Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross-correction in mice with Hurler syndrome

Wang, Daren; Zhang, Wei; Kalfa, Theodosia A.; Grabowski, Gregory A.; Davies, Stella M.; Pan, Dao

doi:10.1073/pnas.0908528106

Cited by 47 publications

(55 citation statements)

References 41 publications

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“…Subsequent studies using more effi cient lentiviral-based vectors that transduced a greater number of the donor hematopoietic stem cells and that resulted in the secretion of higher levels of the enzyme (i.e., arylsulfatase A) completely prevented the development of neuropathology and behavioral abnormalities in mice ( 141,151 ). Similar encouraging results were obtained in mouse models of other LSDs including MPS I, MPS IIIA, globoid cell leukodystrophy, and GM1 gangliosidosis ( 142,(152)(153)(154)(155). In addition to the correction of the neurological disease, transplantation of gene-modifi ed donor cells also provided an additional benefi t of addressing the visceral components of the disease.…”

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

confidence: 69%

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: 69%

Gene therapy for the neurological manifestations in lysosomal storage disorders

Cheng¹

2014

Journal of Lipid Research

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“…Such an approach led to widespread distribution of the expressed enzyme in the brain following intravenous administration with resultant biochemical and phenotypic improvement. Transplantation of hematopoietic, embryonic, neural progenitor, or induced pluripotent stem cells with or without transduced additional genes is being used to deliver the needed therapeutic enzymes (299)(300)(301)(302)(303). Such cells can either add to existing cell populations in the brain, i.e., glia or neurons, and/or act as metabolic factories for the enzymes that can then be secreted and taken up by enzyme defi cient cells in the CNS and other organs to varying degrees.…”

Section: Treatments By Increasing Gsl Degradationmentioning

confidence: 99%

Multi-system disorders of glycosphingolipid and ganglioside metabolism

Xu¹,

Barnes²,

Sun³

et al. 2010

Journal of Lipid Research

149

121

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important to a variety of cellular functions. GSLs and gangliosides are synthesized at the endoplasmic reticulum (ER) and are remodeled during transit from cis to trans Golgi by a series of glycosyl-and sialyl-transferases. These are then transported to the intracellular compartments and the plasma membrane where they become enriched in microdomains and membrane bilayers. During plasma membrane turnover, GSLs and gangliosides can be internalized and partially or completely degraded in the endosomal/lysosomal system to sphingosine and free fatty acids that are then transported or fl ipped across late endosomal and lysosomal membranes for recycling or for use as signaling molecules ( 2, 3 ). GSL metabolic pathwaysGSL biosynthesis begins with condensation of serine and palmitoyl-CoA catalyzed by serine-palmitoyltransferase (SPT) on the cytoplasmic face of the ER, leading to de novo biosynthesis of ceramide, the core of GSLs (

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“…This approach resulted in decreased accumulation of GAG in the liver, spleen, heart, and CNS via enzyme expression in erythroblasts [101].…”

Section: Mucopolysaccharidosis (Mps)mentioning

confidence: 99%