TRPML1 agonists synergize with enzyme replacement therapy in fibroblasts from Pompe disease patients

Pompe disease is a severe and progressive metabolic myopathy caused by pathogenic variants of the GAA gene, deficiency of acid alpha-glucosidase (GAA), and lysosomal glycogen storage. The current standard of treatment for PD is enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Despite significant success of ERT in correcting some disease manifestations, limitations of its efficacy have emerged, due to several factors. Poor expression or abnormal intracellular distribution of the cation-independent mannose-6-phosphate receptor (M6PR) at the plasma membrane of specific cells has been identified as one of these factors. Here, we investigated whether activation of Transient Receptor Potential Mucolipin 1 (TRPML1) synergizes with ERT. TRPML1 is a lysosomal ion channel that has been shown to induce multiple effects, including regulation of calcium homeostasis, stimulation of autophagy, activation of lysosomal biogenesis and exocytosis, enhancement of vesicle and membrane trafficking.

We studied the effects of two TRPML1 agonists in cultured fibroblasts from Pompe disease patients. Specifically, we analyzed M6PR availability at the plasma membrane of control and mutant cells, level of correction of GAA activity by rhGAA, processing and lysosomal trafficking of the recombinant enzyme.

Treatment with two TRPML1 agonist drugs increased M6PR total amounts and its availability at the plasma membrane and improved M6PR intracellular recycling. The improvements in M6PR distribution translated into better correction of GAA activity in cells incubated with rhGAA and in improved lysosomal trafficking and processing of the recombinant enzyme.

These data provide in vitro proof-of-concept evidence supporting the combination of ERT with pharmacological manipulation of secondarily altered M6PR distribution as a strategy to obtain better exposure of cells to therapeutic enzymes.