Examination of a blood-brain barrier targeting β-galactosidase-monoclonal antibody fusion protein in a murine model of GM1-gangliosidosis

Michael Przybilla,Christine Stewart,Timothy Carlson,Li Ou,Brenda Koniar,Rohini Sidhu,Pamela Kell,Xuntian Jiang,Jeanine R Jarnes,M Gerard O'Sullivan,Chester B Whitley

doi:10.1016/j.ymgme.2020.12.210

Abstract

Examination of a blood-brain barrier targeting β-galactosidase-monoclonal antibody fusion protein in a murine model of GM1-gangliosidosis

Highlights

Lysosomal diseases are a group of rare, inherited, metabolic disor ders that are caused by deficiencies in lysosomal proteins, leading to the accumulation of their cellular substrates within the lysosome
Fusion enzymes have been developed, which allows for the enzyme to bind to a receptor that is present on the epithelial cells of the blood-brain barrier (BBB) and undergo receptor-mediated transcytosis
The present study describes the assessment of such a protein, mTfRGLB1, as a potential therapy for GM1-gangliosidosis. mTfR-GLB1 fuses the human β-gal enzyme to the carboxyl terminus of each heavy chain of a mouse chimeric monoclonal antibody against the mouse transferrin receptor, meaning there are two human β-gal enzymes present in each molecule

Summary

Introduction

Lysosomal diseases are a group of rare, inherited, metabolic disor ders that are caused by deficiencies in lysosomal proteins, leading to the accumulation of their cellular substrates within the lysosome. Numerous therapeutics have been developed and tested for treating lysosomal diseases, including enzyme replacement therapy (ERT) Due to their size, lysosomal enzymes are unable to cross the blood-brain barrier (BBB), limiting their effect on the neurological pathology. For this reason, ERT has not been developed for many lysosomal diseases, including GM1-gangliosidosis, which has widespread neurological involvement. Patients with the most severe form of the disease, the infantile form, exhibit progressive neurodegeneration, including profound hypotonia and weakness, global developmental delay, and skeletal abnormalities. These patients typically never learn to ambulate by crawling or walking. There are no clini cally approved treatments for GM1-gangliosidosis

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