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ABSTRACT: Duchenne muscular dystrophy is a genetic muscle disease caused by absence of a functional dystrophin protein. Lack of dystrophin protein disrupts the dystrophin-glycoprotein complex causing muscle membrane instability and degeneration. One of the secondary manifestations resulting from lack of functional dystrophin in muscle tissue is increased level of cytokines that recruit inflammatory cells, leading to chronic up-regulation of the nuclear factor κB (NF-κB). Negative regulators of the classical NF-κB pathway improve muscle health in the mdx mouse model for DMD. We have previously shown in vitro that a negative regulator of the NF-κB pathway, A20, plays a role in muscle regeneration. Here, we show that over-expression of A20 using a muscle-specific promoter delivered with an adeno-associated virus serotype 8 vector to the mdx mouse decreases activation of the NF-κB pathway in skeletal muscle. Recombinant A20 expression resulted in a reduction in number of fibers with centrally placed nuclei and a reduction in the number of T-cells infiltrating muscle transduced with AAV8-A20 vector. Taken together, we conclude that over-expression of A20 in mdx skeletal muscle provides improved muscle health by reduction of chronic inflammation and muscle degeneration. These results suggest A20 is a potential therapeutic target to ameliorate symptoms of DMD.
Molecular Medicine 11/2012; · 3.76 Impact Factor
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ABSTRACT: This article reviews the recent literature regarding bone health as it relates to the patient living with neuromuscular disease (NMD). Studies defining the scope of bone-related disease in NMD are scant. The available evidence is discussed, focusing on abnormal calcium metabolism, increased fracture risk, and the prevalence of both scoliosis and hypovitaminosis D in Duchenne muscular dystrophy, amyotrophic lateral sclerosis, and spinal muscular atrophy. Future directions are discussed, including the urgent need for studies both to determine the nature and extent of poor bone health, and to evaluate the therapeutic effect of available osteoporosis treatments in patients with NMD.
Physical Medicine and Rehabilitation Clinics of North America 11/2012; 23(4):773-99. · 1.40 Impact Factor
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Ans T van der Ploeg,
Richard Barohn,
Lisa Carlson,
Joel Charrow, Paula R Clemens,
Robert J Hopkin,
Priya S Kishnani,
Pascal Laforêt,
Claire Morgan,
Sharon Nations,
Alan Pestronk,
Horacio Plotkin,
Barry E Rosenbloom,
Katherine B Sims,
Elisa Tsao
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ABSTRACT: OBJECTIVE: Late-onset Pompe disease is a progressive, debilitating, and often fatal neuromuscular disorder resulting from the deficiency of a lysosomal enzyme, acid α-glucosidase. This extension study was conducted to determine the durability of the efficacy and safety of alglucosidase alfa observed over a period of 78weeks in the Late-Onset Treatment Study (LOTS). METHODS: Patients who completed the LOTS study were eligible for this open-label extension study and received alglucosidase alfa 20mg/kg biweekly for an additional 26weeks. The primary efficacy assessments were the distance walked during a 6-minute walk test and the percentage of predicted forced vital capacity in the upright position. Data are reported as change from patient's original LOTS baseline for each measure. RESULTS: The benefit of alglucosidase alfa treatment observed in LOTS at Week 78 was, in general, maintained at Week 104. The mean increase in distance walked measured 28.2±66.5m from LOTS baseline to Week 78 and 21.3±78.0m from LOTS baseline to Week 104. The mean change from baseline in percentage of predicted forced vital capacity was 1.3%±5.7% from LOTS baseline to Week 78 and 0.8%±6.7% from LOTS baseline to Week 104. Treatment-related adverse events were mainly infusion-associated reactions observed in 35% of patients. No deaths or anaphylactic reactions were observed during the extension study. CONCLUSIONS: The LOTS Extension study showed that patients treated with alglucosidase alfa for up to 104weeks maintained the improved walking distance and stabilization in pulmonary function observed in the first 78weeks of alglucosidase alfa therapy.
Molecular Genetics and Metabolism 09/2012; · 3.19 Impact Factor
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ABSTRACT: The study reviews recent advances in pharmacological management of muscular dystrophies. Similarities and differences among the pathophysiology of different forms of muscular dystrophy lead to a broad array of approaches to provide new treatments.
