Emerging trends in transplantation of inherited metabolic diseases

Prasad, Vinod K.; Kurtzberg, Joanne

doi:10.1038/sj.bmt.1705970

Cited by 75 publications

(61 citation statements)

References 31 publications

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“…Oral administration of trehalose, a known pharmacological enhancer of autophagy, increases the life span and normalizes several behavioral and neuropathological features of MPS IIIB mice, most notably rescuing their retinal degeneration. Because no disease-modifying therapies are currently available for MPS IIIB or related disorders, this study establishes a viable new approach to pharmacotherapy that could be tested either alone or in combination with other approaches under development [5,12–15,52]. …”

Section: Discussionmentioning

confidence: 99%

“…Enzyme replacement therapy and gene therapy have been considered the most promising routes for therapeutic intervention in lysosomal storage disorders, particularly those caused by enzyme deficiency [5,12–15]. However, some of these enzymes – including NAGLU – are not able to cross the blood-brain barrier [13], which precludes systemic administration of the deficient enzyme as a direct route of enzyme supply.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, these approaches have inherent challenges because enzymes provided by HSCT or ERT have only limited ability to transit through the blood-brain barrier [14,15]. Promising results have been obtained with the injection of either gene therapy vectors [16] or the recombinant protein in a mouse model of MPS IIIB [14], but exogenous protein treatments stimulate the humoral immune response, which poses a problem for treatments based on long-term administration [14].…”

Section: Introductionmentioning

confidence: 99%

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Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

et al. 2018

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The accumulation of undegraded molecular material leads to progressive neurodegeneration in a number of lysosomal storage disorders (LSDs) that are caused by functional deficiencies of lysosomal hydrolases. To determine whether inducing macroautophagy/autophagy via small-molecule therapy would be effective for neuropathic LSDs due to enzyme deficiency, we treated a mouse model of mucopolysaccharidosis IIIB (MPS IIIB), a storage disorder caused by deficiency of the enzyme NAGLU (alpha-N-acetylglucosaminidase [Sanfilippo disease IIIB]), with the autophagy-inducing compound trehalose. Treated naglu–/ – mice lived longer, displayed less hyperactivity and anxiety, retained their vision (and retinal photoreceptors), and showed reduced inflammation in the brain and retina. Treated mice also showed improved clearance of autophagic vacuoles in neuronal and glial cells, accompanied by activation of the TFEB transcriptional network that controls lysosomal biogenesis and autophagic flux. Therefore, small-molecule-induced autophagy enhancement can improve the neurological symptoms associated with a lysosomal enzyme deficiency and could provide a viable therapeutic approach to neuropathic LSDs.Abbreviations: ANOVA: analysis of variance; Atg7: autophagy related 7; AV: autophagic vacuoles; CD68: cd68 antigen; ERG: electroretinogram; ERT: enzyme replacement therapy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GNAT2: guanine nucleotide binding protein, alpha transducing 2; HSCT: hematopoietic stem cell transplantation; INL: inner nuclear layer; LC3: microtubule-associated protein 1 light chain 3 alpha; MPS: mucopolysaccharidoses; NAGLU: alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); ONL: outer nuclear layer; PBS: phosphate-buffered saline; PRKCA/PKCα: protein kinase C, alpha; S1BF: somatosensory cortex; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; VMP/VPL: ventral posterior nuclei of the thalamus

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

et al. 2018

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“…In the past 25 years, nearly a thousand patients with metabolic storage disorders have received allogeneic hematopoietic stem cell transplantation for curative purposes using bone marrow from HLA-matched or mismatched related donors. This results in clinical benefit by replacing the missing enzyme produced by the donor cells circulating in the blood [39][40][41][42][43].…”

Section: Non-oncologymentioning

confidence: 99%

Umbilical cord blood banking: an update

Butler

Menitove²

2011

J Assist Reprod Genet

101

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Background Umbilical cord blood is a potential vast source of primitive hematopoietic stem and progenitor cells available for clinical application to reconstitute the hematopoietic system and/or restore immunological function in affected individuals requiring treatment. Cord blood can be used as an alternative source for bone marrow transplantation and its use is developing into a new field of treatment for pediatric and adult patients presenting with hematological disorders, immunological defects and specific genetic diseases. Discussion More than 25,000 allogeneic cord blood transplantations have been performed worldwide since the first cord blood transplantation in 1988. There are two banking options for storing umbilical cord blood [private (family) and public]. Cord blood stored in private banks are used for either autologous or allogeneic transplants for the infant donor or related family members but private cord blood banks are not searchable or available to the public. More than 780,000 cord blood units are stored in over 130 private cord blood banks, worldwide, and over 400,000 units in more than 100 quality controlled public cord blood banks.Conclusions Researchers continue to evaluate the usefulness of cord blood cells in treating human diseases or disorders for purposes other than hematological disorders including heart disease, strokes, brain or spinal cord injuries and cancer. This review summarizes the status of umbilical cord blood banking, its history and current and potential use in the treatment of human disease.

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“…[10][11][12][13][14] Cord blood (CB) has been clinically proven to be an effective stem cell source to prevent neurological deterioration in patients with inborn metabolic disorders, that is, Krabbe's disease and Hurler's syndrome. 15,16 A significant advantage of HUCB cells over other sources of stem cells in tissue regeneration is the ready availability of HUCB. This is particularly important for diseases such as HIE, where at least one of the proven windows of opportunity for rescue therapy (hypothermia) is within a few hours after the insult.…”

Section: Introductionmentioning

confidence: 99%

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

Liao

Cotten

Tan

et al. 2012

Bone Marrow Transplant

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Brain injury resulting from perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of acute mortality in infants and chronic neurologic disability in surviving children. Recent multicenter clinical trials demonstrated the effectiveness of hypothermia initiated within the first 6 postnatal hours to reduce the risk of death or major neurological disabilities among neonates with HIE. However, in these trials, approximately 40% of cooled infants died or survived with significant impairments. Therefore, adjunct therapies are required to improve the outcome in neonates with HIE. Cord blood (CB) is a rich source of stem cells. Administration of human CB cells in animal models of HIE has generally resulted in improved outcomes and multiple mechanisms have been suggested including anti-inflammation, release of neurotrophic factors and stimulation of endogenous neurogenesis. Investigators at Duke are conducting studies of autologous CB infusion in neonates with HIE and in children with cerebral palsy. These pilot studies indicate no added risk from the regimens used, but results of ongoing placebo-controlled trials are needed to assess efficacy. Meanwhile, further investigations are warranted to determine the best strategies, that is, timing, dosing, route of delivery, choice of stem cells and ex vivo modulations, to attain long-term benefits of CB stem cell therapy.

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Emerging trends in transplantation of inherited metabolic diseases

Cited by 75 publications

References 31 publications

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

Umbilical cord blood banking: an update

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

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