Treatment of Inherited Eye Defects by Systemic Hematopoietic Stem Cell Transplantation

Rocca, Céline J.; Kreymerman, Alexander; Ur, Sarah N.; Frizzi, Katie; Naphade, Swati; Lau, Athena; Tran, Tammy; Calcutt, Nigel A.; Goldberg, Jeffrey L.; Cherqui, Stéphanie

doi:10.1167/iovs.15-17107

Cited by 31 publications

(33 citation statements)

References 45 publications

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“…7). Similar protection has been demonstrated in the eyes and thyroid of Ctns -knockout mice, leading to near complete clearance of corneal cystine crystals and preservation of corneal structure 188 , as well as normalization of thyroid-stimulating hormone level and preservation of thyroid follicles, repectively 189 .…”

Section: Treatment and Therapeutic Perspectivessupporting

confidence: 66%

The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives

2016

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Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. It is caused by a defect in the lysosomal cystine transporter, cystinosin, which results in an accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, a renal Fanconi syndrome is often the first manifestation of cystinosis, usually presenting within the first year of life and characterized by the early and severe dysfunction of proximal tubule cells, highlighting the unique vulnerability of this cell type. The current therapy for cystinosis, cysteamine, facilitates lysosomal cystine clearance and greatly delays progression to kidney failure but is unable to correct the Fanconi syndrome. This Review summarizes decades of studies that have fostered a better understanding of the pathogenesis of the renal Fanconi syndrome associated with cystinosis. These studies have unraveled some of the early molecular changes that occur before the onset of tubular atrophy and identified a role for cystinosin beyond cystine transport, in endolysosomal trafficking and proteolysis, lysosomal clearance, autophagy and the regulation of energy balance. These studies have also led to the identification of new potential therapeutic targets and here, we outline the potential role of stem cell therapy for cystinosis and provide insights into the mechanism of haematopoietic stem cell-mediated kidney protection.

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Section: Treatment and Therapeutic Perspectivessupporting

confidence: 66%

The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives

2016

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“…Together, these data demonstrated that wild-type mouse HSPC transplantation in 2-month-old YG8R mice rescued the progressive neurobehavioral and muscular deficits characteristic of this FRDA animal model. In contrast to our previous findings in a cystinosis model (14, 16), the YG8R mouse exhibiting the lowest percentage of donor-derived cell engraftment (35%; table S1) still exhibited physiological rescue of the behavioral deficits (table S2). …”

Section: Resultscontrasting

confidence: 99%

Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich’s ataxia

et al. 2017

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Friedreich’s ataxia (FRDA) is an incurable autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin due to an intronic GAA-repeat expansion in the FXN gene. We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart. Transplanted HSPCs engrafted and then differentiated into microglia in the brain and spinal cord and into macrophages in the DRGs, heart, and muscle of YG8R FRDA mice. We observed the transfer of wild-type frataxin and Cox8 mitochondrial proteins from HSPC-derived microglia/macrophages to FRDA mouse neurons and muscle myocytes in vivo. Our results show the HSPC-mediated phenotypic rescue of FRDA in YG8R mice and suggest that this approach should be investigated further as a strategy for treating FRDA.

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“…After euthanasia, retinas were isolated and processed immediately following the method described by Rocca et al 27 In brief, the retinas were homogenized using a precellys 24-tissue homogenizer (Bertin Technology, Siège, France). Their total RNA was prepared using the RNeasy Lipid Tissue Mini Kit (Qiagen, Germantown, MD, USA) according to the manufacturer's instructions and was then quantified using a NanoDrop ND 1000 spectrophotometer (Thermo Fisher Scientific).…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

Suppression of HSP27 Restores Retinal Function and Protects Photoreceptors From Apoptosis in a Light-Induced Retinal Degeneration Animal Model

Chien

Huang

Tien

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. We used a light-induced retinal degeneration animal model to investigate possible roles of heat shock protein 27 (HSP27) in retinal/photoreceptor protection.METHODS. Sprague-Dawley rats were used for the light-induced retinal degeneration animal model. The histology of eye sections was observed for morphologic changes in the retina. Cell apoptosis was examined in each group using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electroretinography was used to evaluate retinal function. Protein and mRNA expression levels of different retinal cell markers were also detected through immunofluorescence staining, Western blotting, and real-time PCR.RESULTS. The thickness of the outer nuclear layer significantly decreased after 7-day light exposure. Moreover, we injected a viral vector for silencing HSP27 expression into the eyes and observed that photoreceptors were better preserved in the HSP27-suppressed (sHSP27) retina 2 weeks after injection. HSP27 suppression also reduced retinal cell apoptosis caused by light exposure. In addition, the loss of retinal function caused by light exposure was reversed on suppressing HSP27 expression. We subsequently found that the expression of the Rho gene and immunofluorescence staining of rhodopsin and arrestin (cell markers for photoreceptors) increased in sHSP27-treated retinas. HSP27 suppression did not affect the survival of ganglion and amacrine cells. CONCLUSIONS.Retinal cell apoptosis and functional loss were observed after 7-day light exposure. However, in the following 2 weeks after light exposure, HSP27 suppression may initiate a protective effect for retinal cells, particularly photoreceptors, from light-induced retinal degeneration.

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Treatment of Inherited Eye Defects by Systemic Hematopoietic Stem Cell Transplantation

Cited by 31 publications

References 45 publications

The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives

The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives

Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich’s ataxia

Suppression of HSP27 Restores Retinal Function and Protects Photoreceptors From Apoptosis in a Light-Induced Retinal Degeneration Animal Model

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