In this review, we include only those muscular dystrophies for which advances have been published in the past year. This represents the 'advancing edge' of a large body of research over more than 20 years. This runs the gamut of new discoveries in symptomatic management to mutation-specific strategies that attempt to correct the root cause of the disorder.
The field of pharmacological therapies for the muscular dystrophies continues to steadily advance. It is encouraging that research into new therapies is increasingly exploring pharmacological strategies with the potential to ameliorate disease pathology to a clinically significant degree.
Current opinion in neurology 08/2012; 25(5):604-8. · 5.43 Impact Factor
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Jeremy S Tilstra,
Andria R Robinson,
Jin Wang,
Siobhán Q Gregg,
Cheryl L Clauson,
Daniel P Reay,
Luigi A Nasto,
Claudette M St Croix,
Arvydas Usas,
Nam Vo,
Johnny Huard, Paula R Clemens,
Donna B Stolz,
Denis C Guttridge,
Simon C Watkins,
George A Garinis,
Yinsheng Wang,
Laura J Niedernhofer,
Paul D Robbins
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ABSTRACT: The accumulation of cellular damage, including DNA damage, is thought to contribute to aging-related degenerative changes, but how damage drives aging is unknown. XFE progeroid syndrome is a disease of accelerated aging caused by a defect in DNA repair. NF-κB, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-κB drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-κB in WT and progeroid model mice. As both WT and progeroid mice aged, NF-κB was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence. These results indicate that the mechanism by which DNA damage drives aging is due in part to NF-κB activation. IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging.
The Journal of clinical investigation 06/2012; 122(7):2601-12. · 15.39 Impact Factor
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ABSTRACT: An increasing incidence of myasthenia gravis (MG) has been reported in the elderly, but the full clinical ramifications of late-onset myasthenia gravis (LOMG) remain unclear. We describe the clinical features of our cohort of patients with MG with an emphasis on an onset after the age of 50. This was a retrospective analysis of medical records of a cohort of patients followed in two tertiary neuromuscular clinics and comparison of early onset MG (EOMG) versus LOMG. There were 174 patients with a mean age of onset of 55.2 ± 19.1 years, and 44 % were women. Late onset of myasthenia gravis after age 50 was reported in 114 patients (66 %). Anti-AChR antibody titers were elevated in 78 % of patients (65 % with EOMG vs. 85 % with LOMG; p = 0.003), and frequency of elevated titers of anti-MuSK antibodies was similar in both groups (present in 38 % of all tested seronegative patients). Myasthenic crisis was equally common in generalized EOMG and LOMG (13 %). Ocular MG was more common in LOMG compared to EOMG (40 vs. 18 %, p = 0.021). Diabetes was more prevalent with LOMG (27 vs. 5 %; p = 0.0002). Overlapping clinical features of EOMG and LOMG are consistent with a continuous clinical spectrum of a single condition, with more frequent occurrence of seropositive and ocular MG with a late onset. A higher burden of comorbidities, such as diabetes mellitus, may warrant a modified approach to treatment of myasthenia in LOMG. However, overall disease severity may not be higher with aging. These observations have implications for design of MG clinical trials and outcomes studies.
Journal of Neurology 04/2012; 259(10):2167-71. · 3.47 Impact Factor
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ABSTRACT: Duchenne muscular dystrophy (DMD) is caused by the lack of a functional dystrophin protein that results in muscle fiber membrane disruption and, ultimately, degeneration. Regeneration of muscle fibers fails progressively, and muscle tissue is replaced with connective tissue. As a result, DMD causes progressive limb muscle weakness and cardiac and respiratory failure. The absence of dystrophin from muscle fibers triggers the chronic activation of the nuclear factor of kappa B (NF-κB). Chronic activation of NF-κB in muscle leads to infiltration of macrophages, up-regulation of the ubiquitin-proteosome system, and down-regulation of the helix-loop-helix muscle regulatory factor, MyoD. These processes, triggered by NF-κB activation, promote muscle degeneration and failure of muscle regeneration. A20 (TNFAIP3) is a critical negative regulator of NF-κB. In this study, we characterize the role of A20 in regulating NF-κB activation in skeletal muscle, identifying a novel role in muscle regeneration. A20 is highly expressed in regenerating muscle fibers, and knockdown of A20 impairs muscle differentiation in vitro, which suggests that A20 expression is critically important for regeneration of dystrophic muscle tissue. Furthermore, down-regulation of the classic pathway of NF-κB activation is associated with up-regulation of the alternate pathway in regenerating muscle fibers, suggesting a mechanism by which A20 promotes muscle regeneration. These results demonstrate the important role of A20 in muscle fiber repair and suggest the potential of A20 as a therapeutic target to ameliorate the pathology and clinical symptoms of DMD.
