New Fabry disease nanomedicine takes two-pronged approach in cells
Study combined gene supplementation and substrate reduction strategies
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A team of scientists in Spain has developed a new experimental nanoparticle-based treatment approach that aims to address the root cause of Fabry disease through two distinct biological pathways.
The new nanomedicine aims to deliver a working copy of the GLA gene, while also reducing production of Gb3, a fatty molecule that builds up to toxic levels in the disease. The approach showed early proof-of-concept effects in Fabry disease cell models, though researchers noted that further work, including tests in animal models, is still needed.
“These data validate a co-delivery platform that integrates complementary gene therapy approaches within a single nanomedicine and support its potential to expand therapeutic avenues for [Fabry disease],” the scientists wrote.
Nanomedicine targets Fabry from two angles
The study, “Nanomedicines for DNA and interference RNA co-delivery: Combined gene therapy for Fabry disease,” was published in the International Journal of Pharmaceutics: X.
Fabry disease is a genetic disorder caused by mutations in the GLA gene, which provides instructions to make an enzyme called alpha-galactosidase A (alpha-Gal A). This enzyme is normally needed to break down certain fatty molecules, most notably globotriaosylceramide (Gb3). People with Fabry disease lack enough working alpha-Gal A enzyme; as a result, Gb3 builds up to toxic levels in the body’s cells, leading to tissue damage that drives disease symptoms.
Available treatments for Fabry include enzyme replacement therapy, in which a functional version of the alpha-Gal A enzyme is infused into the body, and chaperone therapy, which uses small molecules to boost the enzyme’s activity in people with certain eligible mutations. But while these treatment strategies have improved the lives of people with Fabry disease, “none have been able to completely revert clinical manifestations and there are still many clinical needs to be met … Consequently, new strategies should be developed,” the researchers wrote.
Several experimental treatment strategies for Fabry disease are in development. One such strategy is gene supplementation, a type of gene therapy that aims to deliver a working version of the GLAÂ gene to the body’s cells, allowing them to produce their own functional alpha-Gal A enzyme to clear toxic Gb3. Another strategy is substrate reduction, which aims to decrease production of Gb3, thereby reducing the toxic buildup of this molecule.
The researchers in this study proposed a relatively simple idea: what if both of these treatment strategies could be combined into one therapy? Theoretically, this approach could reduce toxic Gb3 more potently than either strategy alone. Designing one medicine that can achieve both goals is a major technical challenge, but the scientists developed a way to do this using solid lipid nanoparticles that incorporate tiny gold nanoparticles.
Nanoparticles carry two genetic payloads
Essentially, the nanoparticles serve as a packaging material for two molecules. One molecule is a piece of DNA containing a working version of the GLAÂ gene, with the goal of helping cells produce functional alpha-Gal A enzyme. The second molecule is a small interfering RNA (siRNA), which is a small piece of genetic material that can decrease the activity of a specific target gene. In this case, the siRNA reduces the activity of the gene that encodes Gb3 synthase, the enzyme involved in producing Gb3.
In their study, the researchers presented detailed data characterizing the molecular properties of their new nanoparticle-based medicine, along with early proof-of-concept experiments showing that it appears to function as intended in Fabry disease cell models. Notably, nanoparticles loaded with both DNA and siRNA led to a greater reduction in Gb3 levels than nanoparticles carrying either molecule on its own.
“These results demonstrate, for the first time, the efficacy of a nanomedicine combining gene supplementation and [siRNA]-mediated suppression for the treatment of [Fabry disease],” the researchers wrote.
The scientists stressed that their study was limited to cell models and other laboratory experiments, noting that further work, including studies in living animals, will be needed to further test the safety and efficacy of this approach.
