Publications by authors named "Patricia I Dickson"

45 Publications

Biochemical evaluation of intracerebroventricular rhNAGLU-IGF2 enzyme replacement therapy in neonatal mice with Sanfilippo B syndrome.

Mol Genet Metab 2021 Mar 31. Epub 2021 Mar 31.

Department of Pediatrics, The Lundquist Institute (formally Los Angeles Biomedical Research Institute) at Harbor-UCLA Medical Center, Torrance, CA 90502, United States of America; Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States of America. Electronic address:

Mucopolysaccharidosis IIIB (MPS IIIB, Sanfilippo syndrome type B) is caused by a deficiency in α-N-acetylglucosaminidase (NAGLU) activity, which leads to the accumulation of heparan sulfate (HS). MPS IIIB causes progressive neurological decline, with affected patients having an expected lifespan of approximately 20 years. No effective treatment is available. Recent pre-clinical studies have shown that intracerebroventricular (ICV) ERT with a fusion protein of rhNAGLU-IGF2 is a feasible treatment for MPS IIIB in both canine and mouse models. In this study, we evaluated the biochemical efficacy of a single dose of rhNAGLU-IGF2 via ICV-ERT in brain and liver tissue from Naglu neonatal mice. Twelve weeks after treatment, NAGLU activity levels in brain were 0.75-fold those of controls. HS and β-hexosaminidase activity, which are elevated in MPS IIIB, decreased to normal levels. This effect persisted for at least 4 weeks after treatment. Elevated NAGLU and reduced β-hexosaminidase activity levels were detected in liver; these effects persisted for up to 4 weeks after treatment. The overall therapeutic effects of single dose ICV-ERT with rhNAGLU-IGF2 in Naglu neonatal mice were long-lasting. These results suggest a potential benefit of early treatment, followed by less-frequent ICV-ERT dosing, in patients diagnosed with MPS IIIB.
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http://dx.doi.org/10.1016/j.ymgme.2021.03.013DOI Listing
March 2021

Enzyme Replacement Therapy for Mucopolysaccharidosis IIID using Recombinant Human α--Acetylglucosamine-6-Sulfatase in Neonatal Mice.

Mol Pharm 2021 01 15;18(1):214-227. Epub 2020 Dec 15.

Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center and The Lundquist Institute, Torrance, California 90502, United States.

There is currently no cure or effective treatment available for mucopolysaccharidosis type IIID (MPS IIID, Sanfilippo syndrome type D), a lysosomal storage disorder (LSD) caused by the deficiency of α--acetylglucosamine-6-sulfatase (GNS). The clinical symptoms of MPS IIID, like other subtypes of Sanfilippo syndrome, are largely localized to the central nervous system (CNS), and any treatments aiming to ameliorate or reverse the catastrophic and fatal neurologic decline caused by this disease need to be delivered across the blood-brain barrier. Here, we report a proof-of-concept enzyme replacement therapy (ERT) for MPS IIID using recombinant human α--acetylglucosamine-6-sulfatase (rhGNS) intracerebroventricular (ICV) delivery in a neonatal MPS IIID mouse model. We overexpressed and purified rhGNS from CHO cells with a specific activity of 3.9 × 10 units/mg protein and a maximal enzymatic activity at lysosomal pH (pH 5.6), which was stable for over one month at 4 °C in artificial cerebrospinal fluid (CSF). We demonstrated that rhGNS was taken up by MPS IIID patient fibroblasts the mannose 6-phosphate (M6P) receptor and reduced intracellular glycosaminoglycans to normal levels. The delivery of 5 μg of rhGNS into the lateral cerebral ventricle of neonatal MPS IIID mice resulted in normalization of the enzymatic activity in brain tissues; rhGNS was found to be enriched in lysosomes in MPS IIID-treated mice relative to the control. Furthermore, a single dose of rhGNS was able to reduce the accumulated heparan sulfate and β-hexosaminidase. Our results demonstrate that rhGNS delivered into CSF is a potential therapeutic option for MPS IIID that is worthy of further development.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00831DOI Listing
January 2021

Fatal COVID-19 infection in a patient with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: A case report.

JIMD Rep 2020 Nov 10;56(1):40-45. Epub 2020 Sep 10.

Division of Genetics and Genomic Medicine, Department of Pediatrics Washington University School of Medicine St Louis Missouri USA.

Long-chain fatty-acyl CoA dehydrogenase deficiency (LCHADD) is an inborn error of long chain fatty acid oxidation with various features including hypoketotic hypoglycemia, recurrent rhabdomyolysis, pigmentary retinopathy, peripheral neuropathy, cardiomyopathy, and arrhythmias. Various stresses trigger metabolic decompensation. Coronavirus disease 2019 (COVID-19) is a pandemic caused by the RNA virus SARS-CoV-2 with diverse presentations ranging from respiratory symptoms to myocarditis. We report a case of a patient with LCHADD who initially presented with typical metabolic decompensation symptoms including nausea, vomiting, and rhabdomyolysis in addition to mild cough, and was found to have COVID-19. She developed acute respiratory failure and refractory hypotension from severe cardiomyopathy which progressed to multiple organ failure and death. Our case illustrates the need for close monitoring of cardiac function in patients with a long-chain fatty acid oxidation disorder.
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http://dx.doi.org/10.1002/jmd2.12165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653242PMC
November 2020

Myelin and Lipid Composition of the Corpus Callosum in Mucopolysaccharidosis Type I Mice.

