Publications by authors named "Troy C Lund"

95 Publications

Mucopolysaccharidosis Type I: Current Treatments, Limitations, and Prospects for Improvement.

Biomolecules 2021 Jan 29;11(2). Epub 2021 Jan 29.

Immusoft Corp, Minneapolis, MN 55413, USA.

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded HS and DS with subsequent disease manifestations in multiple organs. The disease can be divided into severe (Hurler syndrome) and attenuated (Hurler-Scheie, Scheie) forms. Currently approved treatments consist of enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). Patients with attenuated disease are often treated with ERT alone, while the recommended therapy for patients with Hurler syndrome consists of HSCT. While these treatments significantly improve disease manifestations and prolong life, a considerable burden of disease remains. Notably, treatment can partially prevent, but not significantly improve, clinical manifestations, necessitating early diagnosis of disease and commencement of treatment. This review discusses these standard therapies and their impact on common disease manifestations in patients with MPS I. Where relevant, results of animal models of MPS I will be included. Finally, we highlight alternative and emerging treatments for the most common disease manifestations.
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http://dx.doi.org/10.3390/biom11020189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911293PMC
January 2021

Consensus opinion on immune-mediated cytopenias after hematopoietic cell transplant for inherited metabolic disorders.

Bone Marrow Transplant 2021 Jan 13. Epub 2021 Jan 13.

Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.

Hematopoietic stem cell transplantation (HCT) has been increasingly used for patients with inherited metabolic disorders (IMD). Immune mediated cytopenias (IMCs) after HCT, manifesting as hemolytic anemia, thrombocytopenia, and/or neutropenia, are recognized as a significant complication in this patient population, yet our understanding of the incidence, risk factors, and pathophysiology is currently limited. Review of the published literature demonstrates a higher incidence in younger patients who undergo HCT for a nonmalignant disease indication. However, a few reports suggest that the incidence is even higher among those with IMD (incidence ranging from 10 to 56%). This review summarizes the literature, provides an approach to better understanding of the possible etiology of IMCs, and proposes a diagnostic and management plan for patients with IMD who develop single or multi-lineage cytopenias after HCT.
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http://dx.doi.org/10.1038/s41409-020-01179-5DOI Listing
January 2021

Aspartylglucosaminuria: Clinical Presentation and Potential Therapies.

J Child Neurol 2021 Jan 13:883073820980904. Epub 2021 Jan 13.

University of Minnesota, Department of Pediatrics, Minneapolis, MN, USA.

Aspartylglucosaminuria (AGU) is a recessively inherited neurodegenerative lysosomal storage disease characterized by progressive intellectual disability, skeletal abnormalities, connective tissue overgrowth, gait disturbance, and seizures followed by premature death. AGU is caused by pathogenic variants in the aspartylglucosaminidase () gene, leading to glycoasparagine accumulation and cellular dysfunction. Although more prevalent in the Finnish population, more than 30 variants have been identified worldwide. Owing to its rarity, AGU may be largely underdiagnosed. Recognition of the following early clinical features may aid in AGU diagnosis: developmental delays, hyperactivity, early growth spurt, inguinal and abdominal hernias, clumsiness, characteristic facial features, recurring upper respiratory and ear infections, tonsillectomy, multiple sets of tympanostomy tube placement, and sleep problems. Although no curative therapies currently exist, early diagnosis may provide benefit through the provision of anticipatory guidance, management of expectations, early interventions, and prophylaxis; it will also be crucial for increased clinical benefits of future AGU disease-modifying therapies.
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http://dx.doi.org/10.1177/0883073820980904DOI Listing
January 2021

MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines.

J Inherit Metab Dis 2020 Dec 29. Epub 2020 Dec 29.

Division of Neurogenetics and The Moser Center for Leukodystrophies, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland, USA.

Background: Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy.

Methods: To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus.

Results: One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI.

Conclusion: Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.
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http://dx.doi.org/10.1002/jimd.12356DOI Listing
December 2020

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation.

JCI Insight 2020 Oct 15;5(20). Epub 2020 Oct 15.

Greenwood Genetic Center, J.C. Self Research Institute, Greenwood, South Carolina, USA.

Although congenital heart defects (CHDs) represent the most common birth defect, a comprehensive understanding of disease etiology remains unknown. This is further complicated since CHDs can occur in isolation or as a feature of another disorder. Analyzing disorders with associated CHDs provides a powerful platform to identify primary pathogenic mechanisms driving disease. Aberrant localization and expression of cathepsin proteases can perpetuate later-stage heart diseases, but their contribution toward CHDs is unclear. To investigate the contribution of cathepsins during cardiovascular development and congenital disease, we analyzed the pathogenesis of cardiac defects in zebrafish models of the lysosomal storage disorder mucolipidosis II (MLII). MLII is caused by mutations in the GlcNAc-1-phosphotransferase enzyme (Gnptab) that disrupt carbohydrate-dependent sorting of lysosomal enzymes. Without Gnptab, lysosomal hydrolases, including cathepsin proteases, are inappropriately secreted. Analyses of heart development in gnptab-deficient zebrafish show cathepsin K secretion increases its activity, disrupts TGF-β-related signaling, and alters myocardial and valvular formation. Importantly, cathepsin K inhibition restored normal heart and valve development in MLII embryos. Collectively, these data identify mislocalized cathepsin K as an initiator of cardiac disease in this lysosomal disorder and establish cathepsin inhibition as a viable therapeutic strategy.
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http://dx.doi.org/10.1172/jci.insight.133019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605527PMC
October 2020

Outcome After Cord Blood Transplantation Using Busulfan Pharmacokinetics-Targeted Myeloablative Conditioning for Hurler Syndrome.

