Pompe disease is a rare genetic disorder with an estimated incidence of 1 in 40,000 individuals worldwide. This autosomal recessive disease is a neuromuscular disorder caused by nonsense/missense mutations, insertions, deletions, and splice site variations in the gene coding for α-glucosidase. Substitutions leading to a deficiency of α-glucosidase activity cause a multitude of defects involving cardiac, respiratory, and neuromuscular functions due to the accumulation of glycogen inside cells. Although enzyme replacement therapy has been approved for the treatment of Pompe disease and has shown promise, it is exorbitantly expensive with its own set of limitations. There have been efforts by different groups to engineer the recombinant α-glucosidase enzyme to address the issues associated with enzyme replacement therapy. This article proposes that α-glucosidase with a high specific activity can efficiently break down the accumulated glycogen in tissues of Pompe disease patients. Such a variant with a high turnover number can bring down the dosage of treatment potentially leading to a lowered treatment cost. A phenotype-based screening strategy employing Saccharomyces cerevisiae is suggested for the identification of high-specific activity variants of human α-glucosidase. Such mutants once identified, can be tested using in vitro and in vivo models of Pompe disease, to assess their benefits over the wild-type counterpart. Similar screening strategies can be employed to identify high-specific activity mutants of other enzymes involved in lysosomal storage diseases, for them to be employed in enzyme replacement therapy.