Replacing the enzyme alpha-L-iduronidase at birth ameliorates symptoms in the brain and periphery of dogs with mucopolysaccharidosis type I.


:Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by loss of activity of α-l-iduronidase and attendant accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate. Current treatments are suboptimal and do not address residual disease including corneal clouding, skeletal deformities, valvular heart disease, and cognitive impairment. We treated neonatal dogs with MPS I with intravenous recombinant α-l-iduronidase replacement therapy at the conventional 0.58 mg/kg or a higher 1.57 mg/kg weekly dose for 56 to 81 weeks. In contrast to previous results in animals and patients treated at a later age, the dogs failed to mount an antibody response to enzyme therapy, consistent with the induction of immune tolerance in neonates. The higher dose of enzyme led to complete normalization of lysosomal storage in the liver, spleen, lung, kidney, synovium, and myocardium, as well as in the hard-to-treat mitral valve. Cardiac biochemistry and function were restored, and there were improvements in skeletal disease as shown by clinical and radiographic assessments. Glycosaminoglycan levels in the brain were normalized after intravenous enzyme therapy, in the presence or absence of intrathecal administration of recombinant α-l-iduronidase. Histopathological evidence of glycosaminoglycan storage in the brain was ameliorated with the higher-dose intravenous therapy and was further improved by combining intravenous and intrathecal therapy. These findings argue that neonatal testing and early treatment of patients with MPS I may more effectively treat this disease.


Sci Transl Med


Dierenfeld AD,McEntee MF,Vogler CA,Vite CH,Chen AH,Passage M,Le S,Shah S,Jens JK,Snella EM,Kline KL,Parkes JD,Ware WA,Moran LE,Fales-Williams AJ,Wengert JA,Whitley RD,Betts DM,Boal AM,Riedesel EA,Gross W,Ellinwo




Has Abstract


2010-12-01 00:00:00














  • Grease fires turn up the heat in autoimmune disease.

    abstract::Restoring reverse cholesterol transport ameliorates the B cell hyperexpansion and autoimmune disease found to be associated with accumulation of cholesterol in CD11c+ antigen-presenting cells. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章


    authors: Bhakta NR

    更新日期:2017-01-25 00:00:00

  • Long-term follow-up after gene therapy for canavan disease.

    abstract::Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of p...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Leone P,Shera D,McPhee SW,Francis JS,Kolodny EH,Bilaniuk LT,Wang DJ,Assadi M,Goldfarb O,Goldman HW,Freese A,Young D,During MJ,Samulski RJ,Janson CG

    更新日期:2012-12-19 00:00:00

  • Epidermal electronics for noninvasive, wireless, quantitative assessment of ventricular shunt function in patients with hydrocephalus.

    abstract::Hydrocephalus is a common and costly neurological condition caused by the overproduction and/or impaired resorption of cerebrospinal fluid (CSF). The current standard of care, ventricular catheters (shunts), is prone to failure, which can result in nonspecific symptoms such as headaches, dizziness, and nausea. Current...

    journal_title:Science translational medicine

    pub_type: 临床试验,杂志文章


    authors: Krishnan SR,Ray TR,Ayer AB,Ma Y,Gutruf P,Lee K,Lee JY,Wei C,Feng X,Ng B,Abecassis ZA,Murthy N,Stankiewicz I,Freudman J,Stillman J,Kim N,Young G,Goudeseune C,Ciraldo J,Tate M,Huang Y,Potts M,Rogers JA

    更新日期:2018-10-31 00:00:00

  • Proteoglycan 4 expression protects against the development of osteoarthritis.

    abstract::Osteoarthritis (OA) is a common degenerative condition that afflicts more than 70% of the population between 55 and 77 years of age. Although its prevalence is rising globally with aging of the population, current therapy is limited to symptomatic relief and, in severe cases, joint replacement surgery. We report that ...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Ruan MZ,Erez A,Guse K,Dawson B,Bertin T,Chen Y,Jiang MM,Yustein J,Gannon F,Lee BH

    更新日期:2013-03-13 00:00:00

  • Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model.

    abstract::Sepsis remains a major public health problem with no major therapeutic advances over the last several decades. The clinical and biological heterogeneity of sepsis have limited success of potential new therapies. Accordingly, there is considerable interest in developing a precision medicine approach to inform more rati...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Wong HR,Caldwell JT,Cvijanovich NZ,Weiss SL,Fitzgerald JC,Bigham MT,Jain PN,Schwarz A,Lutfi R,Nowak J,Allen GL,Thomas NJ,Grunwell JR,Baines T,Quasney M,Haileselassie B,Lindsell CJ