Biol Blood Marrow Transplant 2020 Sep 20. Epub 2020 Sep 20.

Department of Paediatric Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, UK. Electronic address:

Background: Successful hematopoietic cell transplantation (HCT) provides life-long disease-modifying therapy for children with Hurler syndrome (HS). Umbilical cord blood (CB) is an important alternative stem cell source for HS children requiring HCT but lacking a suitable human leucocyte antigen (HLA)-matched, non-carrier sibling donor. This is the largest unrelated cord blood transplantation (CBT) series for HS collected from three large, experienced metabolic transplant centers.

Objective: The aims of this study were to examine outcomes and performed a predictive analysis after a CBT for HS using intravenous busulfan pharmacokinetic (Bu-pk) directed myeloablative conditioning (MAC).

Study Design: This collaborative retrospective included 97 children with HS who received their first CBT between 2004 and 2016 at Royal Manchester Children's Hospital, University Medical Center Utrecht and University of Minnesota Children's Hospital. Outcomes of interest were overall survival (OS), engrafted survival (ES), graft failure, graft-versus-host disease (GvHD), latest donor chimerism and IDUA enzyme level. Engrafted survival (ES) was defined as the probability of being alive with ≥20% whole blood donor-cell engraftment after the first CBT. Cox proportional hazards regression modelling was used to perform univariate analysis of predictors on OS and ES. Cumulative incidence of GvHD was calculated using a competing risk analysis, considering death and graft failure as competing events. All factors associated with a p-value <0.10 by univariate analysis were included into multivariate analysis. All p-values quoted are two-sided, with a level of significance of 0.05. Statistical analyses were performed using STATA 14.2.

Results: Patient and transplantation characteristics were summarised in table 1. The median age at transplant was 10.8 months (range 0.23 - 63.2 months). The median follow-up for surviving patients was 4.2 years (range, 1.0 to 12.8 years). 5-year overall survival (OS) and engrafted survival (ES) were 88% and 79%. OS was 95% after BuFluATG, 90% after BuCyATG and 74% after BuCyAlemtuzumab (p=0.02) (Figure 1a). Age, conventional HLA matching, allele level HLA matching, washed CB, cell doses were not associated with OS. ES was 84% for BuFluATG, 83% for BuCyATG and 65% for BuCyAlemtuzumab (p=0.34). Washed CB unit (p=0.03, figure 1b) and HLA ≤ 6/10 (p=0.02) were associated with significantly lower ES. The one-year cumulative incidence of graft-failure was 11% (95% CI, 6-21%). Five (5%) had grade III-IV acute GvHD. Five had limited chronic GvHD and one had extensive GvHD. The incidence of veno-occlusive disease was higher in patients conditioned with BuCy (n=10, 19%) compared to BuFlu (n=2, 5%) (p=0.03). Of the 11 patients with graft failure, 8 (73%) were aplastic and 3 (27%) autologous reconstitution. Of 11 patients with graft failure, 9 received a second transplant, and 8 (89%) survived. 89% after first CBT and all after second transplant had full donor chimerism. All had IDUA enzyme levels of above the lower limit of normal range.

Conclusions: Survival after CBT for HS has improved but better strategies are needed to improve graft outcome. Mismatched ≤6/10 and washing of the cord blood graft are associated with inferior engrafted survival. Cord blood graft is associated with low risk of acute and chronic graft-versus-host disease.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.033DOI Listing
September 2020

Dysostosis Multiplex in Human Mucopolysaccharidosis Type 1 H and in Animal Models of the Disease.

Pediatr Endocrinol Rev 2020 Aug;17(4):317-326

Immusoft Corp, Minneapolis, MN 55413, USA, Department of Genetics, Cell Biology and Development and Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder, caused by deficiency of α-L-iduronidase, and consequent accumulation of dermatan and heparan sulfates. Severity of the disease ranges from mild (Scheie) to moderate (Hurler-Scheie) to severe (Hurler or MPS-IH). A prominent clinical manifestation of MPS-IH is dysostosis multiplex, a constellation of skeletal abnormalities. We performed a retrospective review comparing manifestations of dysostosis multiplex in patients presenting with MPSIH and relevant animal models. Dog, cat and mouse models of MPS-IH are extensively studied to better understand the pathology of the disease. While all animal models display certain characteristics of human MPSIH, species-specific manifestations must be considered when evaluating skeletal abnormalities. Moreover, some skeletal abnormalities emerge at species-specific developmental stages, e.g. thoracolumbar kyphosis is an early manifestation in humans, while it appears late in the mouse model. The choice of the appropriate diagnostic test is of importance to avoid misleading conclusions.
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http://dx.doi.org/10.17458/per.vol17.2020.hpl.dysostosismultiplexhumananimalDOI Listing
August 2020

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.

Cells 2020 08 5;9(8). Epub 2020 Aug 5.

Immusoft Corp, Minneapolis, MN 55413, USA.

