Whole Body and CNS Biodistribution of rhHNS in Cynomolgus Monkeys after Intrathecal Lumbar Administration: Treatment Implications for Patients with MPS IIIA

Chung, Jou-Ku; Pan, Luying; Palmieri, Kathleen; Youssef, Amir S; McCauley, Thomas G.

doi:10.3390/ijms18122594

Cited by 8 publications

(4 citation statements)

References 28 publications

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“…Here, we show that in juvenile NHPs, at an age when CI-MPR is expressed by brain vasculature endothelial cells, CI-MPR was not able to transport BMN 250 across the BBB. Importantly, other large animal studies show similar lack of trans-BBB transport with mannose 6-phosphorylated enzyme [39,40]. This perhaps suggests specific developmental changes to receptor-mediated transport mediated by CI-MPR of mannose 6-phosphorylated enzyme at post-neonatal age despite continued expression, or other developmentally related BBB changes in the mouse.…”

Section: Cerebellum -Superficialmentioning

confidence: 64%

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

Grover

Crippen-Harmon

Nave

et al. 2020

Drug Deliv. and Transl. Res.

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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.

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Section: Cerebellum -Superficialmentioning

confidence: 64%

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

Grover

Crippen-Harmon

Nave

et al. 2020

Drug Deliv. and Transl. Res.

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“…The patients who developed antibodies against the ERT agents in the CSF did before the IT-ERT administration, and no safety issues were a concern. It is important to point out that significant ERT agent leakage occurs to the systemic circulation during IT-ERT administrations (Chung et al, 2017 ). For this reason, CSF-administered ERT agents can eventually result in systemic effects in non-CNS areas of patients receiving only this route as ERT administration.…”

Section: Therapeutic Strategies Potentially Targeting Cns Manifestatimentioning

confidence: 99%

CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges

Edelmann

Maegawa

2020

Front. Mol. Biosci.

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During the past decades, several therapeutic approaches have been developed and made rapidly available for many patients afflicted with lysosomal storage disorders (LSDs), inborn organelle disorders with broad clinical manifestations secondary to the progressive accumulation of undegraded macromolecules within lysosomes. These conditions are individually rare, but, collectively, their incidence ranges from 1 in 2,315 to 7,700 live-births. Most LSDs are manifested by neurological symptoms or signs, including developmental delay, seizures, acroparesthesia, motor weakness, and extrapyramidal signs. The chronic and later-onset clinical forms are at one end of the continuum spectrum and are characterized by a subtle and slow progression of neurological symptoms. Due to its inherent physiological properties, unfortunately, the blood-brain barrier (BBB) constitutes a significant obstacle for current and upcoming therapies to achieve the central nervous system (CNS) and treat neurological problems so prevalent in these conditions. To circumvent this limitation, several strategies have been developed to make the therapeutic agent achieve the CNS. This narrative will provide an overview of current therapeutic strategies under development to permeate the BBB, and address and unmet need for treatment of the progressive neurological manifestations, which are so prevalent in these inherited lysosomal disorders.

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“…Intrathecal (IT) administration involves mechanically bypassing the BBB and infusing therapeutics into the cerebrospinal fluid (CSF) of the spinal canal or subarachnoid space typically via lumbar puncture or cisterna magna injection. Preclinical studies using IT administration of ERT have been conducted and shown efficacious in several animal models [128,129,130,131,132,133]. Recently, phase I/II clinical trials were completed for IT administration of heparan- N -sulfatase (rhHNS) in patients with MPS IIIA using an implantable intrathecal drug delivery device (IDDD) [134].…”

Section: Delivery Of Base Editors To the Cns For Treatment Of Neurmentioning

confidence: 99%

Cell and Gene Therapies for Mucopolysaccharidoses: Base Editing and Therapeutic Delivery to the CNS

2019

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Although individually uncommon, rare diseases collectively account for a considerable proportion of disease impact worldwide. A group of rare genetic diseases called the mucopolysaccharidoses (MPSs) are characterized by accumulation of partially degraded glycosaminoglycans cellularly. MPS results in varied systemic symptoms and in some forms of the disease, neurodegeneration. Lack of treatment options for MPS with neurological involvement necessitates new avenues of therapeutic investigation. Cell and gene therapies provide putative alternatives and when coupled with genome editing technologies may provide long term or curative treatment. Clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing technology and, more recently, advances in genome editing research, have allowed for the addition of base editors to the repertoire of CRISPR-based editing tools. The latest versions of base editors are highly efficient on-targeting deoxyribonucleic acid (DNA) editors. Here, we describe a number of putative guide ribonucleic acid (RNA) designs for precision correction of known causative mutations for 10 of the MPSs. In this review, we discuss advances in base editing technologies and current techniques for delivery of cell and gene therapies to the site of global degeneration in patients with severe neurological forms of MPS, the central nervous system, including ultrasound-mediated blood-brain barrier disruption.

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Whole Body and CNS Biodistribution of rhHNS in Cynomolgus Monkeys after Intrathecal Lumbar Administration: Treatment Implications for Patients with MPS IIIA

Cited by 8 publications

References 28 publications

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

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

CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges

Cell and Gene Therapies for Mucopolysaccharidoses: Base Editing and Therapeutic Delivery to the CNS

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