IPLEX administration improves motor neuron survival and ameliorates motor functions in a severe mouse model of spinal muscular atrophy.
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.
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
Michela
M
Murdocca
Arianna
A
Malgieri
Andrea
A
Luchetti
Luciano
L
Saieva
Gabriella
G
Dobrowolny
Elvira
E
de Leonibus
Antonio
A
Filareto
Maria Chiara
MC
Quitadamo
Giuseppe
G
Novelli
Antonio
A
Musarò
Federica
F
Sangiuolo
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology*; D009132:Muscles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009134:Muscular Atrophy, Spinal / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
C543394:IGF-I-IGFBP-3 complex; D018972:Insulin-Like Growth Factor Binding Protein 3; D055540:Survival of Motor Neuron 2 Protein; D007334:Insulin-Like Growth Factor I