Lipids 2020 11 14;55(6):627-637. Epub 2020 Jun 14.

Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA, 90502, USA.

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease with progressive central nervous system involvement. This study examined the lipid, cholesterol, and myelin basic protein composition of white matter in the corpus callosum of MPS I mice. We studied 50 week-old, male MPS I mice and littermate, heterozygote controls (n = 12 per group). Male MPS I mice showed lower phosphatidylcholine and ether-linked phosphatidylcholine quantities than controls (p < 0.05). Twenty-two phospholipid or ceramide species showed significant differences in percent of total. Regarding specific lipid species, MPS I mice exhibited lower quantities of sphingomyelin 18:1, phosphatidylserine 38:3, and hexosylceramide d18:1(22:1) mH O than controls. Principal components analyses of polar, ceramide, and hexosylceramide lipids, respectively, showed some separation of MPS I and control mice. We found no significant differences in myelin gene expression, myelin basic protein, or total cholesterol in the MPS I mice versus heterozygous controls. There was a trend toward lower proteolipid protein-1 levels in MPS I mice (p = 0.06). MPS I mice show subtle changes in white matter composition, with an unknown impact on pathogenesis in this model.
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http://dx.doi.org/10.1002/lipd.12261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992919PMC
November 2020

Comparison of dermatan sulfate and heparan sulfate concentrations in serum, cerebrospinal fluid and urine in patients with mucopolysaccharidosis type I receiving intravenous and intrathecal enzyme replacement therapy.

Clin Chim Acta 2020 Sep 20;508:179-184. Epub 2020 May 20.

Biochemical Genetics Laboratory, Duke University Health System, Durham, NC, USA; Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.

Aims: To validate a liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the measurement of glycosaminoglycans (GAGs) in plasma and serum. To establish plasma, cerebrospinal fluid (CSF) and urine reference intervals. To compare GAGs in serum with that in urine and CSF from patients with MPS I.

Methods: Dermatan sulfate (DS), heparan sulfate (HS), and chondroitin sulfate (CS) in serum/plasma, urine and CSF were methanolysed into dimers and analyzed using pseudo isotope dilution UPLC-MS/MS assay. Serum, CSF and urine DS and HS were quantified for 11 patients with mucopolysaccharidosis (MPS) type I before and after treatment with Aldurazyme® (laronidase) enzyme replacement therapy (ERT).

Results: The method showed acceptable imprecision and recovery for the quantification of serum/plasma CS, DS, and HS. The serum, urine, and CSF DS and HS concentrations were reduced after 26 weeks of ERT in 4 previously untreated patients. Serum DS and HS concentrations normalized in some patients, and were mildly elevated in others after ERT. In contrast, urine and CSF DS and HS values remained elevated above the reference ranges. Compared with serum GAGs, urine and CSF DS and HS were more sensitive biomarkers for monitoring the ERT treatment of patients with MPS I.
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http://dx.doi.org/10.1016/j.cca.2020.05.035DOI Listing
September 2020

Phenotypic expansion of KMT2D-related disorder: Beyond Kabuki syndrome.

Am J Med Genet A 2020 05 21;182(5):1053-1065. Epub 2020 Feb 21.

Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.

Pathogenic variants in KMT2D, which encodes lysine specific methyltransferase 2D, cause autosomal dominant Kabuki syndrome, associated with distinctive dysmorphic features including arched eyebrows, long palpebral fissures with eversion of the lower lid, large protuberant ears, and fetal finger pads. Most disease-causing variants identified to date are putative loss-of-function alleles, although 15-20% of cases are attributed to missense variants. We describe here four patients (including one previously published patient) with de novo KMT2D missense variants and with shared but unusual clinical findings not typically seen in Kabuki syndrome, including athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. These individuals also lack the typical dysmorphic facial features found in Kabuki syndrome. Two of the four patients had severe interstitial lung disease. All of these variants cluster within a 40-amino-acid region of the protein that is located just N-terminal of an annotated coiled coil domain. These findings significantly expand the phenotypic spectrum of features associated with variants in KMT2D beyond those seen in Kabuki syndrome and suggest a possible new underlying disease mechanism for these patients.
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http://dx.doi.org/10.1002/ajmg.a.61518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295006PMC
May 2020

Intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis type I, a randomized, open-label, controlled pilot study.

Mol Genet Metab 2020 02 30;129(2):80-90. Epub 2019 Nov 30.

Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States of America.

Central nervous system manifestations of mucopolysaccharidosis type I (MPS I) such as cognitive impairment, hydrocephalus, and spinal cord compression are inadequately treated by intravenously-administered enzyme replacement therapy with laronidase (recombinant human alpha-L-iduronidase). While hematopoietic stem cell transplantation treats neurological symptoms, this therapy is not generally offered to attenuated MPS I patients. This study is a randomized, open-label, controlled pilot study of intrathecal laronidase in eight attenuated MPS I patients with cognitive impairment. Subjects ranged between 12 years and 50 years old with a median age of 18 years. All subjects had received intravenous laronidase prior to the study over a range of 4 to 10 years, with a mean of 7.75 years. Weekly intravenous laronidase was continued throughout the duration of the study. The randomization period was one year, during which control subjects attended all study visits and assessments, but did not receive any intrathecal laronidase. After the first year, all eight subjects received treatment for one additional year. There was no significant difference in neuropsychological assessment scores between control or treatment groups, either over the one-year randomized period or at 18 or 24 months. However, there was no significant decline in scores in the control group either. Adverse events included pain (injection site, back, groin), headache, neck spasm, and transient blurry vision. There were seven serious adverse events, one judged as possibly related (headache requiring hospitalization). There was no significant effect of intrathecal laronidase on cognitive impairment in older, attenuated MPS I patients over a two-year treatment period. A five-year open-label extension study is underway.
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http://dx.doi.org/10.1016/j.ymgme.2019.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813548PMC
February 2020

Evaluation of non-reducing end pathologic glycosaminoglycan detection method for monitoring therapeutic response to enzyme replacement therapy in human mucopolysaccharidosis I.

