Deflazacort in Duchenne muscular dystrophy: a comparison of two different protocols

Biggar, W. Douglas; Politano, Luisa; Harris, Valerie; Passamano, Luigia; Vajsar, Jiri; Alman, Benjamin A.; Palladino, Alberto; Comi, L.I.; Nigro, Giovanni

doi:10.1016/j.nmd.2004.05.001

Cited by 98 publications

(57 citation statements)

References 40 publications

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“…In addition to having therapeutic efficacy on its own, the unique action of biglycan in recruiting utrophin to the sarcolemma could synergize with these other utrophin-directed strategies. Finally, rhBGN could be used in combination with therapies aimed at increasing muscle mass (21,22), reducing inflammation (46,47), or restoring dystrophin by antisense oligonucleotide-mediated exon skipping (48,49).…”

Section: Discussionmentioning

confidence: 99%

Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice

Amenta¹,

Yilmaz

Bogdanovich

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

136

103

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Duchenne muscular dystrophy (DMD) is caused by mutations in dystrophin and the subsequent disruption of the dystrophin-associated protein complex (DAPC). Utrophin is a dystrophin homolog expressed at high levels in developing muscle that is an attractive target for DMD therapy. Here we show that the extracellular matrix protein biglycan regulates utrophin expression in immature muscle and that recombinant human biglycan (rhBGN) increases utrophin expression in cultured myotubes. Systemically delivered rhBGN upregulates utrophin at the sarcolemma and reduces muscle pathology in the mdx mouse model of DMD. RhBGN treatment also improves muscle function as judged by reduced susceptibility to eccentric contraction-induced injury. Utrophin is required for the rhBGN therapeutic effect. Several lines of evidence indicate that biglycan acts by recruiting utrophin protein to the muscle membrane. RhBGN is well tolerated in animals dosed for as long as 3 months. We propose that rhBGN could be a therapy for DMD.biotherapeutics | protein therapeutics D uchenne muscular dystrophy (DMD) is a hereditary disease that affects ∼1:3,500 boys, the majority of whom will die by their midtwenties (1). DMD is caused by mutations in dystrophin that result in the faulty assembly and function of an ensemble of structural and signaling molecules at the muscle cell surface termed the dystrophin-associated protein complex (DAPC) (2-4). There are currently no treatments that target the primary pathology of DMD.One attractive therapeutic approach for DMD is the stabilization of the muscle cell membrane through up-regulation of utrophin, a dystrophin homolog. Transgenic overexpression of utrophin rescues dystrophic pathology and restores function in the dystrophin-deficient mdx mouse (5-7). In mature muscle, utrophin expression is restricted to the neuromuscular and myotendinous junctions. However, utrophin is expressed over the entire myofiber in developing and regenerating muscle (8-10). These observations raise the possibility that marshalling pathways that normally regulate utrophin expression in developing muscle could be a productive approach for developing DMD treatments.The extracellular matrix protein biglycan plays an important role in developing muscle. In both humans and mice, biglycan is most highly expressed in immature and regenerating muscle (11,12). Biglycan is a component of the DAPC, where it binds to α-dystroglycan (13) and α-and γ-sarcoglycan (14). Biglycan regulates the expression of the sarcoglycans as well as dystrobrevins, syntrophins, and nNOS, particularly in immature muscle. Finally, biglycan is important for timely muscle regeneration (11).Locally delivered recombinant human biglycan (rhBGN) incorporates into the extracellular matrix of bgn −/o muscle where it persists for at least 2 wk and rescues the expression of several DAPC components (15). These results raise the possibility that rhBGN might enhance function in muscle that lacks dystrophin. Here we show that utrophin is down-regulated in immature biglycan null (...

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Section: Discussionmentioning

confidence: 99%

Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice

Amenta¹,

Yilmaz

Bogdanovich

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

136

103

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“…There is evidence that using steroids in patients with DMD can have numerous positive effects including prolonged independent ambulation, decreased progression of scoliosis, increased muscle strength, respiratory function, cardiac function and quality of life (18,(21)(22)(23)(24)(25)(26). The use of steroid therapy has been associated with a reduction in the incidence of scoliosis in DMD because prolonging ambulation means that some boys will undergo their pubertal growth spurt before loss of ambulation.…”

Section: Interventions Before Surgerymentioning

confidence: 99%

Duchenne muscular dystrophy: the management of scoliosis

et al. 2016

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This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy.A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy.Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group.

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“…In a study in which the inclusion criterion was a minimum of 4 years of treatment with deflazacort in an alternating 20/10 scheme, Biggar et al [8] reported that 35% of the patients were still ambulant at age 12. In young healthy children, functional scores, such as running or standing up from a sitting position on the floor, improve as the child ages from 4 to 10 years due to the growth-related physiological increase in strength [23].…”

Section: Discussionmentioning

confidence: 99%

“…3). Most randomized studies have evaluated corticosteroid treatment using functional scores, with a surprisingly large variation in outcome depending whether a metric or non-metric measure was chosen; for example, time to run has been evaluated in 10 [7,8], 9 (30 feet) [4,5,9,10,14,24] or 8.54 m (28 feet) [11,25].…”

Section: Discussionmentioning

confidence: 99%

“…This conclusion was based on trials using daily doses of corticosteroids, which proved to be superior to placebo [3,4] and to prednisone on an alternate-day scheme (1 day on/ 1 day off) [5]. Different doses as well as different intermittent schemes of administration have been tried in clinical trials with the aim of reducing side effects [6][7][8][9][10]. However, there is as yet no internationally accepted consensus on which corticosteroid treatment scheme is the best for patients with DMD.…”

Section: Introductionmentioning

confidence: 99%

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Prednisone 10 days on/10 days off in patients with Duchenne muscular dystrophy

et al. 2009

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Corticosteroids are effective in improving motor function in Duchenne muscular dystrophy (DMD) patients within 6 months-2 years of treatment initiation, but there is as yet no consensus on which treatment scheme is the best. We retrospectively analyzed data of 35 DMD patients who were treated with prednisone 0.75 mg/kg per day intermittently 10 days on/10 days off. Prednisone was started during the ambulant phase at age 3.5-9.7 years (median 6.5 years). The median period of treatment was 27 months (range 3-123 months). The median age at which ambulation was lost was 10.8 years (mean 10.9 years; 95% confidence interval 10.0-11.8 years). Nine patients (26%) had excessive weight gain. Eight boys (21%) had a bone fracture, which was when four of these eight children lost the ability to walk. Treatment was stopped in two obese patients, two hyperactive boys and one patient following a fracture. Our data suggest that prednisone 10 on/10 off has relatively few side effects and extends the ambulant phase by 1 year compared to historical controls.

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Deflazacort in Duchenne muscular dystrophy: a comparison of two different protocols

Cited by 98 publications

References 40 publications

Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice

Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice

Duchenne muscular dystrophy: the management of scoliosis

Prednisone 10 days on/10 days off in patients with Duchenne muscular dystrophy

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