Bone Abstracts

Objectives: Lysosomal diseases (LDs) are a heterogenous group of 40+ genetic disorders that can affect virtually all organs and systems, including the skeletal system. They are often caused by the loss of an enzyme critical for the breakdown of macromolecules in the lysosome, leading to accumulation of these substrates and subsequent lysosomal dysfunction. Enzyme replacement therapy (ERT) is the primary treatment option for many LDs, but several issues hinder the efficacy of this therapy. Poor delivery of replacement enzyme to key tissues – notably skeletal muscle, cartilage, and bone – leaves critical organs undertreated. Additionally, many recombinant enzymes are immunogenic, and due to difficulties delivering ERT by infusion patients may not be getting enough recombinant enzyme to get full benefits. Our goal is to develop an approach to address all these key issues.

Methods: Here, we present an antibody-guided enzyme replacement therapy approach wherein antibodies are fused to replacement enzyme. The antibody portion of the molecule guides the enzyme to critical tissues by targeting cell-surface internalizing proteins. The targeted internalizing proteins are chosen based on their superior expression and kinetics compared to the endogenous uptake receptors. By combining this approach with gene therapy, we can also address immunogenicity and delivery issues.

Results: In the Pompe disease model mice, where loss of acid alpha-glucosidase (GAA) causes glycogen accumulation in muscles, we show that antibodies against broadly-expressed or skeletal muscle-specific internalizers fused to hGAA (antibody::GAA) were able re-direct GAA independently of the endogenous uptake receptor in vitro and in vivo. By further combining this approach with gene-therapy delivery, we showed that a single dose of an AAV antibody::GAA cleared glycogen in cardiac and skeletal muscles in Pompe mice to wild-type levels, while AAV GAA was only able to reduce 50% of muscle glycogen at the same dose. We further show that downstream markers of disease in these mice, such as elevated autophagy and reduced grip strength were rescued in the AAV antibody::GAA treated mice.

Conclusions: AAV-delivered antibody-guided ERT shows promise in the mouse model of Pompe disease and may be generalizable to other lysosomal storage diseases, including those affecting bone and cartilage.

Disclosure: The authors are employees of Regeneron Pharmaceuticals.