Cancer Therapy Tamoxifen May Hold Promise for 2 Batten Types
A screening of U.S.-approved therapies revealed that tamoxifen, an oral cancer therapy, is able to effectively reduce the accumulation of a fatty molecule called globotriaosylceramide, or Gb3, in cellular models of two forms of Batten disease. It worked without compromising cell survival, a study showed.
That study found that the levels of Gb3 are abnormally increased in cellular and mouse models of these two Batten types, specifically neuronal ceroid lipofuscinosis type 3 — known as CLN3 — and type 7, called CLN7.
In addition, tamoxifen was shown to lower neuroinflammation and improve motor coordination in a mouse model of CLN7 disease, researchers said.
The study, “Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype,” was published in the journal EMBO Molecular Medicine.
Batten disease is the most common group of pediatric neurodegenerative disorders. It is associated with the toxic accumulation of lipofuscins — deposits of fats and proteins — inside lysosomes. Lysosomes are small structures within cells that break down waste products and unused proteins into smaller components to be discarded or recycled.
The buildup of lipofuscins mainly affects the central nervous system, comprised of the brain and spinal cord, and the retina, the light-sensitive inside lining of the eye.
While the genetic cause of each type of Batten disease is well-established, “protein functional understanding remains elusive making it challenging to target therapeutic drugs by intelligent design,” the investigators wrote.
Now, an international team of researchers discovered a new biomarker of CLN3 and CLN7 diseases, which helped run a therapy repurposing assay. That subsequently identified a new potential treatment for these conditions.
Repurposing compounds already approved — and thus tested for safety — for one health condition for use in treating 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 the ages of 5 and 10. With a symptom onset between ages 1.5 and 5, CLN7 disease is a rare form of late-infantile Batten disease, but one of the most prevalent in southern and Mediterranean Europe.
Both forms are caused by mutations in genes that provide instructions to produce proteins located at 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 cellular models of the diseases.
These models also included lab-grown, patient-derived cells, such as fibroblasts, the most common cell type in the tissue that surrounds and supports organs, and neural progenitor cells.
They found that among tested molecules, Gb3 was the most significantly increased, showing twice as high levels in CLN3 and CLN7 models relative to healthy cells. Gb3 accumulated in cellular 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 Gb3 buildup also was observed in brain tissue, particularly in nerve cells, of mouse models of both diseases, when compared with healthy mice. This accumulation started earlier in the CLN7 model, resembling its earlier disease onset relative to CLN3 disease.
Further analyses suggested that Gb3 is not just a collateral effect of lysosomal dysfunction, since suppressing the activity of the Gb3-producing enzyme reduced the accumulation of SCMAS, a hallmark component of disease-associated storage in CLN3 and CLN7 diseases.
Notably, no abnormal levels of Gb3 were found in a cellular model of CLN6 disease, also known as variant late infantile Batten.
These findings highlight Gb3 storage as a disease biomarker of CLN3 and CLN7 diseases.
The team then assessed whether any of 1,280 U.S.-approved compounds could lessen Gb3 accumulation within lysosomes of cellular models of these conditions.
The screening showed that treatment with tamoxifen resulted in the most potent reduction of Gb3 levels in both models, without compromising cell survival. It also lowered SCMAS accumulation.
Tamoxifen is an oral hormonal therapy used around the world for treating certain breast cancers and other hormone-related disorders. Sold under the brand names Nolvadex and Soltamox, it previously was shown to be safe for use in pediatric conditions.
Notably, the therapy can cross the blood-brain barrier, a highly selective membrane that prevents microbes and potentially harmful molecules in circulation from reaching the brain and spinal cord.
Further analyses revealed that tamoxifen promoted Gb3 clearance through a mechanism independent of its hallmark hormone receptor and that involved the activation of TFEB, a master gene of lysosomal function that boosts toxic storage clearance.
The researchers then tested tamoxifen in a mouse model of CLN7, since it shows a more severe disease than existing CLN3 mouse models and closely recapitulates disease features seen in CLN7 patients.
Mice treated with tamoxifen showed significantly lower levels of both Gb3 and SCMAS in the brain, reduced signs of neuroinflammation, and a partial recovery of motor coordination, compared with untreated mice.
These findings highlight that “Gb3 is a novel biomarker for CLN3 and CLN7 diseases,” and that “tamoxifen-mediated clearance via TFEB activation may represent a small molecule-based strategy to treat common types of [Batten disease],” the researchers wrote.