Importantly, AT2220 was found to cross the blood-brain barrier in mice, with less-frequent AT2220 administration significantly reducing brain glycogen levels. In contrast, multiple administrations of rhGAA had no effect on brain GAA activity or glycogen levels in preclinical or clinical studies, underscoring the challenges associated with CNS penetration of exogenous replacement enzymes. These data suggest that AT2220 may offer an advantage over ERT for treating the CNS manifestations of Pompe disease, which should be explored AS-604850 further. We have shown previously that only a subset of GAA mutants respond to AT2220. Given that most GAA missense mutations are rare, or ��private��, and that most late-onset patients have at least one copy of a common splicing mutation, the fraction of Pompe patients who have responsive mutant missense forms is unknown, though it is expected to be low. To this end, the P545L variant has only been identified in a small number of Pompe patients. However, there is evidence that certain GAA mutations are more common in certain geographical regions or within certain ethnic groups, some of which may be enriched for chaperone responsive mutant forms. Given this Tolazoline hydrochloride potentially low prevalence of responsive mutant forms, AT2220 has also recently been investigated in co-administration studies with rhGAA. We and others have shown that AT2220 binds and stabilizes exogenous rhGAA, thereby leading to improved cellular uptake and glycogen reduction in disease-relevant tissues, including skeletal muscles. Notably, repeat administration of rhGAA to Gaa KO mice is also known to result in an immune response that manifests as severe anaphylaxis, often leading to death. The Gaa KO mice form anti-rhGAA IgGs that not only limit the number of injections of rhGAA that can be administered before the onset of anaphylaxis, but may also impact efficacy. These observations are similar to what has been reported in some Pompe patients, where rhGAA infusion leads to severe immune responses that are mediated by IgGs, some of which inhibit the catalytic activity of GAA.