Mecasermin rinfabate: rhIGF-I/rhIGFBP-3 complex: iPLEX<sup>™</sup>

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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“…Notably, rhIGF-I complexed to rhIGFBP-3, was developed in an attempt to prolong the half-life of IGF-1 and potentially reduce side effects (52).…”

Section: Discussionmentioning

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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“…14), a 1:1 molecular complex of rhIGF-I and IGFBP-3. Yet clinical trials with this drug did not improve efficacy and showed similar side effect profiles including GH suppression (15)(16)(17), suggesting that acute disruption of the homeostatic system due to inappropriate delivery remains a major limitation of rhIGF-I therapy.…”

Section: Insulin-like Growth Factor (Igf-i)mentioning

confidence: 99%

Separation of Fast from Slow Anabolism by Site-specific PEGylation of Insulin-like Growth Factor I (IGF-I)

Metzger

Sajid²,

Saenger

et al. 2011

Journal of Biological Chemistry

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Insulin-like growth factor I (IGF-I) has important anabolic and homeostatic functions in tissues like skeletal muscle, and a decline in circulating levels is linked with catabolic conditions. Whereas IGF-I therapies for musculoskeletal disorders have been postulated, dosing issues and disruptions of the homeostasis have so far precluded clinical application. We have developed a novel IGF-I variant by site-specific addition of polyethylene glycol (PEG) to lysine 68 (PEG-IGF-I). In vitro, this modification decreased the affinity for the IGF-I and insulin receptors, presumably through decreased association rates, and slowed down the association to IGF-I-binding proteins, selectively limiting fast but maintaining sustained anabolic activity. Desirable in vivo effects of PEG-IGF-I included increased half-life and recruitment of IGF-binding proteins, thereby reducing risk of hypoglycemia. PEG-IGF-I was equipotent to IGF-I in ameliorating contraction-induced muscle injury in vivo without affecting muscle metabolism as IGF-I did. The data provide an important step in understanding the differences of IGF-I and insulin receptor contribution to the in vivo activity of IGF-I. In addition, PEG-IGF-I presents an innovative concept for IGF-I therapy in diseases with indicated muscle dysfunction.

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“…The adverse effects that have been reported with Increlex include hypoglycemia, jaw pain, headache, myalgias, and fluid retention (Williams et al, 2008). Mecasermin rinfabate (rhIGF-I bound to rhIGFBP-3 in equimolar proportions) appears to be associated with fewer adverse effects, because the drug forms a ternary complex with ALS, more readily than rhIGF-I alone (Kemp, 2007).…”

Section: Adverse Effectsmentioning

confidence: 99%

Hormone Use and Abuse

Lanfranco¹,

Motta²

2014

Reference Module in Biomedical Sciences

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Mecasermin rinfabate: rhIGF-I/rhIGFBP-3 complex: iPLEX^™

Cited by 42 publications

References 83 publications

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

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

Separation of Fast from Slow Anabolism by Site-specific PEGylation of Insulin-like Growth Factor I (IGF-I)

Hormone Use and Abuse

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Mecasermin rinfabate: rhIGF-I/rhIGFBP-3 complex: iPLEX™

Cited by 42 publications

References 83 publications

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

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

Separation of Fast from Slow Anabolism by Site-specific PEGylation of Insulin-like Growth Factor I (IGF-I)

Hormone Use and Abuse

Contact Info

Product

Resources

About

Mecasermin rinfabate: rhIGF-I/rhIGFBP-3 complex: iPLEX^™