Open-Label Trial of Recombinant Human Insulin-like Growth Factor 1/Recombinant Human Insulin-like Growth Factor Binding Protein 3 in Myotonic Dystrophy Type 1

Heatwole, Chad; Eichinger, Katy; Friedman, Deborah I.; Hilbert, James E.; Jackson, Carlayne E.; Logigian, Eric L.; Martens, William; McDermott, Michael P.; Pandya, Shree; Quinn, Christine; Smirnow, Alexis M.; Thornton, Charles A.; Moxley, Richard T.

doi:10.1001/archneurol.2010.227

Cited by 46 publications

(33 citation statements)

References 34 publications

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“…In accordance with previous reports [14], we detected low levels of IGF1 in our DM1 population. IGF1 is a peptide hormone similar to insulin that is considered one of the major muscle growth factors.…”

Section: Discussionsupporting

confidence: 93%

“…IGF1 is a peptide hormone similar to insulin that is considered one of the major muscle growth factors. Human recombinant IGF1 has been proposed as a therapeutic tool for muscle weakness in DM1 [14]. Vitamin D has been described to condition IGF1 by a genomic effect and probably values below a putative threshold have to be reached in order to cause a relevant change in circulating IGF1 levels.…”

Section: Discussionmentioning

confidence: 99%

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Vitamin D deficiency in myotonic dystrophy type 1

et al. 2013

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Myotonic dystrophy type 1 (DM1) is a multisystemic\ud disorder affecting, among others, the endocrine\ud system, with derangement of steroid hormones functions.\ud Vitamin D is a steroid recognized for its role in calcium\ud homeostasis. In addition, vitamin D influences muscle\ud metabolism by genomic and non-genomic actions,\ud including stimulation of the insulin-like-growth-factor 1\ud (IGF1), a major regulator of muscle trophism. To verify\ud the presence of vitamin D deficit in DM1 and its possible\ud consequences, serum 25-hydroxyvitamin D (25(OH)D),\ud calcium, parathormone (PTH), and IGF1 levels were\ud measured in 32 DM1 patients and in 32 age-matched\ud controls. Bone mineral density (BMD) and proximal\ud muscle strength were also measured by DXA and a\ud handheld dynamometer, respectively. In DM1 patients,\ud 25(OH)D levels were reduced compared to controls, and a\ud significant decrease of IGF1 was also found. 25(OH)D\ud levels inversely correlated with CTG expansion size,\ud while IGF1 levels and muscle strength directly correlated\ud with levels of 25(OH)D lower than 20 and 10 ng/ml,\ud respectively. A significantly higher percentage of DM1\ud patients presented hyperparathyroidism as compared to\ud controls. Calcium levels and BMD were comparable\ud between the two groups. Oral administration of cholecalciferol\ud in 11 DM1 patients with severe vitamin D deficiency\ud induced a normal increase of circulating 25(OH)D,\ud ruling out defects in intestinal absorption or hepatic\ud hydroxylation. DM1 patients show a reduction of circulating\ud 25(OH)D, which correlates with genotype and may\ud influence IGF1 levels and proximal muscle strength. Oral\ud supplementation with vitamin D should be considered in\ud DM1 and might mitigate muscle weakness

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Vitamin D deficiency in myotonic dystrophy type 1

et al. 2013

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“…IPLEX is available commercially and employed to treat short growth failure in children and adolescents with severe primary deficiency (30). When used in an open-label trial for myotonic dystrophy type 1 patients, it was generally well tolerated and patients showed an increased lean body mass and improvement, but no increase in muscle strength or function (31).…”

Section: Iplex Administration Improves Motor Neuron Survival and Amelmentioning

confidence: 99%

IPLEX Administration Improves Motor Neuron Survival and Ameliorates Motor Functions in a Severe Mouse Model of Spinal Muscular Atrophy

Murdocca¹,

Malgieri²,

Luchetti³

et al. 2012

Mol Med

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Spinal muscular atrophy (SMA) is an inherited neurodegenerative disorder and the first genetic cause of death in childhood. SMA is caused by low levels of survival motor neuron (SMN) protein that induce selective loss of α-motor neurons (MNs) in the spinal cord, resulting in progressive muscle atrophy and consequent respiratory failure. To date, no effective treatment is available to counteract the course of the disease. Among the different therapeutic strategies with potential clinical applications, the evaluation of trophic and/or protective agents able to antagonize MNs degeneration represents an attractive opportunity to develop valid therapies. Here we investigated the effects of IPLEX (recombinant human insulinlike growth factor 1 [rhIGF-1] complexed with recombinant human IGF-1 binding protein 3 [rhIGFBP-3]) on a severe mouse model of SMA. Interestingly, molecular and biochemical analyses of IGF-1 carried out in SMA mice before drug administration revealed marked reductions of IGF-1 circulating levels and hepatic mRNA expression. In this study, we found that perinatal administration of IPLEX, even if does not influence survival and body weight of mice, results in reduced degeneration of MNs, increased muscle fiber size and in amelioration of motor functions in SMA mice. Additionally, we show that phenotypic changes observed are not SMN-dependent, since no significant SMN modification was addressed in treated mice. Collectively, our data indicate IPLEX as a good therapeutic candidate to hinder the progression of the neurodegenerative process in SMA.

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“…There have been several treatment trials using free IGF-1 therapy in amyotrophic lateral sclerosis (ALS) [68][69][70] and one trial of free IGF-1 complexed with IGF-1 binding protein-3 in myotonic dystrophy [71]. ALS trials failed to show a clear beneficial result but demonstrated safety of IGF-1 in these patients.…”

Section: Insulin-like Growth Factormentioning

confidence: 99%

“…The trial in myotonic dystrophy showed encouraging results in seven of the nine patients treated. Two patients discontinued treatment because of cardiovascular complications [68][69][70][71][72]. More recently, treatment trials in children with primary growth hormone deficiency, elderly women following hip replacement surgery and patients with complications of HIV infection, have trialed IGF-1 complexed with IGF-1 binding protein-3, and each group of patients have tolerated this preparation without significant side effects [74][75][76].…”

Section: Insulin-like Growth Factormentioning

confidence: 99%