The FASEB Journal 02/2012; 26(2):587-95. · 5.71 Impact Factor
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ABSTRACT: Gene therapy studies for Duchenne muscular dystrophy (DMD) have focused on viral vector-mediated gene transfer to provide therapeutic protein expression or treatment with drugs to limit dystrophic changes in muscle. The pathological activation of the nuclear factor (NF)-κB signaling pathway has emerged as an important cause of dystrophic muscle changes in muscular dystrophy. Furthermore, activation of NF-κB may inhibit gene transfer by promoting inflammation in response to the transgene or vector. Therefore, we hypothesized that inhibition of pathological NF-κB activation in muscle would complement the therapeutic benefits of dystrophin gene transfer in the mdx mouse model of DMD. Systemic gene transfer using serotype 9 adeno-associated viral (AAV9) vectors is promising for treatment of preclinical models of DMD because of vector tropism to cardiac and skeletal muscle. In quadriceps of C57BL/10ScSn-Dmd(mdx)/J (mdx) mice, the addition of octalysine (8K)-NF-κB essential modulator (NEMO)-binding domain (8K-NBD) peptide treatment to AAV9 minidystrophin gene delivery resulted in increased levels of recombinant dystrophin expression suggesting that 8K-NBD treatment promoted an environment in muscle tissue conducive to higher levels of expression. Indices of necrosis and regeneration were diminished with AAV9 gene delivery alone and to a greater degree with the addition of 8K-NBD treatment. In diaphragm muscle, high-level transgene expression was achieved with AAV9 minidystoophin gene delivery alone; therefore, improvements in histological and physiological indices were comparable in the two treatment groups. The data support benefit from 8K-NBD treatment to complement gene transfer therapy for DMD in muscle tissue that receives incomplete levels of transduction by gene transfer, which may be highly significant for clinical applications of muscle gene delivery.
Molecular Medicine 01/2012; 18(1):466-76. · 3.76 Impact Factor
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ABSTRACT: Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. Therapeutic gene replacement of a dystrophin cDNA into dystrophic muscle can provide functional dystrophin protein to the tissue. However, vector-mediated gene transfer is limited by anti-vector and anti-transgene host immunity that causes rejection of the therapeutic protein. We hypothesized that rapamycin (RAPA) would diminish immunity due to vector-delivered recombinant dystrophin in the adult mdx mouse model for DMD. To test this hypothesis, we injected limb muscle of mdx mice with RAPA-containing, poly-lactic-co-glycolic acid (PLGA) microparticles prior to dystrophin gene transfer and analyzed treated tissue after 6 weeks. RAPA decreased host immunity against vector-mediated dystrophin protein, as demonstrated by decreased cellular infiltrates and decreased anti-dystrophin antibody production. The interpretation of the effect of RAPA on recombinant dystrophin expression was complex because of an effect of PLGA microparticles.
Scientific Reports 01/2012; 2:399.
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ABSTRACT: The activation of nuclear factor κB (NF-κB) contributes to muscle degeneration that results from dystrophin deficiency in human Duchenne muscular dystrophy (DMD) and in the mdx mouse. In dystrophic muscle, NF-κB participates in inflammation and failure of muscle regeneration. Peptides containing the NF-κB Essential Modulator (NEMO) binding domain (NBD) disrupt the IκB kinase complex, thus blocking NF-κB activation. The NBD peptide, which is linked to a protein transduction domain to achieve in vivo peptide delivery to muscle tissue, was systemically delivered to mdx mice for 4 or 7 weeks to study NF-κB activation, histological changes in hind limb and diaphragm muscle and ex vivo function of diaphragm muscle. Decreased NF-κB activation, decreased necrosis and increased regeneration were observed in hind limb and diaphragm muscle in mdx mice treated systemically with NBD peptide, as compared to control mdx mice. NBD peptide treatment resulted in improved generation of specific force and greater resistance to lengthening activations in diaphragm muscle ex vivo. Together these data support the potential of NBD peptides for the treatment of DMD by modulating dystrophic pathways in muscle that are downstream of dystrophin deficiency.
