Novel treatment shows promise in cell model of Fabry disease

Substrate reduction therapy may help reduce Gb3S enzyme levels

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A dropper is poised over a petri dish alongside an aerial view of another petri dish.

Researchers have developed a novel treatment — an experimental substrate reduction therapy, or SRT — that may hold promise for Fabry disease, according to a new preclinical study.

The treatment is designed to reduce levels of Gb3 synthase (Gb3S), an enzyme involved in the production of globotriaosylceramide (Gb3), which accumulates to toxic levels in Fabry.

In a cell model of the disease, the new SRT was able to reduce Gb3S levels without compromising cell survival.

The study, “Novel Golden Lipid Nanoparticles with Small Interference Ribonucleic Acid for Substrate Reduction Therapy in Fabry Disease,” was published in Pharmaceutics.

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Looking for new treatment options for Fabry disease

In Fabry, mutations in the GLA gene cause its protein product, alpha-galactosidase A, or Gal A, to be absent, deficient, or faulty.

Because Gal A is an enzyme needed to break down certain fatty molecules, such mutations mean that these molecules, particularly Gb3, toxically accumulate in the body’s cells. There they cause tissue and organ damage.

Patients are treated with enzyme replacement therapy to provide a working version of the missing enzyme, or chaperone therapy, that helps any remaining enzyme to be more functional.

Substrate reduction therapy, known as SRT for short, is under investigation as another treatment option for Fabry disease. The approach, essentially, aims to reduce how much Gb3 is made by blocking other enzymes necessary for its production.

If significantly less Gb3 is being made, it is thought that the lack of Gal A to break it down in Fabry patients would no longer be a problem.

A couple of SRTs are under investigation for Fabry, including Idorsia’s lucerastat and Sanofi Genzyme’s venglustat. Both are oral molecules designed to block an enzyme called glucosylceramide synthase, or GCS, that is needed for Gb3 to be made.

However, blocking GCS also suppresses molecules other than Gb3, which can cause side effects, according to the researchers.

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New SRT aims for more specific target in Fabry

Now, the team proposed the development of a novel SRT for Fabry that instead inhibits Gb3S, a more specific target for reducing only Gb3.

The researchers created several versions of such a therapy. Each used a molecule called a small-interfering RNA (siRNA) to regulate the activity of the gene responsible for producing Gb3S. But of them differed in terms of their formulation.

Ultimately, the scientists found one version that seemed to be very stable, was taken up efficiently, and had a strong ability to silence Gb3S in a cell model of Fabry disease.

In this version, the siRNA was packaged into tiny molecules called gold nanoparticles that are known for their safety and therapeutic efficacy when used to package gene therapies.

The siRNA-based therapies could silence the gene activity associated with Gb3S by up to 90%, the testing showed.

Suppression of the Gb3S enzyme in the Fabry cells was found to be sustained for at least 15 days with the most effective versions.

These results show the potential of the siRNA–golden [nanoparticles] targeted to Gb3S for the treatment of [Fabry disease] by specific SRT.

Importantly, the gold nanoparticle-encapsulated therapy did not compromise the health or survival of the cells and was not found to interact with blood components, which can be a drawback with these types of treatments.

“These results show the potential of the siRNA–golden [nanoparticles] targeted to Gb3S for the treatment of [Fabry disease] by specific SRT,” the researchers wrote.

While the findings altogether indicate that the new version of SRT may show promise for Fabry, the researchers emphasized that the studies here were only conducted in cells (in vitro) and have not been tested in live animal models (in vivo).

“The lack of in vitroin vivo correlation in the gene therapy field is well known,” the researchers wrote. “Therefore, future in vivo studies in animal models of the disease would help to confirm the potential of our formulations to treat [Fabry disease].”