The induction of antigen-based oral tolerance can help prevent the formation of antidrug antibodies in protein replacement therapies such as the ones used in Pompe disease.

Oral tolerance is dependent on regulatory T-cell induction, and plant-based antigen expression for oral tolerance has been tested in models of Pompe disease, among others.

The paper was recently published in the journal Cellular Immunology. It outlined the general perceptions and current knowledge about the mechanisms of oral tolerance.


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Protein replacement therapy has dramatically improved patients’ quality of life. However, the immune response against the therapeutic protein poses a problem and can render the treatment inefficient at best and put patients’ safety at risk at worst, Jyoti Rana, of the Indiana University School of Medicine in Indianapolis, and colleagues noted.

The induction of antigen-based oral tolerance, which exploits regulatory mechanisms that start in the gut-associated lymphoid tissue to suppress orally ingested antigens, can prevent the formation of antidrug antibodies against protein replacement therapies, they added.

Read more about other treatments for Pompe disease

In the present review, a team of investigators defined tissue-specific sites of tolerance induction and the cells that are involved in this tolerance, such as antigen-presenting cells and regulatory T cells.

The researchers also highlighted several preclinical studies that have been performed to induce oral tolerance to therapeutic proteins. 

“These studies mainly utilize a transgenic plant-based system for oral delivery of antigen in conjugation with fusion protein technology that favors the prevention of antigen degradation in the stomach while enhancing uptake in the small intestine by antigen-presenting cells and regulatory T cell induction, thereby promoting antigen-specific systemic tolerance,” the study authors wrote.

Pompe disease is caused by a mutation in the gene that codes for the lysosomal enzyme acid alpha-glucosidase (GAA), the role of which is to break down glycogen to form glucose. When the enzyme does not function properly because of the mutation, glycogen accumulates inside tissues causing damage.

Enzyme replacement therapy for Pompe disease consists of a recombinant human GAA enzyme known as alglucosidase alfa.

Reference

Rana J, Munoz M, Biswas M. Oral tolerance to prevent anti-drug antibody formation in protein replacement therapies. Cell Immunol. Published online November 14, 2022. doi:10.1016/j.cellimm.2022.104641