Brain transplantation of genetically corrected Sanfilippo type B neural stem cells induces partial cross-correction of the disease

Pearse, Yewande; Clarke, Don; Kan, Shinichi; Le, Steven Q.; Sanghez, Valentina; Luzzi, Anna; Pham, Ivy; Nih, Lina R.; Cooper, Jonathan D.; Dickson, Patricia I.; Iacovino, Michelina

doi:10.1016/j.omtm.2022.10.013

Cited by 3 publications

(10 citation statements)

References 50 publications

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“…Overall, even though the efficacy of this therapeutic approach must be improved to reach all brain sections and counteract the Sanfilippo-associated neuroimmune response throughout the whole brain, truth is that, once more, this team has gathered evidence on the possibility of ex vivo gene therapy, with remarkable ameliorated MPS IIIB phenotypic aspects. Moreover, this was the first report documenting a significant reduction of the neuronal marker MAP2 and accumulation of synaptophysin-positive aggregates, both well-known to be related with neuropathophysiology [137].…”

Section: Genetically Corrected Mpss-derived Ipscsmentioning

confidence: 78%

“…A similar pattern was observed after LAMP-1 staining, meaning that transplanted mice showed a significant decrease in storage material, a reduction in astrocyte activation, and complete prevention of microglial activation within the area of engrafted cells and neighboring regions, with beneficial effects extending partway along the rostrocaudal axis of the brain. Altogether, this study provided evidence that the transplantation of genetically corrected iPSCs-derived NSCs, may indeed represent a potential treatment for MPS IIIB and this is particularly relevant since no approved therapeutic approach exists for this neurological MPS [136,137].…”

Section: Genetically Corrected Mpss-derived Ipscsmentioning

confidence: 80%

“…9 months post-transplantation, this downregulation was actually reversed, with treated animals presenting MAP2 levels similar to those observed in Naglu+/-mice. Moreover, the accumulation of aggregates of synaptophysin, which is a known indicator of axonal damage in inflammatory conditions, was higher in Naglu-/-mice than in wild type and engrafted animals [137].…”

Section: Genetically Corrected Mpss-derived Ipscsmentioning

confidence: 94%

“…In the case of pathophysiological events, glial activation and storage accumulation, measured, respectively through the staining of CD68/GFAP and LAMP-1, revealed a pattern similar to that of wild type animals. Both effects were more pronounced in closer injection sites [137]. Furthermore, the authors also assessed a parameter, which had not yet been looked at in previous studies: the downregulation of MAP2.…”

Section: Genetically Corrected Mpss-derived Ipscsmentioning

confidence: 99%

“…The latest ex vivo gene therapy experience to be performed in MPS models is extremely recent. It was pubished in 2022 [137] and took advantage of results we have just reviewed, for MPS IIIB [136]. In fact, the same team, which originally published the proof of principle on the potential of ex vivo corrected NSCs to positively impact the brain neuropathology in Naglu -/-mice, later extended that study by using a modified Naglu enzyme with the fusion protein IFGII (named NAGLU-IGFII) for the ex vivo correction of the NSCs.…”

Section: Genetically Corrected Mpss-derived Ipscsmentioning

confidence: 99%

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Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step Towards Understanding and Treating Mucopolysaccharidoses

Carvalho¹,

Santos²,

Moreira³

et al. 2023

Preprint

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Despite extensive research, the links between the accumulation of glycosaminoglycans (GAGs) and the clinical features seen in patients suffering from various forms of Mucopolysaccharidoses (MPSs) have yet to be further elucidated. This is particularly true for the neuropathology of these disorders, even though the neurological symptoms are currently incurable, even in the cases where a dis-ease-specific therapeutic approach does exist. One of the best ways to get insights on the molecular mechanisms driving that pathogenesis is the analysis of patient-derived cells. Yet, not every pa-tient-derived cell holds potential to recapitulate relevant disease features. For the neurodegenerative forms of these diseases in particular, it is challenging to grow neuronal cultures that accurately represent them because of the obvious inability to access live neurons. This scenario changed sig-nificantly since Yamanaka et al. published their protocol for induction of pluripotent stem cells (SC) from adult human fibroblasts. From then on, a series of differentiation protocols to generate neurons from induced pluripotent stem cells (iPSC) was developed and extensively used for disease mod-eling. Currently, human iPSC and iPSC-derived cell models have been generated for several MPS and numerous lessons were learnt from their analysis. Here we review most of those studies, not only listing the currently available MPS iPSC lines and their derived models, but also summarizing how they were generated and the major information different groups have gathered from their analysis. Finally, and taking into account that iPSC generation is a laborious/expensive protocol that holds significant limitations, we also comment on a tempting alternative to establish MPS pa-tient-derived neuronal cells in a much more expedite way by taking advantage of the existence of a population of multipotent SC in human dental pulp, to establish mixed neuronal and glial cultures.

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Section: Genetically Corrected Mpss-derived Ipscsmentioning

confidence: 78%

Section: Genetically Corrected Mpss-derived Ipscsmentioning

confidence: 80%

Section: Genetically Corrected Mpss-derived Ipscsmentioning

confidence: 94%

Section: Genetically Corrected Mpss-derived Ipscsmentioning

confidence: 99%

Section: Genetically Corrected Mpss-derived Ipscsmentioning

confidence: 99%

See 3 more Smart Citations

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step Towards Understanding and Treating Mucopolysaccharidoses

Carvalho¹,

Santos²,

Moreira³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Human iPSC-derived neural stem cells engraft and improve pathophysiology of MPS I mice

Calhoun,

Kan,

Stover

et al. 2024

Molecular Therapy - Methods & Clinical Development

View full text Add to dashboard Cite

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step towards Understanding and Treating Mucopolysaccharidoses

et al. 2023

View full text Add to dashboard Cite

Despite extensive research, the links between the accumulation of glycosaminoglycans (GAGs) and the clinical features seen in patients suffering from various forms of mucopolysaccharidoses (MPSs) have yet to be further elucidated. This is particularly true for the neuropathology of these disorders; the neurological symptoms are currently incurable, even in the cases where a disease-specific therapeutic approach does exist. One of the best ways to get insights on the molecular mechanisms driving that pathogenesis is the analysis of patient-derived cells. Yet, not every patient-derived cell recapitulates relevant disease features. For the neuronopathic forms of MPSs, for example, this is particularly evident because of the obvious inability to access live neurons. This scenario changed significantly with the advent of induced pluripotent stem cell (iPSC) technologies. From then on, a series of differentiation protocols to generate neurons from iPSC was developed and extensively used for disease modeling. Currently, human iPSC and iPSC-derived cell models have been generated for several MPSs and numerous lessons were learnt from their analysis. Here we review most of those studies, not only listing the currently available MPS iPSC lines and their derived models, but also summarizing how they were generated and the major information different groups have gathered from their analyses. Finally, and taking into account that iPSC generation is a laborious/expensive protocol that holds significant limitations, we also hypothesize on a tempting alternative to establish MPS patient-derived neuronal cells in a much more expedite way, by taking advantage of the existence of a population of multipotent stem cells in human dental pulp to establish mixed neuronal and glial cultures.

show abstract

Brain transplantation of genetically corrected Sanfilippo type B neural stem cells induces partial cross-correction of the disease

Cited by 3 publications

References 50 publications

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step Towards Understanding and Treating Mucopolysaccharidoses

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step Towards Understanding and Treating Mucopolysaccharidoses

Human iPSC-derived neural stem cells engraft and improve pathophysiology of MPS I mice

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step towards Understanding and Treating Mucopolysaccharidoses

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