Mol Genet Metab 2020 02 11;129(2):91-97. Epub 2019 Sep 11.

Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA; Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA. Electronic address:

Therapeutic development and monitoring require demonstration of effects on disease phenotype. However, due to the complexity of measuring clinically-relevant effects in rare multisystem diseases, robust biomarkers are essential. For the mucopolysaccharidoses (MPS), the measurement of glycosaminoglycan levels is relevant as glycosaminoglycan accumulation is the primary event that occurs due to reduced lysosomal enzyme activity. Traditional dye-based assays that measure total glycosaminoglycan levels have a high background, due to a normal, baseline glycosaminoglycan content in unaffected individuals. An assay that selectively detects the disease-specific non-reducing ends of heparan sulfate glycosaminoglycans that remain undegraded due to deficiency of a specific enzyme in the catabolic pathway avoids the normal background, increasing sensitivity and specificity. We evaluated glycosaminoglycan content by dye-based and non-reducing end methods using urine, serum, and cerebrospinal fluid from MPS I human samples before and after treatment with intravenous recombinant human alpha-l-iduronidase. We found that both urine total glycosaminoglycans and serum heparan sulfate derived non-reducing end levels were markedly decreased compared to baseline after 26 weeks and 52 weeks of therapy, with a significantly greater percentage reduction in serum non-reducing end (89.8% at 26 weeks and 81.3% at 52 weeks) compared to urine total glycosaminoglycans (68.3% at 26 weeks and 62.4% at 52 weeks, p < 0.001). Unexpectedly, we also observed a decrease in non-reducing end levels in cerebrospinal fluid in all five subjects for whom samples were collected (mean 41.8% reduction, p = 0.01). The non-reducing ends in cerebrospinal fluid showed a positive correlation with serum non-reducing end levels in the subjects (r = 0.65, p = 0.005). Results suggest utility of the non-reducing end assay in evaluating a therapeutic response in MPS I.
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http://dx.doi.org/10.1016/j.ymgme.2019.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219480PMC
February 2020

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

Community Partnership in Precision Medicine: Themes from a Community Engagement Conference.

Ethn Dis 2018 6;28(Suppl 2):503-510. Epub 2018 Sep 6.

Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA.

Background: Patient and community engagement in under-resourced communities is a key issue for precision medicine research. We report proceedings from a community-academic partnered conference in Los Angeles to promote community understanding of precision medicine and generate engagement recommendations.

Methods: Planning group review of planning, presentations, and audience discussions from facilitator notes and participant survey data from a one-day conference.

Findings: Community-academic planning broadened community participation and presentations. More than 80% of survey participants indicated they would participate in the national precision medicine initiative, and most were willing to share diverse sources of data. Discussions identified trust concerns related to historical research abuses, data privacy, potential effects of findings on health care, personal safety, research procedures, the time-frame for benefit, and confusion about different initiatives. Concerns were balanced by belief in science to improve health. Recommendations included a community partnered participatory approach with support for local community and academic teams to engage stakeholders with written/online resources and partnered workgroups addressing key concerns.

Conclusion: Conference participants expressed high willingness to participate in precision medicine studies, but discussions highlighted trust and transparency issues and suggested community partnered research with local capacity building.
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http://dx.doi.org/10.18865/ed.28.S2.503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128349PMC
October 2019

Genetically Corrected iPSC-Derived Neural Stem Cell Grafts Deliver Enzyme Replacement to Affect CNS Disease in Sanfilippo B Mice.

Mol Ther Methods Clin Dev 2018 Sep 23;10:113-127. Epub 2018 Jul 23.

Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.

Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB [MPS IIIB]) is a lysosomal storage disorder primarily affecting the brain that is caused by a deficiency in the enzyme α--acetylglucosaminidase (NAGLU), leading to intralysosomal accumulation of heparan sulfate. There are currently no treatments for this disorder. Here we report that, , lentiviral correction of neural stem cells derived from mice (iNSCs) corrected their lysosomal pathology and allowed them to secrete a functional NAGLU enzyme that could be taken up by deficient cells. Following long-term transplantation of these corrected iNSCs into mice, we detected NAGLU activity in the majority of engrafted animals. Successfully 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. Our results demonstrate long-term engraftment of iNSCs in the brain that are capable of cross-correcting pathology in mice. Our findings suggest that genetically engineered iNSCs could potentially be used to deliver enzymes and treat MPS IIIB.
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http://dx.doi.org/10.1016/j.omtm.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076361PMC
September 2018

IRF2BPL Is Associated with Neurological Phenotypes.

