Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for glycogen storage disease type III

Abstract

We investigated the feasibility of using recombinant human acid-α glucosidase (rhGAA, Alglucosidase alfa), an FDA approved therapy for Pompe disease, as a treatment approach for glycogen storage disease type III (GSD III). An in vitro disease model was established by isolating primary myoblasts from skeletal muscle biopsies of patients with GSD IIIa. We demonstrated that rhGAA significantly reduced glycogen levels in the two GSD IIIa patients' muscle cells (by 17% and 48%, respectively) suggesting that rhGAA could be a novel therapy for GSD III. This conclusion needs to be confirmed in other in vivo models.

Correction of glycogen storage disease type III with rapamycin in a canine model

“…Myoblasts were isolated from skeletal muscle biopsies of two patients with GSD IIIa, and the differentiation of myoblasts into myotubes was induced in low-serum medium [28]. Rapamycin significantly reduced glycogen levels by 41 and 50 %, respectively, in the myotubes derived from two GSD IIIa patients (Fig.…”

“…Primary culture of skeletal muscle cells from human patients Myoblasts were isolated from skeletal muscle biopsies of two patients with GSD IIIa and maintained in high-serum growth medium as described, and differentiation of myoblasts into mature myotubes was induced in low-serum differentiation medium [28]. Rapamycin was added to the culture medium at a final concentration of 0.03 or 0.3 μM.…”

“…After 48 h, cells were washed three times with cold phosphate buffered saline and then collected with a scraper. Glycogen content was determined in the cell lysates as previously described [28]. A glucose uptake experiment was conducted in live myoblasts as assessed by monitoring accumulation of a fluorescent Dglucose analog, 2-[N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG, Invitrogen) per manufacturer's instruction, in the presence or absence of rapamycin (0.03 μM).…”

Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation

“…This case report outlines the benefits that the patient showed while on ERT treatment, the decline to his condition when his infusions were discontinued due to his updated diagnosis, and the significant positive response when alglucosidase alfa ERT was reinitiated. This case study provides several key messages: 1) the importance of confirming the diagnosis of Pompe disease via gene sequencing and doing enzyme analysis in a lab with experience before ERT initiation, 2) our group's previous work showing the potential of GAA as a treatment approach for cytoplasmic GSDs [11] such as PRKAG2, and 3) it also supports the expanded phenotype of PRKAG2 depicting a case with myopathy, seizures, and minimal cardiac involvement.…”

“…Furthermore, the use of ERT with alglucosidase alfa depends upon the mannose 6-phosphate receptor mediated enzyme uptake into lysosomes, which has been effective in reducing lysosomal glycogen storage in Pompe disease. Our group has demonstrated that ERT significantly reduced glycogen levels in the cultured primary myoblasts from skeletal muscle biopsies of patients with GSD IIIa, a cytoplasmic GSD caused by the deficiency of glycogen debranching enzyme that leads to accumulation of abnormally structured cytoplasmic glycogen in liver and muscle [11]. We speculated that administration of recombinant human acid alfa glucosidase enhanced lysosomal glycogen depletion, facilitated glycogen transport from the cytoplasm into lysosomes, and ultimately reduced cytoplasmic glycogen accumulation in the GSD III patient cells.…”