Determination of the role of injection site on the efficacy of intra-CSF enzyme replacement therapy in MPS IIIA mice

Beard, Helen; Luck, Amanda; Hassiotis, Sofia; King, Barbara; Trim, Paul J.; Snel, Marten F.; Hopwood, John J.; Hemsley, Kim M.

doi:10.1016/j.ymgme.2015.03.002

Cited by 26 publications

(27 citation statements)

References 40 publications

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“…Clinical trials investigating the use of anti-inflammatory agents are being developed in MPS-I and other MPS subtypes for the purpose of ameliorating joint and bone disease25. Novel attempts at targeting the CSF with recombinant viral vectors delivering the missing enzyme are being developed in several MPS diseases as well3132333435. Commonly, glycan-based markers are used to show efficacy for these various strategies36.…”

Section: Discussionmentioning

confidence: 99%

Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H

Raymond

Pasquali

Polgreen

et al. 2016

Sci Rep

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Mucopolysaccharidosis (MPS) type-IH is a lysosomal storage disease that results from mutations in the IDUA gene causing the accumulation of glycosaminoglycans (GAGs). Historically, children with the severe phenotype, MPS-IH (Hurler syndrome) develop progressive neurodegeneration with death in the first decade due to cardio-pulmonary complications. New data suggest that inflammation may play a role in MPS pathophysiology. To date there is almost no information on the pathophysiologic changes within the cerebral spinal fluid (CSF) of these patients. We evaluated the CSF of 25 consecutive patients with MPS-IH. While CSF glucose and total protein were within the normal range, we found a significantly mean elevated CSF opening pressure at 24 cm H2O (range 14–37 cm H2O). We observed a 3-fold elevation in CSF heparan sulfate and a 3–8 fold increase in MPS-IH specific non-reducing ends, I0S0 and I0S6. Cytokine analyses in CSF of children with MPS-IH showed significantly elevated inflammatory markers including: MCP-1 SDF-1a, IL-Ra, MIP-1b, IL-8, and VEGF in comparison to unaffected children. This is the largest report of CSF characteristics in children with MPS-IH. Identification of key biomarkers may provide further insight into the inflammatory-mediated mechanisms related to MPS diseases and perhaps lead to improved targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H

Raymond

Pasquali

Polgreen

et al. 2016

Sci Rep

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“…In recent years, preclinical studies (33,34) and clinical trials of intrathecal ERT(i.t.ERT) and i.c.v.ERT in the USA have been making steady progress for neurodegenerative LSDs, including mucopolysaccharidosis (MPS) type I (phase 1) (35), II (phase 2/3) (36), and IIIA (phase 2); Batten disease (phase 1/2); and metachromatic leukodystrophy (MLD) (phase 1/2) (according to ClinicalTrials.gov, https://clinicaltrials.gov/, accessed July 1, 2015). Novel approaches with BBB-penetrating tags have also been attempted in animal disease models (37).…”

Section: Discussionmentioning

confidence: 99%

Protease-resistant modified human β-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model

Kitakaze¹,

Mizutani²,

Sugiyama³

et al. 2016

Journal of Clinical Investigation

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“…Certain functions of the microglia are different.Moreover, the distance from the CSF to the deepest part of the brain is more than 3 xgreater in humans than rabbits. Also, the site of injection into CSF of a test agent may be critically important in regard to the brain response in translational investigations (Beard et al, 2015).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

A balanced view of the cerebrospinal fluid composition and functions: Focus on adult humans

Spector

Snodgrass

Johanson

2015

Experimental Neurology

343

240

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In this review, a companion piece to our recent examination of choroid plexus (CP), the organ that secretes the cerebrospinal fluid (CSF), we focus on recent information in the context of reliable older data concerning the composition and functions of adult human CSF. To accomplish this, we define CSF, examine the methodology employed in studying the CSF focusing on ideal or near ideal experiments and discuss the pros and cons of several widely used analogical descriptions of the CSF including: the CSF as the "third circulation," the CSF as a "nourishing liquor," the similarities of the CSF/choroid plexus to the glomerular filtrate/kidney and finally the CSF circulation as part of the "glymphatic system." We also consider the close interrelationship between the CSF and extracellular space of brain through gap junctions and the paucity of data suggesting that the cerebral capillaries secrete a CSF-like fluid. Recently human CSF has been shown to be in dynamic flux with heart-beat, posture and especially respiration. Functionally, the CSF provides buoyancy, nourishment (e.g., vitamins) and endogenous waste product removal for the brain by bulk flow into the venous (arachnoid villi and nerve roots) and lymphatic (nasal) systems, and by carrier-mediated reabsorptive transport systems in CP. The CSF also presents many exogenous compounds to CP for metabolism or removal, indirectly cleansing the extracellular space of brain (e.g., of xenobiotics like penicillin). The CSF also carries hormones (e.g., leptin) from blood via CP or synthesized in CP (e.g., IGF-2) to the brain. In summary the CP/CSF, the third circulation, performs many functions comparable to the kidney including nourishing the brain and contributing to a stable internal milieu for the brain. These tasks are essential to normal adult brain functioning.

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Determination of the role of injection site on the efficacy of intra-CSF enzyme replacement therapy in MPS IIIA mice

Cited by 26 publications

References 40 publications

Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H

Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H

Protease-resistant modified human β-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model

A balanced view of the cerebrospinal fluid composition and functions: Focus on adult humans

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