Neurobiology of Disease 05/2011; 43(3):598-608. · 5.40 Impact Factor
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ABSTRACT: Duchenne muscular dystrophy (DMD) is an X-linked, lethal, degenerative disease that results from mutations in the dystrophin gene, causing necrosis and inflammation in skeletal muscle tissue. Treatments that reduce muscle fiber destruction and immune cell infiltration can ameliorate DMD pathology. We treated the mdx mouse, a model for DMD, with the immunosuppressant drug rapamycin (RAPA) both locally and systemically to examine its effects on dystrophic mdx muscles. We observed a significant reduction of muscle fiber necrosis in treated mdx mouse tibialis anterior (TA) and diaphragm (Dia) muscles 6 wks post-treatment. This effect was associated with a significant reduction in infiltration of effector CD4(+) and CD8(+) T cells in skeletal muscle tissue, while Foxp3(+) regulatory T cells were preserved. Because RAPA exerts its effects through the mammalian target of RAPA (mTOR), we studied the activation of mTOR in mdx TA and Dia with and without RAPA treatment. Surprisingly, mTOR activation levels in mdx TA were not different from control C57BL/10 (B10). However, mTOR activation was different in Dia between mdx and B10; mTOR activation levels did not rise between 6 and 12 wks of age in mdx Dia muscle, whereas a rise in mTOR activation level was observed in B10 Dia muscle. Furthermore, mdx Dia, but not TA, muscle mTOR activation was responsive to RAPA treatment.
Molecular Medicine 05/2011; 17(9-10):917-24. · 3.76 Impact Factor
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Angela Zimmerman, Paula R Clemens,
Carolina Tesi-Rocha,
Anne Connolly,
Susan T Iannaccone,
Nancy Kuntz,
Adrienne Arrieta,
Lauren Hache,
Erik Henricson,
Fengming Hu,
Jill Mayhew,
Diana M Escolar
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ABSTRACT: In this study we performed an open-label, pilot study of an orally administered liquid formulation of immediate-release pentoxifylline (PTX) on patients with Duchenne muscular dystrophy (DMD). Treatment efficacy, safety, and tolerability were assessed.
The tolerability and safety of PTX and measures of muscle strength and function were evaluated during 12 months of treatment.
Seventeen boys with DMD, between 4 and 8 years of age, were enrolled at one of five Cooperative International Neuromuscular Research Group (CINRG) centers. Only 9 were able to complete the 12-month PTX treatment phase; the primary reason for discontinuation was adverse events. Intolerable gastrointestinal side effects were experienced by 65% of participants. Two participants had severe leukopenia that resolved with medication withdrawal.
Open-label treatment with a liquid formulation of immediate-release PTX resulted in a high incidence of adverse events in boys with DMD. Poor tolerability of this PTX formulation precluded adequate assessment of efficacy.
Muscle & Nerve 04/2011; 44(2):170-3. · 2.37 Impact Factor
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Christophe Pichavant,
Annemieke Aartsma-Rus, Paula R Clemens,
Kay E Davies,
George Dickson,
Shin'ichi Takeda,
Steve D Wilton,
Jon A Wolff,
Christine I Wooddell,
Xiao Xiao,
Jacques P Tremblay
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ABSTRACT: Duchenne muscular dystrophy (DMD) is a genetic disease affecting about one in every 3,500 boys. This X-linked pathology is due to the absence of dystrophin in muscle fibers. This lack of dystrophin leads to the progressive muscle degeneration that is often responsible for the death of the DMD patients during the third decade of their life. There are currently no curative treatments for this disease but different therapeutic approaches are being studied. Gene therapy consists of introducing a transgene coding for full-length or a truncated version of dystrophin complementary DNA (cDNA) in muscles, whereas pharmaceutical therapy includes the use of chemical/biochemical substances to restore dystrophin expression or alleviate the DMD phenotype. Over the past years, many potential drugs were explored. This led to several clinical trials for gentamicin and ataluren (PTC124) allowing stop codon read-through. An alternative approach is to induce the expression of an internally deleted, partially functional dystrophin protein through exon skipping. The vectors and the methods used in gene therapy have been continually improving in order to obtain greater encapsidation capacity and better transduction efficiency. The most promising experimental approaches using pharmaceutical and gene therapies are reviewed in this article.