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues. If untreated, patients with the severe phenotype die within the first decade of life. Early diagnosis is crucial to prevent the development of fatal disease manifestations, prominently cardiac and respiratory disease, as well as cognitive impairment. However, the initial symptoms are nonspecific and impede early diagnosis. This review discusses common phenotypic manifestations in the order in which they develop. Similarities and differences in the three animal models for MPS I are highlighted. Earliest symptoms, which present during the first 6 months of life, include hernias, coarse facial features, recurrent rhinitis and/or upper airway obstructions in the absence of infection, and thoracolumbar kyphosis. During the next 6 months, loss of hearing, corneal clouding, and further musculoskeletal dysplasias develop. Finally, late manifestations including lower airway obstructions and cognitive decline emerge. Cardiac symptoms are common in MPS I and can develop in infancy. The underlying pathogenesis is in the intra- and extracellular accumulation of partially degraded GAGs and infiltration of cells with enlarged lysosomes causing tissue expansion and bone deformities. These interfere with the proper arrangement of collagen fibrils, disrupt nerve fibers, and cause devastating secondary pathophysiological cascades including inflammation, oxidative stress, and other disruptions to intracellular and extracellular homeostasis. A greater understanding of the natural history of MPS I will allow early diagnosis and timely management of the disease facilitating better treatment outcomes.
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http://dx.doi.org/10.3390/cells9081838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463646PMC
August 2020

Neurocognitive benchmarks following transplant for emerging cerebral adrenoleukodystrophy.

Neurology 2020 08 2;95(5):e591-e600. Epub 2020 Jul 2.

From the Departments of Pediatrics (E.I.P., R.S.Z., W.P.M., A.O.G., T.C.L., P.J.O., J.B.E.), Radiology (D.R.N.), Bioinformatics and Biostatistics Core (R.S.), and Neurology (D.L.K.-J.), University of Minnesota, Minneapolis; and Sangamo Therapeutics (W.P.M.), Richmond, CA.

Objective: To quantify benchmark treatment outcomes that may be enabled by newborn screening surveillance for X-linked adrenoleukodystrophy (ALD), we report neurocognitive, neuropsychiatric, and MRI change for boys who underwent hematopoietic stem cell transplant (HSCT) at initial stages of demyelination, prior to neurocognitive signs of disease.

Methods: Retrospective chart review identified 36 patients whose cerebral ALD was detected and treated early, with lesion severity less than 5 on the ALD-specific MRI scoring system. Median age at transplant was 7.3 years (range, 4.0-16.1). Progression of radiologic disease on MRI in the 2 years following HSCT was examined relative to the severity of the initial lesion for 33 patients, and longitudinal neurocognitive and neuropsychiatric outcomes were studied for 30 patients.

Results: Patients whose pretransplant lesion extended beyond the splenium of the corpus callosum and adjacent periventricular white matter (MRI severity score >2) demonstrated lower posttransplant neurocognitive scores, more neuropsychiatric symptoms, and more disease progression on MRI than patients with a less severe lesion. Changes from baseline neurocognitive functioning were greater at 2 years posttransplant as compared to 1 year. There was greater variance and risk of lesion progression as pretransplant MRI severity increased.

Conclusion: To realize the full benefits of newborn screening, clinicians must detect very small demyelinating lesions during surveillance and intervene quickly. Novel interventions that reduce risks inherent in allogeneic transplantation are needed. Trial endpoints should include direct neurocognitive assessment and extend at least 2 years posttreatment to provide the greatest sensitivity to detect neurocognitive morbidity.
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http://dx.doi.org/10.1212/WNL.0000000000009929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455349PMC
August 2020

Volume of Gadolinium Enhancement and Successful Repair of the Blood-Brain Barrier in Cerebral Adrenoleukodystrophy.

Biol Blood Marrow Transplant 2020 10 26;26(10):1894-1899. Epub 2020 Jun 26.

Department of Diagnostic Radiology, University of Minnesota Medical Center, Minneapolis, Minnesota.

Up to 40% of boys with adrenoleukodystrophy develop a severe central nervous system demyelinating form (cALD) characterized by white matter changes and gadolinium enhancement on magnetic resonance imaging (MRI). Hematopoietic cell transplant (HCT) is the only proven means to attenuate cALD progression. The elimination of active neuroinflammation is indicated radiographically by the resolution of gadolinium (Gd) enhancement and correlates to speed of donor neutrophil recovery. We analyzed 66 boys with cALD undergoing HCT for biomarkers correlating with early (30 days post-HCT) Gd signal resolution. We found that log Gd volume (cm) on pre-HCT MRI strongly positively correlated to day 30 Gd resolution (P = .0003) with smaller volume correlating to higher proportion resolved, as was the baseline gadolinium intensity score (P = .04), plasma chitotriosidase activity (P = .04), and faster absolute neutrophil count recovery (P = .03). In multivariate analysis, log Gd volume remained superior in determining which patients would have Gd signal resolution by 30 days post-HCT (P = .016). A final analysis indicated that early Gd resolution also correlated with less neurologic progression from baseline to 1 year following HCT (P = .006). MRI Gd volume may serve as a contributing biomarker to better delineate outcomes and an important metric in comparing therapies in the treatment of cALD.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.019DOI Listing
October 2020

The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases.

Cells 2020 06 5;9(6). Epub 2020 Jun 5.

Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, MN 55455, USA.

The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
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http://dx.doi.org/10.3390/cells9061411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348849PMC
June 2020

Failure of intrathecal allogeneic mesenchymal stem cells to halt progressive demyelination in two boys with cerebral adrenoleukodystrophy.

