Reveglucosidase alfa (BMN 701), an IGF2-Tagged rhAcidα-Glucosidase, Improves Respiratory Functional Parameters in a Murine Model of Pompe Disease

Abstract

Pompe disease is a rare neuromuscular disorder caused by an acid α-glucosidase (GAA) deficiency resulting in glycogen accumulation in muscle, leading to myopathy and respiratory weakness. Reveglucosidase alfa (BMN 701) is an insulin-like growth factor 2-tagged recombinant human acid GAA (rhGAA) that enhances rhGAA cellular uptake via a glycosylation-independent insulin-like growth factor 2 binding region of the cation-independent mannose-6-phosphate receptor (CI-MPR). The studies presented here evaluated the effects of Reveglucosidase alfa treatment on glycogen clearance in muscle relative to rhGAA, as well as changes in respiratory function and glycogen clearance in respiratory-related tissue in a Pompe mouse model (GAA/J). In a comparison of glycogen clearance in muscle with Reveglucosidase alfa and rhGAA, Reveglucosidase alfa was more effective than rhGAA with 2.8-4.7 lower EC values, probably owing to increased cellular uptake. The effect of weekly intravenous administration of Reveglucosidase alfa on respiratory function was monitored in Pompe and wild-type mice using whole body plethysmography. Over 12 weeks of 20-mg/kg Reveglucosidase alfa treatment in Pompe mice, peak inspiratory flow (PIF) and peak expiratory flow (PEF) stabilized with no compensation in respiratory rate and inspiratory time during hypercapnic and recovery conditions compared with vehicle-treated Pompe mice. Dose-related decreases in glycogen levels in both ambulatory and respiratory muscles generally correlated to changes in respiratory function. Improvement of murine PIF and PEF were similar in magnitude to increases in maximal inspiratory and expiratory pressure observed clinically in late onset Pompe patients treated with Reveglucosidase alfa (Byrne et al., manuscript in preparation).

The Respiratory Phenotype of Pompe Disease Mouse Models

“…Similar to Pompe mice, patients with Pompe disease demonstrate respiratory pathophysiology and insufficiency, as well as upper airway pathology [74][75][76][77][78][79]. Furthermore, IPD and LOPD patients have reduced vital capacity [76,80,81], which is reminiscent of the reduced tidal volume during the respiratory challenge demonstrated by WBP in mice [51,62,63,71].…”

“…WBP quantifies minute ventilation, lung volumes, and changes in flow in awake, spontaneously breathing mice [44,51,70]. WBP studies confirm that mouse models of Pompe disease have respiratory dysfunction [42,45,49,51,52,61,63,71,72]. Although results of WBP at baseline vary, most studies found that Gaa −/− mice have abnormal parameters of WBP.…”

“…While breathing room air (FiO 2 0.21; N 2 balance), these mice have greater expiratory time (Te) [45] and lower tidal volume (TV) [49,63], frequency (f) [45,49], tidal volume to inspiratory time ratio (TV/Ti) [49,61], minute ventilation (VE) [49], minute ventilation to expired CO 2 ratio (VE/V CO2 ) [49,61], peak inspiratory flow (PIF) [49,61], and peak expiratory flow (PEF) [49,71]. Furthermore, during a hypercapnic challenge (FiCO 2 : 0.07; FiO 2 0.21; nitrogen balance), Gaa −/− mice on both the B6/129 and the 129SVE backgrounds have a reduced response to respiratory challenge [42,49,51,[61][62][63]71,72]. For example, these mice have lower VE, TV, and PIF relative to WT during hypercapnic challenge, although these factors did increase relative to baseline [42,49,51,[61][62][63]71].…”

“…Furthermore, during a hypercapnic challenge (FiCO 2 : 0.07; FiO 2 0.21; nitrogen balance), Gaa −/− mice on both the B6/129 and the 129SVE backgrounds have a reduced response to respiratory challenge [42,49,51,[61][62][63]71,72]. For example, these mice have lower VE, TV, and PIF relative to WT during hypercapnic challenge, although these factors did increase relative to baseline [42,49,51,[61][62][63]71]. The respiratory cycle in Gaa −/− mice also has higher variability than WT [66].…”

The Respiratory Phenotype of Pompe Disease Rodent Models

“…WBP quantifies minute ventilation, lung volumes and changes in flow, in awake, spontaneously breathing mice [41,50,66]. WBP studies confirm that rodent models of Pompe disease have respiratory dysfunction [39,42,48,50,51,58,60,67]. Although results of WBP at baseline vary, most studies found that Gaa -/-mice have abnormal parameters of WBP.…”