    更新日期:2019-11-13 00:00:00

  • Nonhuman primates exposed to Zika virus in utero are not protected against reinfection at 1 year postpartum.

    abstract::There is limited information about the impact of Zika virus (ZIKV) exposure in utero on the anti-ZIKV immune responses of offspring. We infected six rhesus macaque dams with ZIKV early or late in pregnancy and studied four of their offspring over the course of a year postpartum. Despite evidence of ZIKV exposure in ut...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Vannella KM,Stein S,Connelly M,Swerczek J,Amaro-Carambot E,Coyle EM,Babyak A,Winkler CW,Saturday G,Gai ND,Hammoud DA,Dowd KA,Valencia LP,Ramos-Benitez MJ,Kindrachuk J,Pierson TC,Peterson KE,Brenchley JM,Whitehead SS,

    更新日期:2020-10-28 00:00:00

  • ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy.

    abstract::The aim of treatment in congenital adrenal hyperplasia is to suppress excess adrenal androgens while achieving physiological glucocorticoid replacement. However, current glucocorticoid replacement regimes are inadequate because doses sufficient to suppress excess androgens almost invariably induce adverse metabolic ef...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Nixon M,Mackenzie SD,Taylor AI,Homer NZ,Livingstone DE,Mouras R,Morgan RA,Mole DJ,Stimson RH,Reynolds RM,Elfick AP,Andrew R,Walker BR

    更新日期:2016-08-17 00:00:00

  • Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer's disease mutation.

    abstract::SORLA/SORL1 is a unique neuronal sorting receptor for the amyloid precursor protein that has been causally implicated in both sporadic and autosomal dominant familial forms of Alzheimer's disease (AD). Brain concentrations of SORLA are inversely correlated with amyloid-β (Aβ) in mouse models and AD patients, suggestin...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Caglayan S,Takagi-Niidome S,Liao F,Carlo AS,Schmidt V,Burgert T,Kitago Y,Füchtbauer EM,Füchtbauer A,Holtzman DM,Takagi J,Willnow TE

    更新日期:2014-02-12 00:00:00

  • Functional regulatory T cells produced by inhibiting cyclic nucleotide phosphodiesterase type 3 prevent allograft rejection.

    abstract::Regulatory T cells (T(regs)) manipulated ex vivo have potential as cellular therapeutics in autoimmunity and transplantation. Although it is possible to expand naturally occurring T(regs), an attractive alternative possibility, particularly suited to solid organ and bone marrow transplantation, is the stimulation of t...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Feng G,Nadig SN,Bäckdahl L,Beck S,Francis RS,Schiopu A,Whatcott A,Wood KJ,Bushell A

    更新日期:2011-05-18 00:00:00

  • It ain't over 'til the fat lady sings.

    abstract::The antiatherogenic drug nicotinic acid (niacin) has antidyslipidemic effects independent of free fatty acid suppression mediated by its receptor HCA₂ (GPR109A) (Lauring et al., this issue). ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章


    authors: Offermanns S

    更新日期:2012-08-22 00:00:00

  • Atherosclerosis drug development in jeopardy: the need for predictive biomarkers of treatment response.

    abstract::The limited predictability of phase II biomarkers for atherosclerosis outcomes in phase III studies stands in contrast to the number and varied types of biomarkers--soluble, imaging, and functional--that have been used in a diverse array of trials. Although collectively abundant, these biomarker data exist in a fragme...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Fryburg DA,Vassileva MT

    更新日期:2011-03-02 00:00:00

  • Oxytocin antagonism prevents pregnancy-associated aortic dissection in a mouse model of Marfan syndrome.

    abstract::Women with Marfan syndrome (MFS) are at high risk for pregnancy-associated aortic dissection. Pathogenic models that singularly invoke hemodynamic stress are difficult to reconcile with predominant postnatal occurrence of aortic tear, often occurring weeks to months after delivery. In consideration of events that peak...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Habashi JP,MacFarlane EG,Bagirzadeh R,Bowen C,Huso N,Chen Y,Bedja D,Creamer TJ,Rykiel G,Manning M,Huso D,Dietz HC

    更新日期:2019-05-01 00:00:00

  • Prevention of cystic fibrosis: The beginning of the end?

    abstract::Prenatal and postnatal treatment with a CFTR modifier attenuates pathological changes in a ferret model of cystic fibrosis (Sun et al., this issue). ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章,评审


    authors: Ferkol TW

    更新日期:2019-03-27 00:00:00

  • Advancing translational research collaborations.