Molecular Therapy 04/2011; 19(5):830-40. · 6.87 Impact Factor
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ABSTRACT: Previous studies in humans and in animal models support a key role of histidyl-transfer RNA synthetase (HisRS; also known as Jo-1) in the pathogenesis of idiopathic inflammatory myopathy. While most investigations have focused on the ability of HisRS to trigger adaptive immune responses, in vitro studies clearly indicate that HisRS possesses intrinsic chemokine-like properties capable of activating the innate immune system. The purpose of this study was therefore to examine the ability of HisRS to direct innate immune responses in a murine model of myositis.
Following intramuscular immunization with soluble HisRS in the absence of exogenous adjuvant, selected strains of mice were evaluated at different time points for histopathologic evidence of myositis. Enzyme-linked immunosorbent assay-based assessment of autoantibody formation and carboxyfluorescein succinimidyl ester proliferation studies provided complementary measures of B cell and T cell responses triggered by HisRS immunization.
Compared to appropriate control proteins, a murine HisRS fusion protein induced robust, statistically significant muscle inflammation in multiple congenic strains of C57BL/6 and NOD mice. Time course experiments revealed that this inflammatory response occurred as early as 7 days postimmunization and persisted for up to 7 weeks. Parallel immunization strategies in DO11.10/RAG-2(-/-) and C3H/HeJ (TLR-4(-/-) ) mice indicated that the ability of murine HisRS to drive muscle inflammation was not dependent on B cell receptor or T cell receptor recognition and did not require Toll-like receptor 4 signaling.
Collectively, the findings of these experiments support a model in which HisRS can trigger both innate and adaptive immune responses that culminate in severe muscle inflammation that is the hallmark of idiopathic inflammatory myopathy.
Arthritis & Rheumatism 02/2011; 63(2):479-87. · 7.87 Impact Factor
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ABSTRACT: A 25-year-old woman had childhood-onset muscle weakness and dilated cardiomyopathy. She exhibited predominantly distal weakness with early toe walking. Dilated cardiomyopathy required cardiac transplantation at age 15 years. We identified a de-novo, heterozygous, missense mutation, c.2348G>C (p. Arg783Pro), in exon 21 of the MYH7 gene, which encodes slow skeletal muscle fiber/β-cardiac myosin heavy chain protein, that replaces a highly conserved arginine with a proline. This novel mutation that results in the unusual combined cardiac and skeletal muscle phenotype localizes to the essential light chain binding area, a region only previously shown to be mutated in hypertrophic cardiomyopathy.
Neuromuscular Disorders 01/2011; 21(3):219-22. · 2.80 Impact Factor
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Jennifer M Peterson,
William Kline,
Benjamin D Canan,
Daniel J Ricca,
Brian Kaspar,
Dawn A Delfín,
Kelly DiRienzo, Paula R Clemens,
Paul D Robbins,
Albert S Baldwin,
Pat Flood,
Pravin Kaumaya,
Michael Freitas,
Joe N Kornegay,
Jerry R Mendell,
Jill A Rafael-Fortney,
Denis C Guttridge,
Paul M L Janssen
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ABSTRACT: Deterioration of diaphragm function is one of the prominent factors that contributes to the susceptibility of serious respiratory infections and development of respiratory failure in patients with Duchenne Muscular Dystrophy (DMD). The NF-κB signaling pathway has been implicated as a contributing factor of dystrophic pathology, making it a potential therapeutic target. Previously, we demonstrated that pharmacological inhibition of NF-κB via a small NEMO Binding Domain (NBD) peptide was beneficial for reducing pathological features of mdx mice. Now, we stringently test the effectiveness and clinical potential of NBD by treating mdx mice with various formulations of NBD and use diaphragm function as our primary outcome criteria. We found that administering DMSO-soluble NBD rescued 78% of the contractile deficit between mdx and wild-type (WT) diaphragm. Interestingly, synthesis of a GLP NBD peptide as an acetate salt permitted its solubility in water, but as a negative consequence, also greatly attenuated functional efficacy. However, replacing the acetic acid counterion of the NBD peptide with trifluoroacetic acid retained the peptide's water solubility and significantly restored mdx diaphragm contractile function and improved histopathological indices of disease in both diaphragm and limb muscle. Together, these results support the feasibility of using a mass-produced, water-soluble NBD peptide for clinical use.