Stem Cells Transl Med 2020 May 5;9(5):554-558. Epub 2020 Feb 5.

Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota.

Cerebral adrenoleukodystrophy is an inflammatory demyelinating condition that is the result of a mutation in the X-linked ABCD1 gene, a peroxisomal very long chain fatty acid transporter. Although mutations in this gene result in adrenal insufficiency in the majority of affected individuals, 40% of those affected develop the demyelinating cerebral form, cerebral adrenoleukodystrophy (CALD). CALD is characterized by imaging findings of demyelination and contrast enhancement on magnetic resonance imaging (MRI). Although allogeneic hematopoietic cell transplantation can arrest progression of CALD early in its course, there is no accepted therapy for patients with advanced CALD. Mesenchymal stem cells (MSCs) have been used in a variety of clinical trials to capitalize on their anti-inflammatory properties as well as promote tissue repair. We delivered MSCs via intrathecal (IT) route to two boys with rapidly advancing CALD. The first boy received three doses 1 week apart, whereas the second boy received a single dose of IT MSCs. We note delivery of IT MSCs was feasible and without complication. Follow-up MRI scans after IT MSC delivery showed progressive demyelination in the first patient and no change in demyelination or contrast enhancement in the second patient. Although the infusion of IT MSCs was safe, it did not halt CALD progression in this setting, and future studies should focus on patient selection and dose optimization.
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http://dx.doi.org/10.1002/sctm.19-0304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180290PMC
May 2020

Reduced-Toxicity (BuFlu) Conditioning Is Better Tolerated but Has a Higher Second Transplantation Rate Compared to Myeloablative Conditioning (BuCy) in Children with Inherited Metabolic Disorders.

Biol Blood Marrow Transplant 2020 03 18;26(3):486-492. Epub 2019 Nov 18.

Pediatric Blood and Marrow Transplant Program, University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota.

Hematopoietic stem cell transplantation (HCT) is a primary treatment for various inherited metabolic disorders (IMDs). Achieving stable and sustained engraftment while minimizing transplantation-related morbidity and mortality is critical to optimizing outcomes for IMDs. Traditional regimens have used myeloablative approaches, primarily busulfan and cyclophosphamide (BuCy), which is associated with significant regimen-related toxicity. Alternatively, reduced-toxicity regimens, such as busulfan and fludarabine (BuFlu), have been proposed to offer similar efficacy with reduced toxicities. We compared transplantation-related outcomes with BuCy-based and BuFlu-based conditioning in patients with IMDs. We retrospectively analyzed the University of Minnesota's transplantation database for patients with IMDs who underwent HCT using a BuCy (with alemtuzumab) or BuFlu (with antithymocyte globulin) preparative regimen between March 2008 and September 2017. Overall survival (OS), event-free survival (EFS), and incidence of neutrophil and platelet recovery were determined using standard definitions. Complications such as graft failure, sinusoidal obstruction syndrome, hemorrhagic cystitis, and respiratory failure were compared. Graft failure includes primary and secondary aplastic graft failure with and without autologous recovery. The incidence of viral infections post-transplantation in the 2 regimens was also determined. A total of 99 patients underwent HCT for IMDs during the study period. Sixty-four patients received BuCy conditioning, and the other 35 received BuFlu. Hurler syndrome (46%) and adrenoleukodystrophy (43%) were the most common IMDs, and umbilical cord blood was the most common graft source (74%). One-year OS was similar in the 2 groups (81.2% in BuCy versus 85.5% in BuFlu; P = .8), with an EFS of 75% versus 63%, respectively. The 2 groups also had similar incidences of grade III-IV acute GVHD (9% versus 6%; P = .5) and chronic GVHD (9% versus 7%; P = .67). Neutrophil and platelet recovery were similar in the 2 groups, with a significantly shorter duration of hospital stay noted in the BuFlu cohort (median, 21 days versus 34 days; P = .002). The cumulative incidence of graft failure was significantly higher in the BuFlu group (29% versus 14%; P = .08), as was the rate of second HCT (27% versus 3%; P = .001). The incidences of adenoviral infection (14% versus 0%; P = .02) and hemorrhagic cystitis (23% versus 3%; P = .01) were higher in the BuCy group. T cell engraftment occurred significantly sooner with BuCy conditioning until 1-year post-transplantation, but donor myeloid engraftment was similar in the 2 groups. Our data indicate that reduced-toxicity conditioning is associated with lower rates of infection and other transplantation-related complications but is concerning for a higher rate of graft failure in patients with IMDs. Alternate immunosuppressive agents and novel techniques should be considered to minimize toxicities and reduce complications.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.014DOI Listing
March 2020

Post-transplant laronidase augmentation for children with Hurler syndrome: biochemical outcomes.

Sci Rep 2019 Oct 1;9(1):14105. Epub 2019 Oct 1.

University of Minnesota, Division of Pediatric Blood and Marrow Transplant, Minneapolis, 55455, USA.

