Reaping the Benefits of Plant-Based Enzyme Replacement Therapy for Pompe Disease Treatment

by: Ian Justin Manansala | Chromoplexy & Alodia Iyanla Viray | Chromoplexy

IMAGE SOURCE: https://pompediseasenews.com/pompe-disease-treatments/

What is Pompe Disease?

Until now, Pompe disease—also known as acid-maltase disease or glycogen storage disease II—has long been a formidable challenge in the medical sciences. It is a rare genetic disease belonging to a group known as the ‘lysosomal storage disorders’ (LSDs) and the ‘glycogen storage disorders’ (GSDs), due to a mutation or lack of the enzyme acid alpha-glucosidase (GAA). Deficiency of this protein hampers the breakdown of a complex sugar ‘glycogen’ into a simple sugar ‘glucose,’ which leads to its accumulation in all kinds of tissues, but primarily in skeletal, smooth, and cardiac muscles. Expected effects include structural and functional tissue damage, ultimately leading to organ dysfunction. 

Current treatments for Pompe disease

Despite significant advances in the medical field, Pompe disease remains a genetic disorder without a cure. While therapies help reduce the progression of glycogen buildup in muscles, they cannot fully reverse the damage already done; thus, significant unmet medical needs remain.

Enzyme Replacement Therapy (ERT) or the intravenous administration of recombinant human acid alpha-glucosidase (rhGAA) was first approved by the U.S. Food and Drug Administration (FDA) in 2006. As a replacement for the missing enzyme acid alpha-glucosidase (GAA), healthcare practitioners administer biweekly treatments through alglucosidase alfa, marketed Lumizyme or Myozyme, produced through recombinant DNA technology in a Chinese hamster ovary (CHO) cell line. This genetically engineered enzyme is designed to mimic the function of the missing GAA protein.

Advancements in plant-based oral-ERT

In recent studies, biotechnology has opened up new possibilities for Pompe disease treatment, with emerging plant-based enzymes produced from transgenic plants such as tobacco and rice. These innovations conveniently offer the potential to deliver ERT orally at frequent intervals daily rather than through the conventional intravenous route. Moreover, these plant-based treatments are reported as more affordable, as plants can be grown and harvested on a larger scale, making enzyme production significantly cheaper than mammalian cell-based systems and potentially reducing the financial burden on patients and healthcare systems.

Transgenic Tobacco

Amongst plant parts used for enzyme production, seeds were determined to possess the “necessary machinery” to carry out different metabolic pathways, ensuring long-term stability and protection for recombinant enzymes. One recent study investigated the use of transgenic tobacco seeds grown in a hydroponic system to produce the recombinant human GAA (tobrhGAA) enzyme. Pre-clinical trials using GAA knockout (KO) mice demonstrated that the oral-ERT with ground tobrhGAA seeds experienced reduced glycogen accumulation in tissues and improved muscle strength, coordination, and mobility. This cutting-edge research opens the door for a cost-efficient, safe, and effective alternative solution for Pompe disease therapy. 

Transgenic Rice

Rice was also used in similar research; the GAA gene from human placenta cells was integrated into a vector that uses the rice α-amylase promoter gene (RAmy3D) to control human GAA (hGAA) expression, induced by sucrose starvation. This hGAA vector was delivered into rice callus via Agrobacterium-mediated infection. rhGAA expression in transgenic rice cell culture was confirmed by PCR, Northern, and Western blot analyses. 

In a more recent transgenic rice study, N-acetylglucosaminyltransferase I (GnTI) knock-out rice cells expressing recombinant human acid α-glucosidase (rhGAA) were cultured. Two chemical inhibitors, kifunensine and swainsonine, were added to the cell culture to regulate metabolic processes that promote rhGAA production. N-glycan profiling and additional biochemical tests verified the comparable biological functional activities of the rice-derived rhGAAs. 

Both studies confirmed that rice-derived rhGAA enzymes had similar functional activity to CHO-derived GAA. These findings illustrate the potential of viable and economical plant-derived therapeutics to combat Pompe disease.

Future outlook

Pompe disease remains a challenging genetic disorder with unmet medical needs. Biotechnological progress in ERT, particularly plant-based oral-ERT research, offers new hope for significant potential for commercial use. These studies provide a glimpse of what biotechnology can offer—improving treatment accessibility while reducing costs and inspiring further research with medical applications, especially in rare genetic disease interventions.

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This article was originally published in GENEWS November 2024 Issue