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A review of therapies approved in the United States found that the oral cancer treatment tamoxifen is able to effectively reduce the buildup of a fatty molecule called globotriaosylceramide, or Gb3, in cellular models of two forms of the Batten’s disease. It worked without compromising cell survival, a study showed.

This study found that Gb3 levels are abnormally increased in cellular and mouse models of these two types of Batten, specifically neuronal ceroid lipofuscinosis type 3 – known as CLN3 – and type 7, known as 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, “Tamoxifen reuse improves CLN3 and CLN7 disease phenotypewas published in the journal EMBO molecular medicine.

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Batten disease is the most common group of pediatric neurodegenerative disorders. It is associated with the toxic accumulation of lipofuscins – fat and protein deposits – inside lysosomes. Lysosomes are small structures inside cells that break down waste and unused proteins into smaller components to be discarded or recycled.

Lipofuscin buildup primarily affects the central nervous system, made up of the brain and spinal cord, and the retina, the light-sensitive inner lining of the eye.

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

Now, an international team of researchers has discovered a new disease biomarker CLN3 and CLN7, which has helped run a therapy redirection test. This then identified a potential new treatment for these conditions.

Repurposing compounds already approved – and therefore tested for safety – for one health problem for use in the treatment of another disease or syndrome helps accelerate the development of a safe and effective treatment, while reducing 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. With onset of symptoms between 1.5 and 5 years of age, CLN7 disease is a rare form of late Batten disease. , but one of the most common in southern and Mediterranean Europe.

Both forms are caused by mutations in genes that provide instructions for producing proteins 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 the formation of lipofuscin – in cellular models of disease.

These models also included patient-derived cells grown in the lab, 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 most significantly increased, showing twice higher levels in CLN3 and CLN7 models compared to healthy cells. Gb3 accumulated in cell membranes and inside lysosomes. It should be noted that 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, from mouse models of both diseases, compared to healthy mice. This accumulation began earlier in the CLN7 model, resembling its earlier disease onset compared to CLN3 disease.

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

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

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

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urinary protein

The team then assessed whether any of the 1,280 compounds approved in the United States could reduce Gb3 accumulation in 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 accumulation 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 already been shown to be safe for use in pediatric conditions.

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 and involving the activation of TFEBa master gene of lysosomal function that stimulates the clearance of toxic storage.

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.

Tamoxifen-treated mice 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 novel biomarker for CLN3 and CLN7 disease” and that “tamoxifen-mediated clearance via TFEB activation may represent a small molecule-based strategy to treat common types of [Batten disease]“, wrote the researchers.