Genetically Modified Plant Roots May Be Better for Producing Key Enzyme in Gaucher Therapy, Study Shows

Genetically Modified Plant Roots May Be Better for Producing Key Enzyme in Gaucher Therapy, Study Shows

The large-scale production of glucocerebrosidase — an enzyme that is lacking in Gaucher disease — by genetically modifying plant roots is seen as a viable strategy for enzyme replacement therapy (ERT) to treat the disease, a recent study suggests.

The process could become a safer and less expensive way to produce glucocerebrosidase for ERT to treat Gaucher patients, researchers said.

The study, “The Production of Human β-Glucocerebrosidase in Nicotiana benthamiana Root Culture,” was published in the International Journal of Molecular Sciences.

Gaucher disease is caused by reduced activity of the glucocerebrosidase (GCase) enzyme, which leads to the accumulation of specific fat molecules in some organs, ultimately affecting their function.

Gaucher disease type 1 (GD1) is the most common form, and patients often have an enlarged spleen and liver, as well as low platelet levels and anemia.

One of the most efficient treatments for GD1 is ERT, which relies on the delivery of copies of the GCase enzyme to replace the deficient one, thus breaking down excess fat molecules. Currently approved ERTs for GD1 include Cerezyme (imiglucerase), VPRIV (velaglucerase alfa), and Elelyso (taliglucerase alfa).

While Cerezyme and VPRIV are produced from mammalian cell cultures, Elelyso is produced with a carrot cell culture, and is the first FDA-approved plant-based treatment. Results from previous clinical trials showed no significant differences between the therapeutic benefits of GCase produced in mammalian and plants cells.

Plant-based production of relevant proteins is growing because it is cheaper to produce and scale up with relatively inexpensive greenhouses and simple mineral solutions. It also is considered a safer process, given that plants rarely carry human or animal pathogens.

Researchers at the International Center for Biotechnology at Osaka University, in Japan, evaluated the efficacy and viability of producing glucocerebrosidase with the culture of the roots of genetically modified N. benthamiana, a close relative of the tobacco plant.

The plant was genetically modified to produce GCase, but researchers opted to use root cultures because they can grow faster and are less sensitive to mechanical damage than whole-plant cultures. Also, it can be easily scaled up.

Researchers successfully induced root growth of the GCase-producing plant by adding IAA — a plant hormone involved in plant growth and shown to induce root elongation — in both solid and liquid media. GCase also was detected in the roots of the modified plant, but not in those of the natural plant, supporting the ability of the modified plant to effectively produce GCase.

The enzymatic activity of non-purified GCase produced from root cultures was twice as high as the previously reported GCase activity produced from leaves, suggesting that this root system may be an improved method for producing GCase.

When researchers compared the enzymatic activity of non-purified GCase, purified GCase, and Cerezyme, they found that purified GCase had over 15 times higher enzymatic activity than that of non-purified GCase, and that Cerezyme still had about 30 percent more activity than purified GCase.

While two plant-specific molecular residues are added to plant-based GCase and could potentially induce immune reactions in mammals and humans, additional analysis showed no immune reactions against them, according to the researchers.

The team also noted that Elelyso contains about 90 percent of plant-specific residues, but no side effects related to these molecules have been reported in Phase 3 clinical trials, suggesting that the purified GCase produced in the root system should be a safe strategy to treat Gaucher disease.

“This study presents evidence for a new, safe and efficient system of recombinant GCase production that might be applied to other recombinant proteins,” the researchers wrote.

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