A phase I/IItrial of MYO‐029 in adult subjects with muscular dystrophy

Wagner, Kathryn R.; Fleckenstein, James L.; Amato, Anthony A.; Barohn, Richard J.; Bushby, K.; Escolar, Diana M.; Flanigan, Kevin M.; Pestronk, Alan; Tawil, Rabi; Wolfe, Gil I.; Eagle, Michelle; Florence, Julaine; King, Wendy; Pandya, Shree; Straub, Volker; Juneau, Paul; Meyers, Kathleen N.; Csimma, Cristina; Araujo, Tracey; Allen, Robert H.; Parsons, Stephanie A.; Wozney, John M.; LaVallie, Edward R.; Mendell, Jerry R.

doi:10.1002/ana.21338

Cited by 410 publications

(299 citation statements)

References 34 publications

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“…In effect, myostatin is a skeletal muscle-specific secreted peptide that essentially modulates myoblast proliferation and thus muscle mass/strength . Preclinical trials using myostatin loss or inhibition have been effective in ameliorating symptoms of weakness in several animal Klimek et al 2010;Bogdanovich et al 2002;Lee and McPherron 2001;Liu et al 2008;Morrison et al 2009;Murphy et al 2010;Qiao et al 2009;Siriett et al 2006;Tsuchida 2008;Wagner et al 2008;Zhu et al 2007). In humans, myostatin inhibitors, such as MYO-029, have an adequate safety margin and are able to improve the muscle strength/function or muscle contractile properties in some patients with muscular dystrophy (Krivickas et al 2009;Wagner et al 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical trials using myostatin loss or inhibition have been effective in ameliorating symptoms of weakness in several animal Klimek et al 2010;Bogdanovich et al 2002;Lee and McPherron 2001;Liu et al 2008;Morrison et al 2009;Murphy et al 2010;Qiao et al 2009;Siriett et al 2006;Tsuchida 2008;Wagner et al 2008;Zhu et al 2007). In humans, myostatin inhibitors, such as MYO-029, have an adequate safety margin and are able to improve the muscle strength/function or muscle contractile properties in some patients with muscular dystrophy (Krivickas et al 2009;Wagner et al 2008). All these data are consistent with the growing interest in developing therapeutic inhibitors of myostatin for use in muscle-wasting disorders such as muscular dystrophy, cachexia or ageing-related sarcopenia (Tsuchida 2008) and with the fact that myostatin inhibition is proposed as a potential intervention for frailty and sarcopenia in the elderly (Swan 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Myostatin loss or inhibition has proven effective in ameliorating symptoms of weakness in several animal models of muscle injury, atrophy and disease (Benny Klimek et al 2010;Bogdanovich et al 2002;Lee and McPherron 2001;Liu et al 2008;Morrison et al 2009;Murphy et al 2010;Qiao et al 2009;Siriett et al 2006;Tsuchida 2008;Wagner et al 2008;Zhu et al 2007). Myostatin inhibition, as well as variations in the MSTN gene, can also have functional consequences in humans.…”

Section: Introductionmentioning

confidence: 99%

“…Myostatin inhibitors, such as MYO-029, have an adequate safety margin and are able to improve the muscle strength/function or muscle contractile properties in some patients with muscular dystrophy (Krivickas et al 2009;Wagner et al 2008). Of the identified MSTN variations in humans, the Lys (K)153Arg(R) polymorphism located in exon 2 (rs1805086, 2379 A>G replacement) is one candidate to influence skeletal muscle phenotypes (Ferrell et al 1999).…”

Section: Introductionmentioning

confidence: 99%

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Association of the K153R polymorphism in the myostatin gene and extreme longevity