Am J Hum Genet 2018 08 26;103(2):245-260. Epub 2018 Jul 26.

Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address:

Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.
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http://dx.doi.org/10.1016/j.ajhg.2018.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081494PMC
August 2018

Macrophage enzyme and reduced inflammation drive brain correction of mucopolysaccharidosis IIIB by stem cell gene therapy.

Brain 2018 01;141(1):99-116

Stem Cell and Neurotherapies, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Mucopolysaccharidosis IIIB is a paediatric lysosomal storage disease caused by deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU), involved in the degradation of the glycosaminoglycan heparan sulphate. Absence of NAGLU leads to accumulation of partially degraded heparan sulphate within lysosomes and the extracellular matrix, giving rise to severe CNS degeneration with progressive cognitive impairment and behavioural problems. There are no therapies. Haematopoietic stem cell transplant shows great efficacy in the related disease mucopolysaccharidosis I, where donor-derived monocytes can transmigrate into the brain following bone marrow engraftment, secrete the missing enzyme and cross-correct neighbouring cells. However, little neurological correction is achieved in patients with mucopolysaccharidosis IIIB. We have therefore developed an ex vivo haematopoietic stem cell gene therapy approach in a mouse model of mucopolysaccharidosis IIIB, using a high-titre lentiviral vector and the myeloid-specific CD11b promoter, driving the expression of NAGLU (LV.NAGLU). To understand the mechanism of correction we also compared this with a poorly secreted version of NAGLU containing a C-terminal fusion to IGFII (LV.NAGLU-IGFII). Mucopolysaccharidosis IIIB haematopoietic stem cells were transduced with vector, transplanted into myeloablated mucopolysaccharidosis IIIB mice and compared at 8 months of age with mice receiving a wild-type transplant. As the disease is characterized by increased inflammation, we also tested the anti-inflammatory steroidal agent prednisolone alone, or in combination with LV.NAGLU, to understand the importance of inflammation on behaviour. NAGLU enzyme was substantially increased in the brain of LV.NAGLU and LV.NAGLU-IGFII-treated mice, with little expression in wild-type bone marrow transplanted mice. LV.NAGLU treatment led to behavioural correction, normalization of heparan sulphate and sulphation patterning, reduced inflammatory cytokine expression and correction of astrocytosis, microgliosis and lysosomal compartment size throughout the brain. The addition of prednisolone improved inflammatory aspects further. Substantial correction of lysosomal storage in neurons and astrocytes was also achieved in LV.NAGLU-IGFII-treated mice, despite limited enzyme secretion from engrafted macrophages in the brain. Interestingly both wild-type bone marrow transplant and prednisolone treatment alone corrected behaviour, despite having little effect on brain neuropathology. This was attributed to a decrease in peripheral inflammatory cytokines. Here we show significant neurological disease correction is achieved using haematopoietic stem cell gene therapy, suggesting this therapy alone or in combination with anti-inflammatories may improve neurological function in patients.
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http://dx.doi.org/10.1093/brain/awx311DOI Listing
January 2018

A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I.

Mol Ther Methods Clin Dev 2018 Mar 5;8:42-51. Epub 2017 Oct 5.

Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.

Antibodies against recombinant proteins can significantly reduce their effectiveness in unanticipated ways. We evaluated the humoral response of mice with the lysosomal storage disease mucopolysaccharidosis type I treated with weekly intravenous recombinant human alpha-l-iduronidase (rhIDU). Unlike patients, the majority of whom develop antibodies to recombinant human alpha-l-iduronidase, only approximately half of the treated mice developed antibodies against recombinant human alpha-l-iduronidase and levels were low. Serum from antibody-positive mice inhibited uptake of recombinant human alpha-l-iduronidase into human fibroblasts by partial inhibition compared to control serum. Tissue and cellular distributions of rhIDU were altered in antibody-positive mice compared to either antibody-negative or naive mice, with significantly less recombinant human alpha-l-iduronidase activity in the heart and kidney in antibody-positive mice. In the liver, recombinant human alpha-l-iduronidase was preferentially found in sinusoidal cells rather than in hepatocytes in antibody-positive mice. Antibodies against recombinant human alpha-l-iduronidase enhanced uptake of recombinant human alpha-l-iduronidase into macrophages obtained from MPS I mice. Collectively, these results imply that a humoral immune response against a therapeutic protein can shift its distribution preferentially into macrophage-lineage cells, causing decreased availability of the protein to the cells that are its therapeutic targets.
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http://dx.doi.org/10.1016/j.omtm.2017.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684429PMC
March 2018

Treatment of brain disease in the mucopolysaccharidoses.

Mol Genet Metab 2017 12 16;122S:25-34. Epub 2017 Oct 16.

Department of Genetics, UFRGS & Medical Genetics Service, HCPA, INAGEMP, Porto Alegre, RS, Brazil.

