Advances and Pitfalls of Cell Therapy in Metabolic Leukodystrophies

Miranda, Catarina; Brites, Pedro; Sousa, Mónica Mendes; Teixeira, Carla

doi:10.3727/096368912x656117

Cited by 19 publications

(19 citation statements)

References 123 publications

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“…There are no proven treatments for MLD (Batzios and Zafeiriou, 2012;Patil and Maegawa, 2013;Miranda et al, 2013). Because the disease affects all regions of the nervous system, treatment must reestablish the missing enzymatic function throughout (Beck, 2007;Gray, 2013).…”

mentioning

confidence: 99%

Comparative Efficacy and Safety of Multiple Routes of Direct CNS Administration of Adeno-Associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human Arylsulfatase A cDNA to Nonhuman Primates

Rosenberg

Sondhi

Rubin

et al. 2014

Human Gene Therapy Clinical Development

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Metachromatic leukodystrophy (MLD), a fatal disorder caused by deficiency of the lysosomal enzyme arylsulfatase A (ARSA), is associated with an accumulation of sulfatides, causing widespread demyelination in both central and peripheral nervous systems. On the basis of prior studies demonstrating that adeno-associated virus AAVrh.10 can mediate widespread distribution in the CNS of a secreted lysosomal transgene, and as a prelude to human trials, we comparatively assessed the optimal CNS delivery route of an AAVrh.10 vector encoding human ARSA in a large animal model for broadest distribution of ARSA enzyme. Five routes were tested (each total dose, 1.5 · 10 12 genome copies of AAVrh.10hARSA-FLAG): (1) delivery to white matter centrum ovale; (2) deep gray matter delivery (putamen, thalamus, and caudate) plus overlying white matter; (3) convection-enhanced delivery to same deep gray matter locations; (4) lateral cerebral ventricle; and (5) intraarterial delivery with hyperosmotic mannitol to the middle cerebral artery. After 13 weeks, the distribution of ARSA activity subsequent to each of the three direct intraparenchymal administration routes was significantly higher than in phosphate-buffered saline-administered controls, but administration by the intraventricular and intraarterial routes failed to demonstrate measurable levels above controls. Immunohistochemical staining in the cortex, white matter, deep gray matter of the striatum, thalamus, choroid plexus, and spinal cord dorsal root ganglions confirmed these results. Of the five routes studied, administration to the white matter generated the broadest distribution of ARSA, with 80% of the brain displaying more than a therapeutic (10%) increase in ARSA activity above PBS controls. No significant toxicity was observed with any delivery route as measured by safety parameters, although some inflammatory changes were seen by histopathology. We conclude that AAVrh.10-mediated delivery of ARSA via CNS administration into the white matter is likely to be safe and yields the widest distribution of ARSA, making it the most suitable route of vector delivery.

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confidence: 99%

Comparative Efficacy and Safety of Multiple Routes of Direct CNS Administration of Adeno-Associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human Arylsulfatase A cDNA to Nonhuman Primates

Rosenberg

Sondhi

Rubin

et al. 2014

Human Gene Therapy Clinical Development

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“…10 Additional experimental work is being conducted using intracisternal enzyme replacement therapy, 11 though in general, the long-term outcome of such approaches is unclear and further experimental studies are ongoing. 12 …”

Section: Discussionmentioning

confidence: 99%

Ocular findings in a patient with fucosidosis

Sanchez

Oatts

Duncan

et al. 2016

American Journal of Ophthalmology Case Reports

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PurposeTo describe the ocular findings in a patient with fucosidosis, a rare inborn lysosomal storage disease.ObservationsA 14 year-old female presented with angiokeratomas corporis diffusum, coarse facial features, poor verbal skills, hearing impairment and mild developmental delay. A lysosomal storage enzyme screen confirmed absent activity of α-l-fucosidase consistent with a diagnosis of fucosidosis. Her eye exam was remarkable for telangiectatic vessels in the inferior conjunctiva and mild corneal stromal haze bilaterally. Spectral domain–optical coherence tomography scans of the macula and a full-field electroretinogram were normal.Conclusions and importanceWe describe the findings in a 14 year-old patient with fucosidosis and review the systemic and ocular manifestations of this rare lysosomal storage disease.

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“…Although the survival rate of neural progenitor cells (NPCs) was generally high in the juvenile treated mice (Surendran et al, 2004), the migration of these cells was limited, suggesting that much progress has to be made before any results (if seen) will be widespread enough to impact upon the brain pathology of this condition. In addition to the migratory potential, the stability (Amariglio et al, 2009) and safety of transplanted and differentiated NPCs in the CD mice CNS remains to be proven, while acquiring sufficient quantities of NPCs for human transplantation is likely to be difficult (Miranda et al, 2013).…”

Section: Cell Therapymentioning

confidence: 99%