Intrathecal recombinant human 4-sulfatase reduces accumulation of glycosaminoglycans in dura of mucopolysaccharidosis VI cats

Auclair, Dyane; Finnie, John; Walkley, Steven U.; White, Joleen T.; Nielsen, Timothy; Fuller, Maria; Cheng, Alphonsus; O’Neill, Charles; Hopwood, John J.

doi:10.1038/pr.2011.13

Cited by 31 publications

(19 citation statements)

References 29 publications

(79 reference statements)

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“…As with the systemic route, the consideration of intrathecal injection of AAV to treat the CNS disease was supported by early studies using recombinant enzymes. Periodic injections of several different lysosomal enzymes into the intrathecal space or ventricles of mouse, cat, and dog disease models resulted in effi cient clearance of the storage metabolites in the CNS and the consequent correction of motor function (97)(98)(99)(100)(101). Based on these preclinical fi ndings, clinical studies using intrathecal injections of the respective lysosomal enzymes to treat the CNS diseases of MPS I (NCT00852358), MPS II (NCT00920647), and MPS IIIA (NCT01155778) have been initiated.…”

Section: Effi Cacy Of Intracranial Delivery Of Aav Vectors For Neuropmentioning

confidence: 99%

Gene therapy for the neurological manifestations in lysosomal storage disorders

Cheng¹

2014

Journal of Lipid Research

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precise mechanistic links between these altered biochemical and cellular states and disease pathophysiology and pathogenesis remain unclear. Typically, disease severity is correlated with the level of residual activity, with individuals harboring lower levels presenting with more aggressive and severe disease manifestations. A large percentage of individuals, particularly those with signifi cantly diminished lysosomal function, also exhibit CNS involvement, the extent of which is dependent on the nature of the specifi c storage metabolites and the differential sensitivity of the resident cell types to the accumulated substrates. Although individually each LSD may be relatively rare, as a group, these disorders have an incidence of approximately 1 per 5,000 live births ( 4, 5 ).Of the approximately 50 LSDs that have been identifi ed thus far, the majority (greater than 70%) exhibit significant CNS involvement ( 6 ). This fi nding is not surprising given that lysosomes and related organelles are ubiquitously present in most cell types and are involved not only in recycling cellular debris but also in maintaining cellular homeostasis ( 7-9 ). Irrespective of the LSD, these CNS diseases are typically characterized by generalized infl ammation and neurodegeneration in multiple brain regions. In a subset of the diseases, altered calcium homeostasis and oxidative stress may also contribute to the overall pathology ( 10 ). Moreover, each specifi c disease may initially present with a unique temporal and spatial alteration that is dictated by the nature of the storage metabolites prior to the development of a more generalized global derangement ( 11 ). In some diseases, the symptoms are evident in neonates, whereas in others, they become apparent only in early childhood. Consequently, some LSDs may require early therapeutic intervention to affect broad and potentially all regions of the CNS. The lysosomal storage disorders (LSDs) are a heterogeneous group of inherited metabolic diseases that result from a defi ciency in one or more of the 80 enzymes or transporters that normally reside within the lysosomal compartment ( 1-3 ). A reduction or loss of one or more of these activities results in the progressive and relentless accumulation of undegraded macromolecules, a consequent derangement of proper lysosomal and autophagosomal functions, and ultimately, cellular demise. However, the

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Section: Effi Cacy Of Intracranial Delivery Of Aav Vectors For Neuropmentioning

confidence: 99%

Gene therapy for the neurological manifestations in lysosomal storage disorders

Cheng¹

2014

Journal of Lipid Research

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“…Reports of trials with IT ERT in MPS I and VI animals as well as MPS I patients have also been described [17,18,19,20,21]. The use of the drug in the canine model of MPS I with CNS manifestations resulted in achieving very high enzyme levels and a noticeable reduction of GAG storage in the spinal meninges after 4 weekly doses [17].…”