The mucopolysaccharidosis (MPS) disorders are a group of lysosomal storage diseases caused by lysosomal enzyme deficits that lead to glycosaminoglycan accumulation, affecting various tissues throughout the body based on the specific enzyme deficiency. These disorders are characterized by their progressive nature and a variety of somatic manifestations and neurological symptoms. There are established treatments for some MPS disorders, but these mostly alleviate somatic and non-neurological symptoms and do not cure the disease. Patients with MPS I, II, III, and VII can present with neurological manifestations such as neurocognitive decline and behavioral problems. Treatment of these neurological manifestations remains challenging due to the blood-brain barrier (BBB) that limits delivery of therapeutic agents to the central nervous system (CNS). New therapies that circumvent this barrier and target brain disease in MPS are currently under development. They primarily focus on facilitating penetration of drugs through the BBB, delivery of recombinant enzyme to the brain by gene therapy, or direct CNS administration. This review summarizes existing and potential future treatment approaches that target brain disease in MPS. The information in this review is based on current literature and presentations and discussions during a closed meeting by an international group of experts with extensive experience in managing and treating MPS.
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http://dx.doi.org/10.1016/j.ymgme.2017.10.007DOI Listing
December 2017

Quantitative diffusion tensor imaging analysis does not distinguish pediatric canines with mucopolysaccharidosis I from control canines.

Neuroradiol J 2017 Oct 13;30(5):454-460. Epub 2017 Jul 13.

2 Department of Radiology, Duke University Medical Center, USA.

Purpose We compared fractional anisotropy and radial diffusivity measurements between pediatric canines affected with mucopolysaccharidosis I and pediatric control canines. We hypothesized that lower fractional anisotropy and higher radial diffusivity values, consistent with dysmyelination, would be present in the mucopolysaccharidosis I cohort. Methods Six canine brains, three affected with mucopolysaccharidosis I and three unaffected, were euthanized at 7 weeks and imaged using a 7T small-animal magnetic resonance imaging system. Average fractional anisotropy and radial diffusivity values were calculated for four white-matter regions based on 100 regions of interest per region per specimen. A 95% confidence interval was calculated for each mean value. Results No difference was seen in fractional anisotropy or radial diffusivity values between mucopolysaccharidosis affected and unaffected brains in any region. In particular, the 95% confidence intervals for mucopolysaccharidosis affected and unaffected canines frequently overlapped for both fractional anisotropy and radial diffusivity measurements. In addition, in some brain regions a large range of fractional anisotropy and radial diffusivity values were seen within the same cohort. Conclusion The fractional anisotropy and radial diffusivity values of white matter did not differ between pediatric mucopolysaccharidosis affected canines and pediatric control canines. Possible explanations include: (a) a lack of white matter tissue differences between mucopolysaccharidosis affected and unaffected brains at early disease stages; (b) diffusion tensor imaging does not detect any existing differences; (c) inflammatory processes such as astrogliosis produce changes that offset the decreased fractional anisotropy values and increased radial diffusivity values that are expected in dysmyelination; and (d) our sample size was insufficient to detect differences. Further studies correlating diffusion tensor imaging findings to histology are warranted.
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http://dx.doi.org/10.1177/1971400917718844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602339PMC
October 2017

Diffusion tensor imaging tensor shape analysis for assessment of regional white matter differences.

Neuroradiol J 2017 Aug 20;30(4):324-329. Epub 2017 Jun 20.

3 Department of Radiology, Duke University Medical Center, USA.

Purpose The purpose of this study was to investigate a novel tensor shape plot analysis technique of diffusion tensor imaging data as a means to assess microstructural differences in brain tissue. We hypothesized that this technique could distinguish white matter regions with different microstructural compositions. Methods Three normal canines were euthanized at seven weeks old. Their brains were imaged using identical diffusion tensor imaging protocols on a 7T small-animal magnetic resonance imaging system. We examined two white matter regions, the internal capsule and the centrum semiovale, each subdivided into an anterior and posterior region. We placed 100 regions of interest in each of the four brain regions. Eigenvalues for each region of interest triangulated onto tensor shape plots as the weighted average of three shape metrics at the plot's vertices: CS, CL, and CP. Results The distribution of data on the plots for the internal capsule differed markedly from the centrum semiovale data, thus confirming our hypothesis. Furthermore, data for the internal capsule were distributed in a relatively tight cluster, possibly reflecting the compact and parallel nature of its fibers, while data for the centrum semiovale were more widely distributed, consistent with the less compact and often crossing pattern of its fibers. This indicates that the tensor shape plot technique can depict data in similar regions as being alike. Conclusion Tensor shape plots successfully depicted differences in tissue microstructure and reflected the microstructure of individual brain regions. This proof of principle study suggests that if our findings are reproduced in larger samples, including abnormal white matter states, the technique may be useful in assessment of white matter diseases.
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http://dx.doi.org/10.1177/1971400917709628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524281PMC
August 2017

Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H.

Sci Rep 2016 12 2;6:38305. Epub 2016 Dec 2.

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

Mucopolysaccharidosis (MPS) type-IH is a lysosomal storage disease that results from mutations in the IDUA gene causing the accumulation of glycosaminoglycans (GAGs). Historically, children with the severe phenotype, MPS-IH (Hurler syndrome) develop progressive neurodegeneration with death in the first decade due to cardio-pulmonary complications. New data suggest that inflammation may play a role in MPS pathophysiology. To date there is almost no information on the pathophysiologic changes within the cerebral spinal fluid (CSF) of these patients. We evaluated the CSF of 25 consecutive patients with MPS-IH. While CSF glucose and total protein were within the normal range, we found a significantly mean elevated CSF opening pressure at 24 cm HO (range 14-37 cm HO). We observed a 3-fold elevation in CSF heparan sulfate and a 3-8 fold increase in MPS-IH specific non-reducing ends, I0S0 and I0S6. Cytokine analyses in CSF of children with MPS-IH showed significantly elevated inflammatory markers including: MCP-1 SDF-1a, IL-Ra, MIP-1b, IL-8, and VEGF in comparison to unaffected children. This is the largest report of CSF characteristics in children with MPS-IH. Identification of key biomarkers may provide further insight into the inflammatory-mediated mechanisms related to MPS diseases and perhaps lead to improved targeted therapies.
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http://dx.doi.org/10.1038/srep38305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133554PMC
December 2016

Behavioral deficits and cholinergic pathway abnormalities in male Sanfilippo B mice.

