Cell type-selective targeted delivery of a recombinant lysosomal enzyme for enzyme therapies

• Published in: Molecular therapy 2021-12, Vol.29 (12), p.3512-3524
• Main Authors: Baik, Andrew D., Calafati, Philip, Zhang, Xiaoli, Aaron, Nina A., Mehra, Antonia, Moller-Tank, Sven, Miloscio, Lawrence, Praggastis, Maria, Giovannone, Nicholas, Pan, Cheryl, Tang, Yajun, Bridges, Susannah, Mujica, Alejo, Barbounis, Peter, Yanolatos, Jean, Gale, Nicholas, Li, Ning, Kyratsous, Christos A., Schoenherr, Christopher J., Murphy, Andrew J., Economides, Aris N., Cygnar, Katherine D.
• Format: Article
• Language: English
• Subjects: alpha-Glucosidases - genetics; Animals; Enzyme Replacement Therapy; enzyme therapy; genetic therapy; glycogen storage disease II; Glycogen Storage Disease Type II - drug therapy; Glycogen Storage Disease Type II - genetics; hydrolases; Hydrolases - metabolism; Lysosomal Storage Diseases - drug therapy; Lysosomal Storage Diseases - genetics; lysosomes; Lysosomes - metabolism; Mice; Original; protein transport; Tissue Distribution
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2021.08.020

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 that require the enzyme. We present here targeted ERT, an approach that utilizes antibody-enzyme fusion proteins to target the enzyme to specific cell types. 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 both as a protein replacement therapeutic and as a gene therapy. [Display omitted] Enzyme replacement therapy for many lysosomal diseases is hindered by poor delivery of enzyme to affected cells. Here, we show that targeted antibody-enzyme fusions can improve delivery of lysosomal alpha glucosidase to muscle in Pompe disease mice, rescuing muscle phenotypes. This technology is amenable to both recombinant protein and gene therapies.