Drug delivery for neuronopathic lysosomal storage diseases: evolving roles of the blood brain barrier and cerebrospinal fluid

Abstract

Whereas significant strides have been made in the treatment of lysosomal storage diseases (LSDs), the neuronopathy associated with these diseases remains impervious mainly because of the blood-brain barrier (BBB), which prevents delivery of large molecules to the brain. However, 100 years of research on the BBB since its conceptualization have clarified many of its functional and structural characteristics, spurring recent endeavors to deliver therapeutics across it to treat central nervous system (CNS) disorders, including neuronopathic LSDs. Along with the BBB, the cerebrospinal fluid (CSF) also functions to protect the microenvironment of the CNS, and it is therefore deeply involved in CNS disorders at large. Recent research aimed at developing therapeutics for neuronopathic LSDs has uncovered a number of critical roles played by the CSF that require further clarification. This review summarizes the most up-to-date understanding of the BBB and the CSF acquired during the development of therapeutics for neuronopathic LSDs, and highlights some of the associated challenges that require further research.

A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B

“…It is classically assumed that the CSF flow is unidirectional and therefore proteins directly administered in the CSF should be rapidly transported out of the brain and into the periphery (16).…”

Treatment of Neuronopathic Mucopolysaccharidoses with Blood–Brain Barrier-Crossing Enzymes: Clinical Application of Receptor-Mediated Transcytosis

“…To overcome these, a relentless process of trial and error leading to ingenious ideas for improvement and serendipitous discoveries was required, and the true innovative originality of many of these advances remains unacknowledged. Indeed, some of the preclinical and clinical findings gained in establishing RMT-applied ERT [1] may, when put in a wider context, clear up many of the historical misconceptions about the CSF, the BBB, and the delivery of drugs to the brain [30].…”

“…In contrast, drug concentrations in the CSF are naturally very high after intra-CSF drug administration, although smaller quantities of the drugs actually reach the brain parenchyma than in RMT-applied ERT. This is because drugs administered via the CSF must be distributed in retrograde (i.e., cephalad or headward) diffusion against the normal CSF flow to reach the brain parenchyma, so drug penetration from the CSF can be minimal [1,78]. Thus, interpretation of the CSF-related pharmacokinetic parameters must take account of the unique characteristics of the CSF circulation in relation to drug delivery.…”

“…Delivery of therapeutics to the brain has always been hampered by the blood-brain barrier (BBB), which protects the brain from external macromolecules, such as pathogenic and toxic substances [1]. Indeed, the brain has been touted as a 'sanctuary' against chemotherapy, because extravasating malignant cells escape from anti-cancer drugs in the peripheral blood stream, lurk in the brain, and eventually cause fatal metastases therein [2].…”

Treatment of CLN1 disease with a blood-brain barrier penetrating lysosomal enzyme

“…Statements about efficacy are difficult to make since this single patient was in an advanced state of disease at the start of ERT. Moreover, no assay was available allowing measurement of PPT1 activity in the CSF, although the BBB-crossing enzyme is believed to be all but consumed within neuronal cells in the brain parenchyma, leaving few or no remnants to be secreted into the CSF [ 14 ]. However, along with the AGT-194 administration, epilepsy markedly improved over time.…”