Allogeneic hematopoietic cell transplantation (HCT) benefits children with Hurler syndrome (MPS-IH). However, survivors remain burdened by substantial MPS-IH related residual disease. We studied the feasibility, safety and biochemical impact of augmentative recombinant intravenous enzyme replacement therapy (IV-ERT) post transplantation. Ten children with MPS-IH and ≥2 years from successful HCT underwent IV-ERT for 2 years' duration. Patients were monitored for anti-drug antibody (ADA) development, including inhibitory capacity and changes in urinary excretion of glycosaminoglycans (uGAG). Three patients demonstrated low-level ADA at baseline, though all children tolerated IV-ERT well. Eight patients developed ADA over the 2-year study, with 3 (38%) meeting criteria for an inhibitory ADA response. The aggregate cohort experienced a reduction in uGAG from baseline to study end, which was enhanced in children with low or no ADA response. Conversely, children with inhibitory ADA showed increase in uGAG over time. IV-ERT in previously transplanted children with MPS-IH appears safe and can reduce uGAG, although this is reversed by the presence of inhibitory ADA. These data show a biochemical change after initiation of post-HCT IV-ERT, but the occurrence of ADA and inhibitory antibodies are a concern and should be monitored in future efficacy trials. This trial was registered at www.clinicaltrials.gov , NCT01173016, 07/30/2010.
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http://dx.doi.org/10.1038/s41598-019-50595-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773848PMC
October 2019

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

Pediatr Res 2020 01 21;87(1):104-111. Epub 2019 Aug 21.

University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.

Background: Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.

Methods: This 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.

Results: The two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.

Conclusions: Laronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made.
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http://dx.doi.org/10.1038/s41390-019-0541-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960090PMC
January 2020

Association between APOE4 and biomarkers in cerebral adrenoleukodystrophy.

Sci Rep 2019 05 27;9(1):7858. Epub 2019 May 27.

University of Minnesota, Division of Pediatric Blood and Marrow Transplantation, 55455, Minneapolis, USA.

Cerebral adrenoleukodystrophy (cALD) is an inflammatory neurodegenerative disease associated with mutation of the ABCD1 gene. Proteomic analysis of cerebral spinal fluid (CSF) from young males with active cALD revealed markers of inflammation including APOE4. APOE4 genotype has been associated with an inferior prognosis following acute and chronic neurologic injury. We assessed APOE4 inheritance among 83 consecutive young males with cALD prior to hematopoietic cell transplant and its association with markers of cerebral disease. The allele frequency of APOE4 was not significantly different from that of the general population at 17%. Young males with cALD that were APOE4 carriers had similar CSF protein and chitotriosidase activity to that of non-carriers. In contrast, APOE4 carriers had an increased burden of cerebral disease involvement as determined by MRI severity score (10.5 vs 7.0 points, p = 0.01), higher gadolinium intensity score (2.0 vs 1.3 points, p = 0.007), inferior neurologic function (neurologic function score 2.4 vs 1.0, p = 0.001), and elevated CSF MMP2 levels compared to that of non-carriers (13168 vs 9472 pg/mL, p = 0.01). These are the first data showing that APOE4 is associated with increased severity of cerebral disease in cALD and suggest it may be a modifier of disease.
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http://dx.doi.org/10.1038/s41598-019-44140-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536544PMC
May 2019

Biochemical and clinical response after umbilical cord blood transplant in a boy with early childhood-onset beta-mannosidosis.

Mol Genet Genomic Med 2019 07 21;7(7):e00712. Epub 2019 May 21.

Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota.

Background: Deficiency in the enzyme β-mannosidase was described over three decades ago. Although rare in occurrence, the presentation of childhood-onset β-mannosidase deficiency consists of hypotonia in the newborn period followed by global development delay, behavior problems, and intellectual disability. No effective pharmacologic treatments have been available.

Methods: We report 2-year outcomes following the first umbilical cord blood transplant in a 4-year-old boy with early childhood-onset disease.

Results: We show restoration of leukocyte β-mannosidase activity which remained normal at 2 years posttransplant, and a simultaneous increase in plasma β-mannosidase activity and dramatic decrease in urine-free oligosaccharides were also observed. MRI of the brain remained stable. Neurocognitive evaluation revealed test point gains, although the magnitude of improvement was less than expected for age, causing lower IQ scores that represent a wider developmental gap between the patient and unaffected peers.

Conclusion: Our findings suggest that hematopoietic cell transplant can correct the biochemical defect in β-mannosidosis, although preservation of the neurocognitive trajectory may be a challenge.
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http://dx.doi.org/10.1002/mgg3.712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625138PMC
July 2019

Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes.

Genet Med 2019 11 25;21(11):2552-2560. Epub 2019 Apr 25.

Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.

Purpose: Abnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change.

Methods: In addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association.

Results: Over treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant.

Conclusion: Intrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome.
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http://dx.doi.org/10.1038/s41436-019-0522-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831510PMC
November 2019

Prevalence of glucose-6-phosphate dehydrogenase deficiency in Cameroonian blood donors.

BMC Res Notes 2019 Apr 2;12(1):195. Epub 2019 Apr 2.

Division of Global Pediatrics, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.

Objective: Deficiency in G6PD is the most common enzymopathy worldwide. It is frequently found in individuals of African descent in whom it can lead to hemolytic crises triggered by the use of certain antimalarial medications and infection. The prevalence of G6PD deficiency and its contribution to morbidity in West Africa is under-studied. To understand the prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in West African blood donors.