    abstract::In February 2010, the U.S. National Institutes of Health (NIH) sponsored a national Clinical and Translational Science Awards forum titled "Promoting Efficient and Effective Collaborations among Academia, Government and Industry." This forum brought together a broad set of stakeholders who were charged with developing...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Portilla LM,Evans G,Eng B,Fadem TJ

    更新日期:2010-12-22 00:00:00

  • Wnt proteins promote bone regeneration.

    abstract::The Wnt signaling pathway plays a central role in bone development and homeostasis. In most cases, Wnt ligands promote bone growth, which has led to speculation that Wnt factors could be used to stimulate bone healing. We gained insights into the mechanism by which Wnt signaling regulates adult bone repair through the...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Minear S,Leucht P,Jiang J,Liu B,Zeng A,Fuerer C,Nusse R,Helms JA

    更新日期:2010-04-28 00:00:00

  • Production and transplantation of bioengineered lung into a large-animal model.

    abstract::The inability to produce perfusable microvasculature networks capable of supporting tissue survival and of withstanding physiological pressures without leakage is a fundamental problem facing the field of tissue engineering. Microvasculature is critically important for production of bioengineered lung (BEL), which req...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Nichols JE,La Francesca S,Niles JA,Vega SP,Argueta LB,Frank L,Christiani DC,Pyles RB,Himes BE,Zhang R,Li S,Sakamoto J,Rhudy J,Hendricks G,Begarani F,Liu X,Patrikeev I,Pal R,Usheva E,Vargas G,Miller A,Woodson L,

    更新日期:2018-08-01 00:00:00

  • Using health information technology to engage communities in health, education, and research.

    abstract::The August 2011 Clinical and Translational Science Awards conference "Using IT to Improve Community Health: How Health Care Reform Supports Innovation" convened four "Think Tank" sessions. Thirty individuals, representing various perspectives on community engagement, attended the "Health information technology (HIT) a...

    journal_title:Science translational medicine



    authors: Marriott LK,Nelson DA,Allen S,Calhoun K,Eldredge CE,Kimminau KS,Lucero RJ,Pineda-Reyes F,Rumala BB,Varanasi AP,Wasser JS,Shannon J

    更新日期:2012-02-01 00:00:00

  • Complexity in common diseases: big biology for all.

    abstract::The Commentary of Mills and Sykes in Science Translational Medicine presented their thesis on the advent of high-throughput technologies and the dangers they may represent for the future of biomedical research. In response, we argue that true progress on the diagnosis and treatment of common human diseases will requir...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章


    authors: Lamb JR,Gibson NW

    更新日期:2010-03-31 00:00:00

  • A noncoding RNA antisense to moesin at 5p14.1 in autism.

    abstract::People with autism spectrum disorder (ASD) are characterized by deficits in social interaction, language, and behavioral flexibility. Rare mutations and copy number variations have been identified in individuals with ASD, but in most patients, the causal variants remain unknown. A genome-wide association study (GWAS),...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Kerin T,Ramanathan A,Rivas K,Grepo N,Coetzee GA,Campbell DB

    更新日期:2012-04-04 00:00:00

  • Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer.

    abstract::KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Molina-Arcas M,Moore C,Rana S,van Maldegem F,Mugarza E,Romero-Clavijo P,Herbert E,Horswell S,Li LS,Janes MR,Hancock DC,Downward J

    更新日期:2019-09-18 00:00:00

  • An EphB-Abl signaling pathway is associated with intestinal tumor initiation and growth.

    abstract::EphB receptors regulate the proliferation and positioning of intestinal stem and progenitor cells. In addition, they can act as tumor promoters for adenoma development but suppress progression to invasive carcinoma. We used imatinib to abrogate Abl kinase activity in Apc(Min/+) mice and in mice with LGR5(+) stem cells...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Kundu P,Genander M,Strååt K,Classon J,Ridgway RA,Tan EH,Björk J,Martling A,van Es J,Sansom OJ,Clevers H,Pettersson S,Frisén J

    更新日期:2015-04-01 00:00:00

  • Tmc gene therapy restores auditory function in deaf mice.

    abstract::Genetic hearing loss accounts for up to 50% of prelingual deafness worldwide, yet there are no biologic treatments currently available. To investigate gene therapy as a potential biologic strategy for restoration of auditory function in patients with genetic hearing loss, we tested a gene augmentation approach in mous...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Askew C,Rochat C,Pan B,Asai Y,Ahmed H,Child E,Schneider BL,Aebischer P,Holt JR

