Translational studies of intravenous and intracerebroventricular routes of administration for CNS cellular biodistribution for BMN 250, an enzyme replacement therapy for the treatment of Sanfilippo type B

Abstract

BMN 250 is being developed as enzyme replacement therapy for Sanfilippo type B, a primarily neurological rare disease, in which patients have deficient lysosomal alpha-N-acetylglucosaminidase (NAGLU) enzyme activity. BMN 250 is taken up in target cells by the cation-independent mannose 6-phosphate receptor (CI-MPR, insulin-like growth factor 2 receptor), which then facilitates transit to the lysosome. BMN 250 is dosed directly into the central nervous system via the intracerebroventricular (ICV) route, and the objective of this work was to compare systemic intravenous (IV) and ICV delivery of BMN 250 to confirm the value of ICV dosing. We first assess the ability of enzyme to cross a potentially compromised blood–brain barrier in the Naglu−/− mouse model and then assess the potential for CI-MPR to be employed for receptor-mediated transport across the blood–brain barrier. In wild-type and Naglu−/− mice, CI-MPR expression in brain vasculature is high during the neonatal period but virtually absent by adolescence. In contrast, CI-MPR remains expressed through adolescence in non-affected non-human primate and human brain vasculature. Combined results from IV administration of BMN 250 in Naglu−/− mice and IV and ICV administration in healthy juvenile non-human primates suggest a limitation to therapeutic benefit from IV administration because enzyme distribution is restricted to brain vascular endothelial cells: enzyme does not reach target neuronal cells following IV administration, and pharmacological response following IV administration is likely restricted to clearance of substrate in endothelial cells. In contrast, ICV administration enables central nervous system enzyme replacement with biodistribution to target cells.

Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches

“…Thus, intravenous administration is not as useful as for other LSDs without CNS pathology, for which ERT is currently approved and in use. On the other hand, direct brain administration for the treatment of neurological disorders seems more beneficial [ 74 ], although it is an aggressive treatment that needs continued injections. Nevertheless, clinical trials based on ERT for Sanfilippo syndrome type A and B have been carried out without clear results [ 75 , 76 , 77 , 78 ].…”

Treatment of Neurological Manifestations of Mucopolysaccharidoses: Translational Considerations in Drug Development

“…With any of these approaches to bypass or cross the BBB, there are a few key sets of data that support drug development, as highlighted in Grover et al study [1].…”

“…Grover et al [1], present translational support for the development of BMN 250, a treatment of Sanfilippo Type B, also known as MPS IIIB, currently in clinical study. BMN 250 is administered directly into the cerebrospinal fluid through a catheter inserted into a lateral ventricle, known as intracerebroventricular (ICV) administration.…”

“…BMN 250 is administered directly into the cerebrospinal fluid through a catheter inserted into a lateral ventricle, known as intracerebroventricular (ICV) administration. The preclinical studies presented by Grover et al [1] present a framework for translational research to address this unmet medical need of neurological symptoms of MPS diseases.…”

“…In Table 2, a summary of clinical programs for the treatment of the CNS manifestations of MPS diseases that focus on restoring the specific enzyme in defect (i.e., not including stem cell transplant or supportive programs such as nutrients or anti-inflammatories) and in which dose can be fine-tuned (i.e., not including ex vivo gene therapy) as of April 2020 are listed. These include direct approaches to bypass the BBB, such as the ICV administration studied in Grover et al study [1], or protein engineering approaches with intravenous administration. Some programs listed in Table 2 have been terminated due to lack of demonstration of efficacy but are included for completeness.…”