Behav Brain Res 2016 10 23;312:265-71. Epub 2016 Jun 23.

Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA. Electronic address:

Sanfilippo B syndrome is a progressive neurological disorder caused by inability to catabolize heparan sulfate glycosaminoglycans. We studied neurobehavior in male Sanfilippo B mice and heterozygous littermate controls from 16 to 20 weeks of age. Affected mice showed reduced anxiety, with a decrease in the number of stretch-attend postures during the elevated plus maze (p=0.001) and an increased tendency to linger in the center of an open field (p=0.032). Water maze testing showed impaired spatial learning, with reduced preference for the target quadrant (p=0.01). In radial arm maze testing, affected mice failed to achieve above-chance performance in a win-shift working memory task (t-test relative to 50% chance: p=0.289), relative to controls (p=0.037). We found a 12.4% reduction in mean acetylcholinesterase activity (p<0.001) and no difference in choline acetyltransferase activity or acetylcholine in whole brain of affected male animals compared to controls. Cholinergic pathways are affected in adult-onset dementias, including Alzheimer disease. Our results suggest that male Sanfilippo B mice display neurobehavioral deficits at a relatively early age, and that as in adult dementias, they may display deficits in cholinergic pathways.
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http://dx.doi.org/10.1016/j.bbr.2016.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970944PMC
October 2016

Immune-Mediated Inflammation May Contribute to the Pathogenesis of Cardiovascular Disease in Mucopolysaccharidosis Type I.

PLoS One 2016 17;11(3):e0150850. Epub 2016 Mar 17.

University of California-San Diego, La Jolla, California, United States of America.

Background: Cardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of α-L-iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease.

Methods: Gene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry.

Results: Gene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9-fold) and protein overexpression (1.3 to 1.62-fold) was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice.

Conclusions: Overexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for which clusterin represents a potential biomarker.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150850PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795702PMC
August 2016

Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction.

Mol Genet Metab 2016 Feb 10;117(2):66-83. Epub 2015 Nov 10.

OTS, CDER, FDA, Silver Spring, MD 20993-0002, USA. Electronic address:

The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes.
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http://dx.doi.org/10.1016/j.ymgme.2015.11.001DOI Listing
February 2016

Safety of laronidase delivered into the spinal canal for treatment of cervical stenosis in mucopolysaccharidosis I.

Mol Genet Metab 2015 Sep-Oct;116(1-2):69-74. Epub 2015 Jul 26.

Department of Neurology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, United States.

Enzyme replacement therapy with laronidase (recombinant human alpha-l-iduronidase) is successfully used to treat patients with mucopolysaccharidosis type I (MPS I). However, the intravenously-administered enzyme is not expected to treat or prevent neurological deterioration. As MPS I patients suffer from spinal cord compression due in part to thickened spinal meninges, we undertook a phase I clinical trial of lumbar intrathecal laronidase in MPS I subjects age 8 years and older with symptomatic (primarily cervical) spinal cord compression. The study faced significant challenges, including a heterogeneous patient population, difficulty recruiting subjects despite an international collaborative effort, and an inability to include a placebo-controlled design due to ethical concerns. Nine serious adverse events occurred in the subjects. All subjects reported improvement in symptomatology and showed improved neurological examinations, but objective outcome measures did not demonstrate change. Despite limitations, we demonstrated the safety of this approach to treating neurological disease due to MPS I.
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http://dx.doi.org/10.1016/j.ymgme.2015.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572891PMC
July 2016

Diffusion tensor imaging and myelin composition analysis reveal abnormal myelination in corpus callosum of canine mucopolysaccharidosis I.

Exp Neurol 2015 Nov 26;273:1-10. Epub 2015 Jul 26.

Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Department of Pediatrics, Torrance, CA, USA. Electronic address:

Children with mucopolysaccharidosis I (MPS I) develop hyperintense white matter foci on T2-weighted brain magnetic resonance (MR) imaging that are associated clinically with cognitive impairment. We report here a diffusion tensor imaging (DTI) and tissue evaluation of white matter in a canine model of MPS I. We found that two DTI parameters, fractional anisotropy (a measure of white matter integrity) and radial diffusivity (which reflects degree of myelination) were abnormal in the corpus callosum of MPS I dogs compared to carrier controls. Tissue studies of the corpus callosum showed reduced expression of myelin-related genes and an abnormal composition of myelin in MPS I dogs. We treated MPS I dogs with recombinant alpha-L-iduronidase, which is the enzyme that is deficient in MPS I disease. The recombinant alpha-L-iduronidase was administered by intrathecal injection into the cisterna magna. Treated dogs showed partial correction of corpus callosum myelination. Our findings suggest that abnormal myelination occurs in the canine MPS I brain, that it may underlie clinically-relevant brain imaging findings in human MPS I patients, and that it may respond to treatment.
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http://dx.doi.org/10.1016/j.expneurol.2015.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644459PMC
November 2015

Intrathecal 2-hydroxypropyl-beta-cyclodextrin in a single patient with Niemann-Pick C1.

