Targeted delivery of acid alpha-glucosidase corrects skeletal muscle phenotypes in Pompe disease mice

Abstract

Lysosomal diseases are a class of genetic disorders predominantly caused by loss of lysosomal hydrolases, leading to lysosomal and cellular dysfunction. Enzyme Replacement Therapy (ERT), where recombinant enzyme is given intravenously, internalized by cells, and trafficked to the lysosome, has been applied to treat several lysosomal diseases. However, current ERT regimens do not correct disease phenotypes in all affected organs because the biodistribution of enzyme uptake does not match that of the affected cells and tissues that require the enzyme. We present here targeted ERT, an approach that utilizes antibody-enzyme fusion proteins to target the enzyme to specific tissues. The antibody moiety recognizes transmembrane proteins involved in lysosomal trafficking and that are also preferentially expressed in those cells most affected in disease. Using Pompe disease (PD) as an example, we show that targeted ERT is superior to ERT in treating the skeletal muscle phenotypes of PD mice.

An innovative strategy to identify new targets for delivering antibodies to the brain has led to the exploration of the integrin family

“…Integrins are ubiquitously expressed, and so are all the above reported transcytosis-mediating receptors. Integrin α7 antibodies have for instance been reported to increase muscle targeting of lysosomal enzymes [ 132 ]. Nevertheless, in our next study, we could include a counter screen of peripheral tissues, to select hits with the highest endothelial brain cell enrichment.…”

Omics-Based Approaches for the Characterization of Pompe Disease Metabolic Phenotypes

“… Graphical representation of the most common dysregulations observed in PD patients, derived from glycogen accumulation but also due to secondary abnormalities (e.g., impaired autophagy, activation of inflammation), and newer therapeutic approaches under investigation directed to restore lysosomal functionality and improve response to therapy in PD patients, including ERT (e.g., Myozyme) [ 69 ], enzyme stabilization (e.g., Cipaglucosidase alfa plus miglustat) [ 79 ], improving rhGAA lysosomal uptake (e.g., Avalglucosidase, Reveglucosidase, anti-CD63-GAA, Clenbuterol) [ 75 , 76 , 77 ], gene therapy (e.g., SPK-3006, ACTUS-101, AT845) [ 78 ], SRT (e.g., MZE001) [ 80 ], ex vivo HSCT gene therapy [ 81 ], immune tolerance induction (e.g., Methotrexate, Rituximab) [ 74 , 82 ] and inhibition of autophagy (e.g., AAV-mediated TSC knockdown) [ 83 , 84 ]. Created with BioRender.…”

“…Moreover, this therapeutic strategy presents some limitations [ 64 ], including variability in its effectiveness among patients [ 9 , 59 ], limited bioavailability in the central nervous system (CNS) [ 72 ] and development of a strong immunologic response to treatment in some patients, that lead to less effective and sustained response to treatment [ 73 , 74 ]. Notably, efforts have been made in recent years towards the development of novel ERTs with improved lysosomal uptake (e.g., Avalglucosidase, Reveglucosidase, anti-CD63-GAA, Clenbuterol) [ 75 , 76 , 77 ], gene-based therapies (e.g., SPK-3006, ACTUS-101, AT845) [ 78 ] and also novel therapies targeting other disease-related mechanisms, including autophagy, immune response and others ( Figure 1 ). In this scenario, identification of molecular markers that could contribute to evaluate the therapeutic efficiency would also be greatly beneficial for the development of these novel treatments.…”