Molecular Medicine 01/2011; 17(5-6):508-15. · 3.76 Impact Factor
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ABSTRACT: OBJECTIVES:: Previous work in humans and in animal models supports a key role for histidyl-tRNA synthetase (HRS=Jo-1) in the pathogenesis of idiopathic inflammatory myopathy. While most investigations have focused on the ability of HRS to trigger adaptive immune responses, in vitro studies clearly indicate that HRS possesses intrinsic chemokine-like properties capable of activating the innate immune system. The purpose of this study was therefore to examine the ability of HRS to direct innate immune responses in a murine model of myositis. METHODS:: Following intramuscular immunization with soluble HRS in the absence of exogenous adjuvant, selected strains of mice were evaluated at different time points for histopathologic evidence of myositis. ELISA-based assessment of autoantibody formation and CFSE proliferation studies provided complementary measures of B and T cell responses triggered by HRS immunization. RESULTS:: Compared to appropriate control proteins, a murine HRS fusion protein induced robust, statistically significant muscle inflammation in multiple congenic strains of C57BL/6 and NOD mice. Time course experiments revealed that this inflammatory response occurred as early as 7 days post immunization and persisted for up to 7 weeks. Parallel immunization strategies in DO11.10/Rag2(-/-) and C3H/HeJ (TLR4(-/-)) mice indicated that the ability of murine HRS to drive muscle inflammation was not dependent on B cell receptor or T cell receptor recognition and did not require TLR4 signaling. CONCLUSION:: Collectively, these experiments support a model in which HRS can trigger both innate and adaptive immune responses which culminate in severe muscle inflammation that is the hallmark of idiopathic inflammatory myopathy.
Arthritis & Rheumatism 10/2010; · 7.87 Impact Factor
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Ans T van der Ploeg, Paula R Clemens,
Deyanira Corzo,
Diana M Escolar,
Julaine Florence,
Geert Jan Groeneveld,
Serge Herson,
Priya S Kishnani,
Pascal Laforet,
Stephen L Lake, [......],
Claire Morgan,
Kenkichi Nozaki,
Dorothy J Park,
Alan Pestronk,
Barry Rosenbloom,
Alison Skrinar,
Carine I van Capelle,
Nadine A van der Beek,
Melissa Wasserstein,
Sasa A Zivkovic
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ABSTRACT: Pompe's disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe's disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe's disease.
Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC).
At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients).
In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)
New England Journal of Medicine 04/2010; 362(15):1396-406. · 53.30 Impact Factor
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ABSTRACT: Efficient, widespread transgene expression in the muscle is one of the major challenges of gene transfer for the treatment
of genetic muscle disorders. A good example of this disease is the Duchenne muscular dystrophy (DMD), a progressive, degenerative
disease whose clinical symptoms manifest after birth, but whose genetic defect causing the disease is present at conception.
The availability of prenatal testing for genetic muscle diseases provides the basis for treatments in utero. In utero gene
transfer has the potential to achieve widespread transgene expression in the muscle by accomplishing gene delivery when the
tissue mass is small and the immune system is still immature. In this chapter, we present preclinical experience with gene
delivery strategies to treat muscle disorders in utero. Important issues include experience with different gene delivery vectors
in preclinical models, gene expression in muscle tissue, and effects on immunity.
11/2009: pages 23-40;
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Katharine Bushby,
Richard Finkel,
David J Birnkrant,
Laura E Case, Paula R Clemens,
Linda Cripe,
Ajay Kaul,
Kathi Kinnett,
Craig McDonald,
Shree Pandya,
James Poysky,
Frederic Shapiro,
Jean Tomezsko,
Carolyn Constantin,
Thomas Sejersen
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ABSTRACT: Duchenne muscular dystrophy (DMD) is a severe, progressive disease that affects 1 in 3600-6000 live male births. Although guidelines are available for various aspects of DMD, comprehensive clinical care recommendations do not exist. The US Centers for Disease Control and Prevention selected 84 clinicians to develop care recommendations using the RAND Corporation-University of California Los Angeles Appropriateness Method. The DMD Care Considerations Working Group evaluated assessments and interventions used in the management of diagnostics, gastroenterology and nutrition, rehabilitation, and neuromuscular, psychosocial, cardiovascular, respiratory, orthopaedic, and surgical aspects of DMD. These recommendations, presented in two parts, are intended for the wide range of practitioners who care for individuals with DMD. They provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care. In part 1 of this Review, we describe the methods used to generate the recommendations, and the overall perspective on care, pharmacological treatment, and psychosocial management.
The Lancet Neurology 11/2009; 9(1):77-93. · 23.46 Impact Factor