Mol Genet Metab 2015 Sep-Oct;116(1-2):75-9. Epub 2015 Jul 15.

Department of Pediatrics, Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.

Niemann-Pick C, type 1 (NPC1) is a progressive autosomal recessive neurologic disease caused by defective intracellular cholesterol and lipid trafficking. There are currently no United States Food and Drug Administration approved treatments for NPC1. We undertook a study evaluating the safety, efficacy, and biomarker response of intrathecal 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in a 12-year old subject with mildly symptomatic NPC. The subject received 200mg intrathecal HP-β-CD administered biweekly via lumbar puncture. To date the subject has received 27 intrathecal HP-β-CD injections. Intrathecal HP-β-CD has been generally safe and well tolerated in this subject. There has been an improvement in vertical gaze. The subject has developed subclinical hearing loss at high frequency that is likely HP-β-CD related. Plasma 24-(S)-hydroxycholesterol, a pharmacodynamic biomarker for cholesterol redistribution in the central nervous system, was significantly increased in response to each of the first 5 drug administrations. Further dosing as well as dose escalations are needed to more completely ascertain the safety and efficacy of intrathecal HP-β-CD.
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http://dx.doi.org/10.1016/j.ymgme.2015.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633280PMC
July 2016

A novel, long-lived, and highly engraftable immunodeficient mouse model of mucopolysaccharidosis type I.

Mol Ther Methods Clin Dev 2015 11;2:14068. Epub 2015 Feb 11.

National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute , Orange, California, USA.

Mucopolysaccharidosis type I (MPS I) is an inherited α-L-iduronidase (IDUA, I) deficiency in which glycosaminoglycan (GAG) accumulation causes progressive multisystem organ dysfunction, neurological impairment, and death. Current MPS I mouse models, based on a NOD/SCID (NS) background, are short-lived, providing a very narrow window to assess the long-term efficacy of therapeutic interventions. They also develop thymic lymphomas, making the assessment of potential tumorigenicity of human stem cell transplantation problematic. We therefore developed a new MPS I model based on a NOD/SCID/Il2rγ (NSG) background. This model lives longer than 1 year and is tumor-free during that time. NSG MPS I (NSGI) mice exhibit the typical phenotypic features of MPS I including coarsened fur and facial features, reduced/abnormal gait, kyphosis, and corneal clouding. IDUA is undetectable in all tissues examined while GAG levels are dramatically higher in most tissues. NSGI brain shows a significant inflammatory response and prominent gliosis. Neurological MPS I manifestations are evidenced by impaired performance in behavioral tests. Human neural and hematopoietic stem cells were found to readily engraft, with human cells detectable for at least 1 year posttransplantation. This new MPS I model is thus suitable for preclinical testing of novel pluripotent stem cell-based therapy approaches.
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http://dx.doi.org/10.1038/mtm.2014.68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449030PMC
June 2015

The individual (single patient) IND for inborn errors of metabolism.

Mol Genet Metab 2015 Sep-Oct;116(1-2):1-3. Epub 2014 Oct 13.

Department of Pediatrics and Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.

Under the United States Food and Drug Administration's Expanded Access program, a physician may treat a single patient with an experimental medication under an individual investigational new drug application (iIND). Metabolic geneticists may be among the specialists most likely to be asked to obtain an iIND, because there are many experimental treatments for inborn errors of metabolism which work in animals but suffer delays in translation to the bedside. The iIND has the potential to help bridge that gap, by gathering initial evidence in support of the use of an experimental drug in humans. If done with experimental rigor, the data will be useful, despite being limited to a single patient. However, iINDs may pose risks to drug development if patients are not carefully selected. Whatever their advantages and disadvantages, iIND studies are here to stay. Metabolic specialists should cautiously consider the iIND as a tremendous opportunity for therapeutic experimentation.
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http://dx.doi.org/10.1016/j.ymgme.2014.10.003DOI Listing
July 2016

Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB.

Proc Natl Acad Sci U S A 2014 Oct 29;111(41):14870-5. Epub 2014 Sep 29.

Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disease characterized by profound intellectual disability, dementia, and a lifespan of about two decades. The cause is mutation in the gene encoding α-N-acetylglucosaminidase (NAGLU), deficiency of NAGLU, and accumulation of heparan sulfate. Impediments to enzyme replacement therapy are the absence of mannose 6-phosphate on recombinant human NAGLU and the blood-brain barrier. To overcome the first impediment, a fusion protein of recombinant NAGLU and a fragment of insulin-like growth factor II (IGFII) was prepared for endocytosis by the mannose 6-phosphate/IGFII receptor. To bypass the blood-brain barrier, the fusion protein ("enzyme") in artificial cerebrospinal fluid ("vehicle") was administered intracerebroventricularly to the brain of adult MPS IIIB mice, four times over 2 wk. The brains were analyzed 1-28 d later and compared with brains of MPS IIIB mice that received vehicle alone or control (heterozygous) mice that received vehicle. There was marked uptake of the administered enzyme in many parts of the brain, where it persisted with a half-life of approximately 10 d. Heparan sulfate, and especially disease-specific heparan sulfate, was reduced to control level. A number of secondary accumulations in neurons [β-hexosaminidase, LAMP1(lysosome-associated membrane protein 1), SCMAS (subunit c of mitochondrial ATP synthase), glypican 5, β-amyloid, P-tau] were reduced almost to control level. CD68, a microglial protein, was reduced halfway. A large amount of enzyme also appeared in liver cells, where it reduced heparan sulfate and β-hexosaminidase accumulation to control levels. These results suggest the feasibility of enzyme replacement therapy for MPS IIIB.
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http://dx.doi.org/10.1073/pnas.1416660111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205671PMC
October 2014

Intra-articular enzyme replacement therapy with rhIDUA is safe, well-tolerated, and reduces articular GAG storage in the canine model of mucopolysaccharidosis type I.