Garatachea

Pinós

Cámara

et al. 2013

AGE

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The myostatin (MSTN) gene is a candidate to influence extreme longevity owing to its role in modulating muscle mass and sarcopenia and especially in inhibiting the main nutrient-sensing pathway involved in longevity, i.e. mammalian target of rapamycin. We compared allele/genotype distributions of the exonic MSTN variants K153R (rs1805086), E164K (rs35781413), I225T and P198A, in Spanish centenarians (cases, n=156; 132 women, age range 100-111 years) and younger adults (controls, n=384; 167 women, age <50 years). No subject of either group carried a mutant allele of the E164K, I225T or AGE (2013) 35:2445-2454 DOI 10.1007 Antoni L. Andreu and Alejandro Lucia share senior authorship. P198A variation. The frequency of the variant R allele was significantly higher in centenarians (7.1 %) than in controls (2.7 %) (P=0.001). The odds ratio of being a centenarian if the subject had the R allele was 3.48 (95 % confidence interval 1.67-7.28, P=0.001), compared to the control group, after adjusting for sex. The results were replicated in an Italian cohort (centenarians, n=79 (40 women), age range 100-104 years; younger controls, n=316 (155 women), age <50 years), where a higher frequency of the R allele in centenarians (7.6 %) compared to controls (3.0 %) (P=0.004) was independently confirmed. Although more research is needed, the variant allele of the MSTN K153R polymorphism could be among the genetic contributors associated with exceptional longevity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association of the K153R polymorphism in the myostatin gene and extreme longevity

Garatachea

Pinós

Cámara

et al. 2013

AGE

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“…Systemic treatment with myostatin inhibitors provides an adequate safety margin for clinical studies (Wagner et al 2008). Whereas Wagner et al (2008) did not show improvements in muscle strength or function, they observed that a few individuals had an increased muscle size (as measured with dual-energy radiographic absorptiometry and muscle histology), supporting the bioactivity of myostatin inhibitors.…”

Section: Introductionmentioning

confidence: 99%

The K153R variant in the myostatin gene and sarcopenia at the end of the human lifespan

González-Freire

Rodríguez-Romo

Santiago

et al. 2010

AGE

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We studied the A55T, E164K, I225T, K153R and P198A variants in the myostatin (GDF8) gene, muscle strength and mass, and physical function during daily living in 41 nonagenarians [33 women, age range, 90, 97]. No participant carried a mutant allele of the aforementioned variants, except three participants (all women), who carried the R allele of the K153R polymorphism, with one of them (woman aged 96 years) being homozygous. Overall, in KR women muscle phenotype values (1RM leg press and estimated muscle mass) were low-to-normal compared to the whole group (∼25th-50th percentile), and their functional capacity (Barthel and Tinetti tests) was normal. In the woman bearing the RR genotype, values of muscle mass and functional capacity were below the 25th percentile. She is the first RR Caucasian whose phenotype has been characterised specifically. In summary, heterozygosity for the GDF8 K153R polymorphism does not seem to exert a negative influence on the muscle phenotypes of women who are at the end of the human lifespan, yet homozygosity might do so. More research on larger cohorts of nonagenarians is needed to corroborate the present findings.

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Facioscapulohumeral Muscular Dystrophy

Tawil

Silvere

2011

Encyclopedia of Life Sciences

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Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited, muscle disease with a distinctive clinical presentation and a wide spectrum of disease severity. In greater than 95% of individuals with FSHD, the genetic defect is a loss of a critical number of D4Z4 macrosatellite repeats on chromosome 4q35. However, D4Z4 contractions are only pathogenic on specific, permissive chromosomal backgrounds. Recent evidence demonstrates that this permissive background facilitates the stable transcription of DUX4 , a retrogene sequence within D4Z4 that codes for a double homeodomain protein of unknown function. These findings implicate DUX4 in the pathophysiology of FSHD and for the first time, offer a target for therapeutic development in FSHD. Key Concepts: Epigenetic modifications can lead to gene derepression. FSHD results from reactivation of a retrogene.

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A phase I/IItrial of MYO‐029 in adult subjects with muscular dystrophy

Abstract: This trial supports the hypothesis that systemic administration of myostatin inhibitors provides an adequate safety margin for clinical studies. Further evaluation of more potent myostatin inhibitors for stimulating muscle growth in muscular dystrophy should be considered.

Cited by 410 publications

References 34 publications

Association of the K153R polymorphism in the myostatin gene and extreme longevity

Association of the K153R polymorphism in the myostatin gene and extreme longevity

The K153R variant in the myostatin gene and sarcopenia at the end of the human lifespan

Facioscapulohumeral Muscular Dystrophy

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