMAS.

Tamoxifen is an oral hormone therapy used worldwide to treat certain breast cancers and other hormone-related disorders. Sold under the brand names Nolvadex and Soltamox, it has previously been shown to be safe for pediatric use.

Notably, the therapy can cross the blood-brain barrier, a highly selective membrane that prevents circulating microbes and potentially harmful molecules from reaching the brain and spinal cord.

Further analyzes revealed that tamoxifen promoted the clearance of Gb3 by a mechanism independent of its characteristic hormone receptor which involved the activation of TFEB, a master gene of lysosomal function that increases toxic storage clearance.

The researchers then tested tamoxifen in a mouse model of CLN7, as it shows more severe disease than existing CLN3 mouse models and closely recapitulates the disease characteristics seen in CLN7 patients.

Mice treated with tamoxifen showed significantly lower levels of Gb3 and SCMAS in the brain, reduced signs of neuroinflammation, and partial recovery of motor coordination, compared to untreated mice.

These results highlight that “Gb3 is a new biomarker for CLN3 and CLN7 diseases” and that “clearance mediated by tamoxifen via TFEB activation may represent a small molecule strategy to treat common types of [Batten disease]The researchers wrote.