Section: Discussionmentioning

confidence: 99%

“…The use of the drug in the canine model of MPS I with CNS manifestations resulted in achieving very high enzyme levels and a noticeable reduction of GAG storage in the spinal meninges after 4 weekly doses [17]. Other animal studies showed that IT ERT can diffuse widely throughout the CNS and treat disease there effectively [19,20,21], and reduction in stored material, improved histopathology, longer lifespan and neurobehavioral improvement has been also observed [20,22]. IT drug administration is an established route for treatment of disorders such as chronic pain (due to cancer or other conditions) and spasticity.…”

Section: Discussionmentioning

confidence: 99%

Spinal Cord Compression in Maroteaux-Lamy Syndrome: Case Report and Review of the Literature with Effects of Enzyme Replacement Therapy

Jurecka

Opoka-Winiarska²,

Jurkiewicz³

et al. 2012

Pediatr Neurosurg

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The purpose of this report is to review the literature regarding spinal cord compression in mucopolysaccharidosis type VI (MPS VI), to discuss the possible impact of enzyme replacement therapy (ERT) and to stress the necessity of timely surgical intervention. A 9.5-year-old female patient with severe MPS VI had been receiving ERT since the age of 7. After 2.5 years of treatment, she developed craniovertebral canal stenosis with spinal cord compression and cervical myelopathy. Conclusions: (1) baseline cervical spine evaluation and regular neurological assessment should be performed in all MPS VI patients, (2) detailed neurological observation should be conducted in patients treated with ERT, especially in the period of improvement in the osteoarticular system, as ERT fails to prevent cervical myelopathy and (3) surgical decompression is required and in order to achieve a satisfying outcome it might be crucial to perform surgery at an early age.

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“…Uptake of lysosomal enzymes is mediated primarily by the mannose 6-phosphate (M6P) receptor, and thus, delivered enzymes must be adequately phosphorylated [185, 186]. ERT is most often administered intravenously, although intrathecal delivery has also been evaluated [115, 117, 187–191]. Similar to HSCT, evidence suggests that intravenous ERT is at best partially effective at treating (or preventing the progression of) spinal manifestations such as disc degeneration, vertebral dysplasia, odontoid hypoplasia, and dural thickening, with efficacy varying significantly between individual patients.…”

Section: Treating the Spinal Manifestations Of Mps: Current And Fumentioning

confidence: 99%

Pathogenesis and treatment of spine disease in the mucopolysaccharidoses

Peck

Casal

Malhotra

et al. 2016

Molecular Genetics and Metabolism

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The mucopolysaccharidoses (MPS) are a family of lysosomal storage disorders characterized by deficient activity of enzymes that degrade glycosaminoglycans (GAGs). Skeletal disease is common in MPS patients, with the severity varying both within and between subtypes. Within the spectrum of skeletal disease, spinal manifestations are particularly prevalent. Developmental and degenerative abnormalities affecting the substructures of the spine can result in compression of the spinal cord and associated neural elements. Resulting neurological complications, including pain and paralysis, significantly reduce patient quality of life and life expectancy. Systemic therapies for MPS such as hematopoietic stem cell transplantation and enzyme replacement therapy have shown limited efficacy for improving spinal manifestations in patients and animal models, and there is therefore a pressing need for new therapeutic approaches that specifically target this debilitating aspect of the disease. In this review, we examine how pathological abnormalities affecting the key substructures of the spine – the discs, vertebrae, odontoid process and dura – contribute to the progression of spinal deformity and symptomatic compression of neural elements. Specifically, we review current understanding of the underlying pathophysiology of spine disease in MPS, how the tissues of the spine respond to current clinical and experimental treatments, and discuss future strategies for improving the efficacy of these treatments.

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Intrathecal recombinant human 4-sulfatase reduces accumulation of glycosaminoglycans in dura of mucopolysaccharidosis VI cats

Cited by 31 publications

References 29 publications

Gene therapy for the neurological manifestations in lysosomal storage disorders

Gene therapy for the neurological manifestations in lysosomal storage disorders

Spinal Cord Compression in Maroteaux-Lamy Syndrome: Case Report and Review of the Literature with Effects of Enzyme Replacement Therapy

Pathogenesis and treatment of spine disease in the mucopolysaccharidoses

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