Development of a Pompe disease CRIM assay for blood samples

Pompe disease is an autosomal-recessive lysosomal storage disorder that is caused by deficiency of lysosomal acid alpha- glucosidase (GAA) enzyme activity and characterized by lysosomal glycogen accumulation in various tissues, but particularly in muscle. In a 52 week trial of 18 infantile-onset children <7 months of age, treatment with alglucosidase alfa enzyme replacement therapy markedly improved survival in comparison with a historical natural history control group. In addition, the hypertrophic cardiomyopathy characteristic of infantile-onset Pompe improved dramatically. Pompe disease patients that do not produce any detectable endogenous GAA protein product are considered to be cross-reacting immunologic material negative [CRIM (-)]. CRIM (-) status is considered a poor prognostic factor because CRIM (-) patients tend to have high antibody titers against enzyme replacement therapy that may interfere with delivery of the infused enzyme to target tissues. Available methods for determining CRIM status take 6 - 8 weeks because they require the establishment and expansion of fibroblast cultures before testing. To reduce this time delay and to facilitate making treatment decisions, we developed a CRIM method that uses blood samples. The development of this assay and its validation in a limited number of Pompe disease patients will be presented.