Infantile-onset Pompe disease (IOPD) is a fatal glycogen storage disease caused by a deficiency of the enzyme acid alpha-glucosidase (GAA), which leads to an accumulation of glycogen and skeletal, cardiac, and smooth muscle damage. IOPD is treated with recombinant human GAA (rhGAA, alglucosidase alfa) enzyme replacement therapy (ERT), which can significantly improve clinical outcomes. However, many IOPD patients treated with rhGAA develop anti-drug antibodies (ADA) that render the therapy ineffective.

A research team at Duke University Medical Center in Durham, North Carolina, previously developed a tool for personalized immunogenicity risk assessment (now called PIMA) to predict the risk of developing ADA. The team has improved on its work, developing a newer version of the tool, the V3J, which performed better than the intermediate versions V2 and V3. The differing T cell epitopes in rhGAA and native GAA drives ADA development, and the tool essentially quantifies T cell epitopes that differ between rhGAA and native GAA. 

The study included genotype data on 62 patients with a confirmed diagnosis of IOPD, out of which 14 were excluded due to presence of late-onset Pompe disease (LOPD). Further, 19 patients (40%) developed high ADA titers, and PIMA V3J was able to correctly predict ADA status for 64% of the patients.

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The study found that patients with PIMA V3J scores of more than 10 and initiation of ERT after 19 weeks of age were over 8 times more likely to develop high ADA than other patients. When considering the results in the context of clinical significance and using PIMA to identify patients at low risk, those with V3J scores of less than 10 and ERT initiation prior to 19 weeks were more than 12 times more likely to have low ADA than all other patients. 

Although the tool has great utility in identify IOPD patients at higher risk of ADA, the researchers believe it would need further validation through prospective studies before it can be implemented in clinical settings. The tool is currently available on the web for preclinical research purposes.


De Groot AS, Desai AK, Lelias S, et al. Immune tolerance-adjusted personalized immunogenicity prediction for Pompe disease. Front Immunol. Published online June 16, 2021. doi:10.3389/fimmu.2021.636731

De Groot AS, Kazi ZB, Martin RF, et al. HLA- and genotype-based risk assessment model to identify infantile onset Pompe disease patients at high-risk of developing significant anti-drug antibodies (ADA). Clin Immunol. 2019;200:66-70. doi:10.1016/j.clim.2019.01.009