    更新日期:2015-07-08 00:00:00

  • In vivo liquid biopsy using Cytophone platform for photoacoustic detection of circulating tumor cells in patients with melanoma.

    abstract::Most cancer deaths arise from metastases as a result of circulating tumor cells (CTCs) spreading from the primary tumor to vital organs. Despite progress in cancer prognosis, the role of CTCs in early disease diagnosis is unclear because of the low sensitivity of CTC assays. We demonstrate the high sensitivity of the ...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Galanzha EI,Menyaev YA,Yadem AC,Sarimollaoglu M,Juratli MA,Nedosekin DA,Foster SR,Jamshidi-Parsian A,Siegel ER,Makhoul I,Hutchins LF,Suen JY,Zharov VP

    更新日期:2019-06-12 00:00:00

  • PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma.

    abstract::Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research. We performed a drug screening assay using PDCs and identified proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Furthermore, we determined that phosphate and tensin homology deleted on chro...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Jiang TY,Pan YF,Wan ZH,Lin YK,Zhu B,Yuan ZG,Ma YH,Shi YY,Zeng TM,Dong LW,Tan YX,Wang HY

    更新日期:2020-09-23 00:00:00

  • One size does not fit all: Size-based plasma DNA diagnostics.

    abstract::Understanding the biological properties of plasma cell-free DNA may expand its applications in oncology (Mouliere et al, this issue). ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章,评审


    authors: Heitzer E,Speicher MR

    更新日期:2018-11-07 00:00:00

  • Therapy with CTLA4-Ig and an antiviral monoclonal antibody controls chikungunya virus arthritis.

    abstract::In 2013, chikungunya virus (CHIKV) transmission was documented in the Western Hemisphere, and the virus has since spread throughout the Americas with more than 1.8 million people infected in more than 40 countries. CHIKV targets the joints, resulting in symmetric polyarthritis that clinically mimics rheumatoid arthrit...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Miner JJ,Cook LE,Hong JP,Smith AM,Richner JM,Shimak RM,Young AR,Monte K,Poddar S,Crowe JE Jr,Lenschow DJ,Diamond MS

    更新日期:2017-02-01 00:00:00

  • Exosomes derived from Vδ2-T cells control Epstein-Barr virus-associated tumors and induce T cell antitumor immunity.

    abstract::Treatment of life-threatening Epstein-Barr virus (EBV)-associated tumors remains a great challenge, especially for patients with relapsed or refractory disease. Here, we found that exosomes derived from phosphoantigen-expanded Vδ2-T cells (Vδ2-T-Exos) contained death-inducing ligands (FasL and TRAIL), an activating re...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Wang X,Xiang Z,Liu Y,Huang C,Pei Y,Wang X,Zhi H,Wong WH,Wei H,Ng IO,Lee PP,Chan GC,Lau YL,Tu W

    更新日期:2020-09-30 00:00:00

  • Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants.

    abstract::Troublesome involuntary movements in the absence of dopaminergic medication, so-called off-medication dyskinesias, are a serious adverse effect of fetal neural grafts that hinders the development of cell-based therapies for Parkinson's disease. The mechanisms underlying these dyskinesias are not well understood, and i...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Politis M,Wu K,Loane C,Quinn NP,Brooks DJ,Rehncrona S,Bjorklund A,Lindvall O,Piccini P

    更新日期:2010-06-30 00:00:00

  • Achieving a nationwide learning health system.

    abstract::We outline the fundamental properties of a highly participatory rapid learning system that can be developed in part from meaningful use of electronic health records (EHRs). Future widespread adoption of EHRs will make increasing amounts of medical information available in computable form. Secured and trusted use of th...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Friedman CP,Wong AK,Blumenthal D

    更新日期:2010-11-10 00:00:00

  • Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer.

    abstract::Acquired ESR1 mutations are a major mechanism of resistance to aromatase inhibitors (AIs). We developed ultra high-sensitivity multiplex digital polymerase chain reaction assays for ESR1 mutations in circulating tumor DNA (ctDNA) and investigated the clinical relevance and origin of ESR1 mutations in 171 women with ad...

    journal_title:Science translational medicine

    pub_type: 杂志文章


    authors: Schiavon G,Hrebien S,Garcia-Murillas I,Cutts RJ,Pearson A,Tarazona N,Fenwick K,Kozarewa I,Lopez-Knowles E,Ribas R,Nerurkar A,Osin P,Chandarlapaty S,Martin LA,Dowsett M,Smith IE,Turner NC

    更新日期:2015-11-11 00:00:00