Enzyme Replacement Therapy Can Reverse Pathogenic Cascade in Pompe Disease

Abstract

Pompe disease, a deficiency of glycogen-degrading lysosomal acid alpha-glucosidase (GAA), is a disabling multisystemic illness that invariably affects skeletal muscle in all patients. The patients still carry a heavy burden of the disease, despite the currently available enzyme replacement therapy. We have previously shown that progressive entrapment of glycogen in the lysosome in muscle sets in motion a whole series of “extra-lysosomal” events including defective autophagy and disruption of a variety of signaling pathways. Here, we report that metabolic abnormalities and energy deficit also contribute to the complexity of the pathogenic cascade. A decrease in the metabolites of the glycolytic pathway and a shift to lipids as the energy source are observed in the diseased muscle. We now demonstrate in a pre-clinical study that a recently developed replacement enzyme (recombinant human GAA; AT-GAA; Amicus Therapeutics) with much improved lysosome-targeting properties reversed or significantly improved all aspects of the disease pathogenesis, an outcome not observed with the current standard of care. The therapy was initiated in GAA-deficient mice with fully developed muscle pathology but without obvious clinical symptoms; this point deserves consideration.

Characterization of Gait and Postural Regulation in Late-Onset Pompe Disease

“…The entrapment of lysosomal glycogen results in muscle damage by a number of pathogenic mechanisms, such as defective autophagy, calcium homeostasis, oxidative stress, and mitochondrial abnormalities [2]. Recently, metabolic abnormalities and energy deficits have also been shown to contribute to this pathogenic cascade [3]. The severity of clinical manifestations, tissue impairment and age of onset correlate with the residual enzymatic activity and can be classified into two forms: the Infantile Onset Pompe Disease (IOPD) or classical form has no or very low enzymatic activity levels, leading to severe general muscular weakness with floppy infant syndrome.…”

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

“…Likewise, the mechanism of impaired autophagosomal-lysosomal fusion, which can be directly observed by time-lapse microscopy of live fibers co-stained with LC3/LAMP1 [67], is not fully understood. Our recent finding of increased levels of galectin 3, a sensitive marker of endosomal/lysosomal damage, in KO muscle offers a possible explanation for the defective fusion [66].…”

“…In a large preclinical study in KO mice, AT-GAA was shown to significantly outperform alglucosidase alfa in all measured outcomes: GAA uptake and activity, muscle strength, reduction in lysosomal size and glycogen levels, and mitigation of autophagic defect [92]. Furthermore, long-term treatment of KO with AT-GAA completely reversed muscle lysosomal glycogen accumulation, eliminated autophagic buildup in >80% of muscle fibers, and to a large degree restored AMPK/mTORC1 signaling, muscle proteostasis, and metabolic abnormalities [66]. This outcome is in striking contrast with the limited effect of a long-term treatment of KO mice with alglucosidase alfa at a similar dose of 20 mg/kg [22].…”

“…The molecular mechanism underlying the defective autophagy in the diseased muscle involves both increased formation of autophagosomes (induction of autophagy) and their inefficient fusion with lysosomes (autophagic block). Elevated levels of proteins required for the initial steps of autophagy (autophagosome nucleation and maturation), such as VPS15 protein kinase, the lipid kinase catalytic subunit VPS34, and the regulatory protein Beclin1, in muscle biopsies from KO and Pompe patients [65,66] argue for autophagy induction. The mechanism of this surge in autophagy is not exactly clear.…”

“…Furthermore, autophagic buildup negatively affects trafficking and lysosomal delivery of the therapeutic enzyme [67][68][69] and contributes to poor skeletal muscle response to ERT [70,71]. Importantly, autophagic accumulation and elevated levels of galectin 3 can be detected as early as in 6-week-old KO mice, well before the disease becomes clinically apparent [66].…”