Results: We evaluated the G6PD status and infectious disease screening tests of 1001 adult male Cameroonian blood donors (mean age 31.7 ± 9.8 years). The prevalence of G6PD deficiency was 7.9%. There was no difference in levels of hemoglobin or ABO subtype between those who were G6PD-normal compared to those that were deficient. Interestingly, G6PD-normal vs. deficient blood donors were less likely to have screened positive for hepatitis C virus (p = 0.02) and rapid plasma reagin (indicative of syphilis, p = 0.03). There was no significant difference in hepatitis B sAg, HIV-1, or HIV-2 reactivity between those with vs. without G6PD sufficiency. These data suggest that G6PD deficiency is common among West African male blood donors and may be associated with specific infectious disease exposure.
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http://dx.doi.org/10.1186/s13104-019-4226-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444568PMC
April 2019

Cerebral adrenoleukodystrophy is associated with loss of tolerance to profilin.

Eur J Immunol 2019 06 10;49(6):947-953. Epub 2019 Mar 10.

Division of Pediatric Blood and Marrow Transplant, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.

Childhood cerebral adrenoleukodystrophy (cALD) is a devastating manifestation of ALD accompanied by demyelination, inflammation, and blood brain barrier (BBB) disruption with shared characteristics of an auto-immune disease. We utilized plasma samples pre- and postdevelopment of cALD to determine the presence of specific auto-antibodies. Mass spectrometry of protein specifically bound with post-cALD plasma antibody identified Profilin1 (PFN1) as the target. In a screen of 94 boys with cALD 48 (51%) had anti-PFN1 antibodies, whereas only 2/29 boys with ALD but without cerebral disease, and 0/30 healthy controls showed anti-PFN1 immunoreactivity. Cerebral spinal fluid from those with cALD showed higher levels of PFN1 protein compared with non-cALD samples (324 ± 634 versus 42 ± 23 pg/mL, p = 0.04). Boys that were anti-PFN positive had a significant increase in the amount of gadolinium signal observed on MRI when compared to boys that were anti-PFN1 negative (p = 0.04) possibly indicating increased BBB disruption. Anti-PFN1 positivity was also associated with elevated levels of very long chain fatty acids (C26 of 1.12 ± 0.41 versus 0.97 ± 0.30 mg/dL, p = 0.03) and increased plasma BAFF (973 ± 277 versus 733 ± 269 pg/mL, p = 0.03). In conclusion, anti-PFN may be a novel biomarker associated with the development of cALD in boys with ALD.
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http://dx.doi.org/10.1002/eji.201848043DOI Listing
June 2019

Successful donor engraftment and repair of the blood-brain barrier in cerebral adrenoleukodystrophy.

Blood 2019 03 11;133(12):1378-1381. Epub 2019 Jan 11.

Division of Pediatric Blood and Marrow Transplant, Department of Pediatrics, University of Minnesota, Minneapolis, MN.

Adrenoleukodystrophy (ALD) is caused by mutations within the X-linked gene, resulting in the inability to transport acylated very long chain fatty acids (VLCFAs) into the peroxisome for degradation. VLCFAs subsequently accumulate in tissues, including the central nervous system. Up to 40% of boys develop a severe progressive demyelinating form of ALD, cerebral ALD, resulting in regions of demyelination observed on brain magnetic resonance imaging that are associated with a "garland ring" of gadolinium contrast enhancement. Gadolinium enhancement indicates blood-brain barrier (BBB) disruption and an active inflammatory disease process. Only hematopoietic cell transplant (HCT) has been shown to halt neurologic progression, although the mechanism of disease arrest is unknown. We evaluated imaging- and transplant-related biomarkers in 66 males who underwent HCT. In 77% of patients, gadolinium contrast resolved by 60 days post-HCT. We determined that time to neutrophil recovery and extent of donor chimerism correlated significantly with time to contrast resolution post-HCT. Graft failure was associated with a significantly slower rate of contrast resolution ( < .0001). Time to neutrophil recovery remained significant in multivariate analysis with other biomarkers ( = .03). Our data suggest that robust donor myeloid recovery is necessary for timely repair of the BBB.
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http://dx.doi.org/10.1182/blood-2018-11-887240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440119PMC
March 2019

Outcomes after Second Hematopoietic Cell Transplantation in Children and Young Adults with Relapsed Acute Leukemia.

Biol Blood Marrow Transplant 2019 02 19;25(2):301-306. Epub 2018 Sep 19.

Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address:

Children with acute leukemia who relapse after hematopoietic cell transplantation (HCT) have few therapeutic options. We studied 251 children and young adults with acute myelogenous or lymphoblastic leukemia who underwent a second HCT for relapse after their first HCT. The median age at second HCT was 11 years, and the median interval between first and second HCT was 17 months. Most of the patients (n = 187; 75%) were in remission, received a myeloablative conditioning regimen (n = 157; 63%), and underwent unrelated donor HCT (n = 230; 92%). The 2-year probability of leukemia-free survival (LFS) was 33% after transplantation in patients in remission, compared with 19% after transplantation in patients not in remission (P = .02). The corresponding 8-year probabilities were 24% and 10% (P = .003). A higher rate of relapse contributed to the difference in LFS. The 2-year probability of relapse after transplantation was 42% in patients in remission and 56% in those in relapse (P = .05). The corresponding 8-year probabilities were 49% and 64% (P = .04). These data extend the findings of others showing that patients with a low disease burden are more likely to benefit from a second transplantation. Late relapse led to a 10% decrement in LFS beyond the second year after second HCT. This differs from first HCT, in which most relapses occur within 2 years after HCT.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339844PMC
February 2019

Filtered sunlight versus intensive electric powered phototherapy in moderate-to-severe neonatal hyperbilirubinaemia: a randomised controlled non-inferiority trial.