Mol Genet Metab 2014 Aug 6;112(4):286-93. Epub 2014 Jun 6.

Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California-San Diego, La Jolla, CA, USA.

Background: Treatment with intravenous enzyme replacement therapy and hematopoietic stem cell transplantation for mucopolysaccharidosis (MPS) type I does not address joint disease, resulting in persistent orthopedic complications and impaired quality of life. A proof-of-concept study was conducted to determine the safety, tolerability, and efficacy of intra-articular recombinant human iduronidase (IA-rhIDUA) enzyme replacement therapy in the canine MPS I model.

Methods: Four MPS I dogs underwent monthly rhIDUA injections (0.58 mg/joint) into the right elbow and knee for 6 months. Contralateral elbows and knees concurrently received normal saline. No intravenous rhIDUA therapy was administered. Monthly blood counts, chemistries, anti-rhIDUA antibody titers, and synovial fluid cell counts were measured. Lysosomal storage of synoviocytes and chondrocytes, synovial macrophages and plasma cells were scored at baseline and 1 month following the final injection.

Results: All injections were well-tolerated without adverse reactions. One animal required prednisone for spinal cord compression. There were no clinically significant abnormalities in blood counts or chemistries. Circulating anti-rhIDUA antibody titers gradually increased in all dogs except the prednisone-treated dog; plasma cells, which were absent in all baseline synovial specimens, were predominantly found in synovium of rhIDUA-treated joints at study-end. Lysosomal storage in synoviocytes and chondrocytes following 6 months of IA-rhIDUA demonstrated significant reduction compared to tissues at baseline, and saline-treated tissues at study-end. Mean joint synovial GAG levels in IA-rhIDUA joints were 8.62 ± 5.86 μg/mg dry weight and 21.6 ± 10.4 μg/mg dry weight in control joints (60% reduction). Cartilage heparan sulfate was also reduced in the IA-rhIDUA joints (113 ± 39.5 ng/g wet weight) compared to saline-treated joints (142 ± 56.4 ng/g wet weight). Synovial macrophage infiltration, which was present in all joints at baseline, was abolished in rhIDUA-treated joints only.

Conclusions: Intra-articular rhIDUA is well-tolerated and safe in the canine MPS I animal model. Qualitative and quantitative assessments indicate that IA-rhIDUA successfully reduces tissue and cellular GAG storage in synovium and articular cartilage, including cartilage deep to the articular surface, and eliminates inflammatory macrophages from synovial tissue.

Clinical Relevance: The MPS I canine IA-rhIDUA results suggest that clinical studies should be performed to determine if IA-rhIDUA is a viable approach to ameliorating refractory orthopedic disease in human MPS I.
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http://dx.doi.org/10.1016/j.ymgme.2014.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122635PMC
August 2014

Insulin-like growth factor II peptide fusion enables uptake and lysosomal delivery of α-N-acetylglucosaminidase to mucopolysaccharidosis type IIIB fibroblasts.

Biochem J 2014 Mar;458(2):281-9

*Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, U.S.A.

Enzyme replacement therapy for MPS IIIB (mucopolysaccharidosis type IIIB; also known as Sanfilippo B syndrome) has been hindered by inadequate mannose 6 phosphorylation and cellular uptake of rhNAGLU (recombinant human α-N-acetylglucosaminidase). We expressed and characterized a modified rhNAGLU fused to the receptor-binding motif of IGF-II (insulin-like growth factor 2) (rhNAGLU-IGF-II) to enhance its ability to enter cells using the cation-independent mannose 6-phosphate receptor, which is also the receptor for IGF-II (at a different binding site). RhNAGLU-IGF-II was stably expressed in CHO (Chinese-hamster ovary) cells, secreted and purified to apparent homogeneity. The Km and pH optimum of the fusion enzyme was similar to those reported for rhNAGLU. Both intracellular uptake and confocal microscopy suggested that MPS IIIB fibroblasts readily take up the fusion enzyme via receptor-mediated endocytosis that was inhibited significantly (P<0.001) by the monomeric IGF-II peptide. Glycosaminoglycan storage was reduced by 60% (P<0.001) to near background levels in MPS IIIB cells after treatment with rhNAGLU-IGF-II, with half-maximal correction at concentrations of 3-12 pM. A similar cellular uptake mechanism via the IGF-II receptor was also demonstrated in two different brain tumour-derived cell lines. Fusion of rhNAGLU to IGF-II enhanced its cellular uptake while maintaining enzymatic activity, supporting its potential as a therapeutic candidate for treating MPS IIIB.
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http://dx.doi.org/10.1042/BJ20130845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993987PMC
March 2014