Myeloid/Microglial Driven Autologous Hematopoietic Stem Cell Gene Therapy Corrects a Neuronopathic Lysosomal Disease

Sergijenko, Ana; Langford-Smith, Alex; Liao, Ai Yin; Pickford, Claire E.; McDermott, John H; Nowinski, Gabriel; Langford-Smith, Kia; Merry, Catherine L.R.; Jones, Simon A.; Wraith, J. Edmond; Wynn, Robert F.; Wilkinson, Fiona L.; Bigger, Brian

doi:10.1038/mt.2013.141

Cited by 104 publications

(131 citation statements)

References 48 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 Neuropsupporting

confidence: 65%

“…In general, more favorable biochemical and clinical outcomes in the mice were obtained using donor cells that had been engineered to express higher levels of the respective lysosomal enzymes. For example, in the study using MPS IIIA mice, the utilization of a strong, myeloid-restricted promoter to enhance transgene expression by microglia in the CNS was necessary for robust effi cacy ( 155 ). For LSDs that are primarily characterized by neurological disease, restriction of the expression to the brain using selective promoters may be further minimized by favoring AAV serotypes that demonstrate a higher tropism for neural cells or a propensity to undergo axonal transport (e.g., AAV1, -5, -9, and -rh.10), Finally, these strategies may also be combined with the use of convection-enhanced delivery to further physically disseminate the vectors ( 114,128 ).…”

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

confidence: 99%

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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 Neuropsupporting

confidence: 65%

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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“…Therefore, transduction efficacy of our vector to HSCs may be another contributing factor to relatively low IDS activity in brains of MPS II mice transplanted with IDS-overexpressing HSCs. Additionally, a previous report showed that lentiviral ex vivo gene therapy using CD11b promoter achieved high GFP expression in CD11b positive cells and more than 10% of wild-type N-sulfoglucosamine sulfohydrolase (SGSH) activity in treated MPS IIIA mice brains 42 . This method could contribute to an improvement in our results.…”

Section: Discussionmentioning

confidence: 98%

Hematopoietic Stem Cell Gene Therapy Corrects Neuropathic Phenotype in Murine Model of Mucopolysaccharidosis Type II

et al. 2015

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Mucopolysaccharidosis type II (MPS II) is a neuropathic lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans (GAGs). We demonstrated that biochemical alterations in the brains of MPS II mice are not corrected by bone marrow transplantation (BMT) or enzyme replacement therapy, although BMT has been shown to be effective for other neurodegenerative MPSs, such as Hurler syndrome. In this study, we demonstrated that lentiviral isogeneic hematopoietic stem cell (HSC) gene therapy corrected neuronal manifestations by ameliorating lysosomal storage and autophagic dysfunction in the brains of MPS II mice. IDS-transduced HSCs increased enzyme activity both in various visceral organs and the CNS. Decreased levels of GAGs were observed in many organs, including cerebra, after transplantation of IDS-transduced HSCs. In addition, lentiviral HSC gene therapy normalized the secondary accumulation of autophagic substrates, such as p62 and ubiquitin-protein conjugates, in cerebra. Furthermore, in contrast to naive MPS II mice, there was no deterioration of neuronal function observed in transplant recipients. These results indicated that lentiviral HSC gene therapy is a promising approach for the treatment of CNS lesions in MPS II.

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“…Stem cell implantation, combined with gene therapy, has been performed in the treatment of nonocular genetic disorders for years (Rideout et al, 2002;Hanna et al, 2007;Sergijenko et al, 2013). hESCs can be genetically manipulated to introduce a therapeutic gene, either active or awaiting later activation once the modified hESC has differentiated into the desired cell type.…”

Section: Combining Stem Cell and Gene Therapymentioning

confidence: 99%

Stem cell based therapies for age-related macular degeneration: The promises and the challenges

Nazari

Zhang

Zhu

et al. 2015

Progress in Retinal and Eye Research

177

142

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Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. AMD is classified as either neovascular (NV-AMD) or non-neovascular (NNV-AMD). Cumulative damage to the retinal pigment epithelium, Bruch's membrane, and choriocapillaris leads to dysfunction and loss of RPE cells. This causes degeneration of the overlying photoreceptors and consequential vision loss in advanced NNV-AMD (Geographic Atrophy). In NV-AMD, abnormal growth of capillaries under the retina and RPE, which leads to hemorrhage and fluid leakage, is the main cause of photoreceptor damage. Although a number of drugs (e.g., anti-VEGF) are in use for NV-AMD, there is currently no treatment for advanced NNV-AMD. However, replacing dead or dysfunctional RPE with healthy RPE has been shown to rescue dying photoreceptors and improve vision in animal models of retinal degeneration and possibly in AMD patients. Differentiation of RPE from human embryonic stem cells (hESC-RPE) and from induced pluripotent stem cells (iPSC-RPE) has created a potentially unlimited source for replacing dead or dying RPE. Such cells have been shown to incorporate into the degenerating retina and result in anatomic and functional improvement. However, major ethical, regulatory, safety, and technical challenges have yet to be overcome before stem cell-based therapies can be used in standard treatments. This review outlines the current knowledge surrounding the application of hESC-RPE and iPSC-RPE in AMD. Following an introduction on the pathogenesis and available treatments of AMD, methods to generate stem cell-derived RPE, immune reaction against such cells, and approaches to deliver desired cells into the eye will be explored along with broader issues of efficacy and safety. Lastly, strategies to improve these stem cell-based treatments will be discussed.

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Myeloid/Microglial Driven Autologous Hematopoietic Stem Cell Gene Therapy Corrects a Neuronopathic Lysosomal Disease

Cited by 104 publications

References 48 publications

Gene therapy for the neurological manifestations in lysosomal storage disorders

Gene therapy for the neurological manifestations in lysosomal storage disorders

Hematopoietic Stem Cell Gene Therapy Corrects Neuropathic Phenotype in Murine Model of Mucopolysaccharidosis Type II

Stem cell based therapies for age-related macular degeneration: The promises and the challenges

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