The new horizons for treatment of Late-Onset Pompe Disease (LOPD)

Abstract

Late-onset Pompe disease (LOPD) is a genetic myopathy causing skeletal muscle weakness and severe respiratory impairment, due to the deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) leading to lysosomal glycogen accumulation along with other complex pathophysiological processes. A major step for treatment of Pompe disease was reached in 2006 with the marketing of alglucosidase alfa, a first enzyme replacement therapy (ERT) that showed a significant motor and respiratory benefit. However, efficacy of alglucosidase alfa is limited in LOPD with a loss of efficacy over time, promoting research on new treatments. Next-generation ERT are new enzymes biochemically modified to increase the uptake of exogenous enzyme by target tissues, and the benefit of two recombinant enzymes (avalglucosidase alfa and cipaglucosidase alfa) has been recently studied in large phase III clinical trials, the latest combined with miglustat. Several innovative therapies, based on GAA gene transfer, antisense oligonucleotides or inhibition of glycogen synthesis with substrate reduction therapy, are currently under study, but are still at an early stage of development. Overall, active research for new treatments raises hope for LOPD patients but challenges remain for the clinician with the need for reliable efficacy assessment tools, long-term registry data, and evidence-based recommendations for the best use of these new molecules recently available or under development.

Keywords: Antisense oligonucleotides; Enzyme replacement therapy; Gene therapy; Glycogen storage disease II; Pompe disease; Substrate reduction therapy.