Lancet Glob Health 2018 10 28;6(10):e1122-e1131. Epub 2018 Aug 28.

Bowen University Teaching Hospital, Ogbomosho, Oyo, Nigeria.

Background: Kernicterus resulting from severe neonatal hyperbilirubinaemia is a leading cause of preventable deaths and disabilities in low-income and middle-income countries, partly because high-quality intensive phototherapy is unavailable. Previously, we showed that filtered-sunlight phototherapy (FSPT) was efficacious and safe for treatment of mild-to-moderate neonatal hyperbilirubinaemia. We aimed to extend these studies to infants with moderate-to-severe hyperbilirubinaemia.

Methods: We did a prospective, randomised controlled non-inferiority trial in Ogbomoso, Nigeria-a simulated rural setting. Near-term or term infants aged 14 days or younger who were of 35 weeks or more gestational age and with total serum bilirubin concentrations at or above the recommended age-dependent treatment levels for high-risk neonates were randomly assigned (1:1) to either FSPT or intensive electric phototherapy (IEPT). Randomisation was computer-generated, and neither clinicians nor the parents or guardians of participants were masked to group allocation. FSPT was delivered in a transparent polycarbonate room lined with commercial tinting films that transmitted effective phototherapeutic light, blocked ultraviolet light, and reduced infrared radiation. The primary outcome was efficacy, which was based on assessable treatment days only (ie, those on which at least 4 h of phototherapy was delivered) and defined as a rate of increase in total serum bilirubin concentrations of less than 3·4 μmol/L/h in infants aged 72 h or younger, or a decrease in total serum bilirubin concentrations in those older than 72 h. Safety was defined as no sustained hypothermia, hyperthermia, dehydration, or sunburn and was based on all treatment days. Analysis was by intention to treat with a non-inferiority margin of 10%.

Findings: Between July 31, 2015, and April 30, 2017, 174 neonates were enrolled and randomly assigned: 87 to FSPT and 87 to IEPT. Neonates in the FSPT group received 215 days of phototherapy, 82 (38%) of which were not assessable. Neonates in the IEPT group received 219 treatment days of phototherapy, 67 (31%) of which were not assessable. Median irradiance was 37·3 μW/cm/nm (IQR 21·4-56·4) in the FSPT group and 50·4 μW/cm/nm (44·5-66·2) in the IEPT group. FSPT was efficacious on 116 (87·2%) of 133 treatment days; IEPT was efficacious on 135 (88·8%) of 152 treatment days (mean difference -1·6%, 95% CI -9·9 to 6·7; p=0·8165). Because the CI did not extend below -10%, we concluded that FSPT was not inferior to IEPT. Treatment was safe for all neonates.

Interpretation: FSPT is safe and no less efficacious than IEPT for treatment of moderate-to-severe neonatal hyperbilirubinaemia in near-term and term infants.

Funding: Thrasher Research Fund and National Center for Advancing Translational Sciences.
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http://dx.doi.org/10.1016/S2214-109X(18)30373-5DOI Listing
October 2018

Assessment of blood levels of heavy metals including lead and manganese in healthy children living in the Katanga settlement of Kampala, Uganda.

BMC Public Health 2018 06 8;18(1):717. Epub 2018 Jun 8.

Department of Paediatrics and Child Health, Makerere University, Kampala, Uganda.

Background: Exposure to environmental heavy metals is common among African children. Although many of these metals are known neurotoxicants, to date, monitoring of this exposure is limited, even in countries such as Uganda that are undergoing rapid industrialization. An assessment of the burden and potential causes of metal exposure is a critical first step in gauging the public health burden of metal exposure and in guiding its elimination.

Methods: In May 2016, we enrolled 100 children between the ages of 6 and 59 months living in the Katanga urban settlement of Kampala, Uganda. We measured whole blood concentrations of antimony, arsenic, barium, cadmium, cesium, chromium, cobalt, copper, lead, manganese, nickel, selenium, and zinc. Applying reference cutoffs, we identified metals whose prevalence of elevated blood concentrations was > 10%. We also administered an environmental questionnaire to each child's caregiver to assess potential exposures, including source of drinking water, cooking location and fuel, materials used for roof, walls, and floor, and proximity to potential pollution sources such as main roads, garbage landfills, and fuel stations. We compared log-transformed blood metal concentrations by exposure category, using t-test for dichotomous comparisons and ANOVA for comparisons of three categories, using Tukeys test to adjust for multiple comparisons.

Results: The prevalence of high blood levels was elevated for six of the metals: antimony (99%), copper (12%), cadmium (17%), cobalt (19.2%), lead (97%), and manganese (36.4%). Higher blood manganese was significantly associated with having cement walls (p = 0.04) or floors (p = 0.04). Cadmium was greater among children who attended school (< 0.01), and cobalt was higher among children who lived near a garbage landfill (p = 0.01).

Conclusions: Heavy metal exposure is prevalent in the Katanga settlement and may limit neurodevelopment of children living there. Future studies are needed to definitively identify the sources of exposure and to correct potential nutritional deficiencies that may worsen metal absorption.
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http://dx.doi.org/10.1186/s12889-018-5589-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994042PMC
June 2018

Umbilical Cord Blood Expansion: Are We There Yet?

Authors:
Troy C Lund

Biol Blood Marrow Transplant 2018 07 10;24(7):1311-1312. Epub 2018 May 10.

Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota. Electronic address:

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http://dx.doi.org/10.1016/j.bbmt.2018.05.002DOI Listing
July 2018

Post-transplant adaptive function in childhood cerebral adrenoleukodystrophy.

Ann Clin Transl Neurol 2018 03 22;5(3):252-261. Epub 2018 Jan 22.

University of Minnesota Minneapolis Minnesota.

Objective: Hematopoietic stem cell transplantation (HSCT) is the only treatment known to slow or halt inflammatory demyelination among boys with the cerebral form of X-linked adrenoleukodystrophy (cALD), a devastating childhood condition affecting the central nervous system. HSCT can lead to a range of adverse outcomes including fatality. Previous studies have examined the potential predictors of post-HSCT survival and neurologic functioning. However, little is known about patients' daily-life adaptive functional outcomes (i.e., ability to communicate, maintain social relationships, and independently execute tasks of daily living). The purpose of this retrospective cohort study was to identify which patient characteristics and treatment-related variables predict long-term adaptive function among the survivors of HSCT for cALD.

Methods: We obtained caregiver ratings of adaptive functioning of 65 transplant survivors at an average of 4.6 years (range: 1.0-24.1 years) post-HSCT. Using linear regression with penalized maximum likelihood estimation, we modeled the relative contribution of pre-transplant neurocognitive test performance, MRI severity, transplant regimen, and length of time since transplant on patient adaptive functioning outcomes.

Results: Higher radiographic disease severity and poorer performance on baseline neurocognitive tests requiring fine motor skills and visual perception were associated with inferior adaptive functioning after HSCT. Use of radiation during the transplant preparative regimen also predicted poorer adaptive outcomes.

Interpretation: In addition to radiological disease severity, baseline neurocognitive test performance is associated with post-transplant adaptive functional outcomes. Neurocognitive measures may play an important role in prognostic counseling and post-transplant treatment planning for patients considering HSCT for cALD.
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http://dx.doi.org/10.1002/acn3.526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846389PMC
March 2018

Publisher Correction: Fast, sensitive method for trisaccharide biomarker detection in mucopolysaccharidosis type 1.

Sci Rep 2018 Mar 19;8(1):4994. Epub 2018 Mar 19.

Drug Discovery, R&D, Sanofi, Waltham, MA, 02451, USA.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-23332-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859120PMC
March 2018

Fast, sensitive method for trisaccharide biomarker detection in mucopolysaccharidosis type 1.

Sci Rep 2018 02 27;8(1):3681. Epub 2018 Feb 27.

Drug Discovery, R&D, Sanofi, Waltham, MA, 02451, USA.

Certain recessively inherited diseases result from an enzyme deficiency within lysosomes. In mucopolysaccharidoses (MPS), a defect in glycosaminoglycan (GAG) degradation leads to GAG accumulation followed by progressive organ and multiple system dysfunctions. Current methods of GAG analysis used to diagnose and monitor the diseases lack sensitivity and throughput. Here we report a LC-MS method with accurate metabolite mass analysis for identifying and quantifying biomarkers for MPS type I without the need for extensive sample preparation. The method revealed 225 LC-MS features that were >1000-fold enriched in urine, plasma and tissue extracts from untreated MPS I mice compared to MPS I mice treated with iduronidase to correct the disorder. Levels of several trisaccharides were elevated >10000-fold. To validate the clinical relevance of our method, we confirmed the presence of these biomarkers in urine, plasma and cerebrospinal fluid from MPS I patients and assessed changes in their levels after treatment.
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http://dx.doi.org/10.1038/s41598-018-22078-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829143PMC
February 2018

Cadherin 17 mutation associated with leaky severe combined immune deficiency is corrected by HSCT.

Blood Adv 2017 Oct 23;1(23):2083-2087. Epub 2017 Oct 23.

Division of Blood and Marrow Transplant, Department of Pediatrics, University of Minnesota, Minneapolis, MN.

is expressed in human thymic epithelial cells. mutations may be a rare cause of leaky severe combined immune deficiency that can be corrected by HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2017010926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728290PMC
October 2017

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.

N Engl J Med 2017 10 4;377(17):1630-1638. Epub 2017 Oct 4.

From Massachusetts General Hospital and Harvard Medical School (F.E., P.L.M.), Dana-Farber and Boston Children's Cancer and Blood Disorders Center (C. Duncan, M.A., C. Dansereau, D.A.W.), and Boston Children's Hospital, Harvard Medical School, and Harvard Stem-Cell Institute (D.A.W.), Boston, and Bluebird Bio, Cambridge (A.M.P., E.S., T.O., D.D.) - all in Massachusetts; University of Minnesota Children's Hospital, Minneapolis (P.J.O., T.C.L., W.P.M., G.V.R.); University of California, Los Angeles, Los Angeles (S.D.O., R.S., A.J.S.); University College London Great Ormond Street Hospital Institute of Child Health and Great Ormond Street Hospital NHS Trust, London (A.J.T., H.B.G., P.G.); Pediatric Neurology Department, Hôpital Bicêtre-Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France (C.S., P.A.); Fundacion Investigar, Buenos Aires (H.A.); and Women's and Children's Hospital, North Adelaide, SA, Australia (D.B., N.J.C.S.).

Background: In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation.

Methods: We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion.

Results: A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.

Conclusions: Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).
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http://dx.doi.org/10.1056/NEJMoa1700554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708849PMC
October 2017