Mucopolysaccharidoses and the blood-brain barrier

Abstract

Mucopolysaccharidoses comprise a set of genetic diseases marked by an enzymatic dysfunction in the degradation of glycosaminoglycans in lysosomes. There are eight clinically distinct types of mucopolysaccharidosis, some with various subtypes, based on which lysosomal enzyme is deficient and symptom severity. Patients with mucopolysaccharidosis can present with a variety of symptoms, including cognitive dysfunction, hepatosplenomegaly, skeletal abnormalities, and cardiopulmonary issues. Additionally, the onset and severity of symptoms can vary depending on the specific disorder, with symptoms typically arising during early childhood. While there is currently no cure for mucopolysaccharidosis, there are clinically approved therapies for the management of clinical symptoms, such as enzyme replacement therapy. Enzyme replacement therapy is typically administered intravenously, which allows for the systemic delivery of the deficient enzymes to peripheral organ sites. However, crossing the blood-brain barrier (BBB) to ameliorate the neurological symptoms of mucopolysaccharidosis continues to remain a challenge for these large macromolecules. In this review, we discuss the transport mechanisms for the delivery of lysosomal enzymes across the BBB. Additionally, we discuss the several therapeutic approaches, both preclinical and clinical, for the treatment of mucopolysaccharidoses.

Keywords: Blood–brain barrier; Enzyme replacement therapy; Lysosomal storage disease; Mucopolysaccharidosis.

Fig. 1

Schematic representation of the RMT system and endosomal trafficking mechanisms in the brain endothelial cells. A Innate RMT systems available at the BBB. The cellular uptake of lysosomal enzymes in brain cells were mostly by CI-MPR in neurons, astrocytes, and oligodendrocytes. However, microglia show mannose and mannan mediations. TfR: Transferrin receptor; IR: Insulin receptor; LDLR: low-density lipoprotein receptor; insulin-like growth factor 1 receptor. B Intracellular vesicle trafficking and Rab small GTPases