IGF1 as a Potential Treatment for Rett Syndrome: Safety Assessment in Six Rett Patients

Abstract

Rett syndrome (RTT) is a devastating neurodevelopmental disorder that affects one in ten thousand girls and has no cure. The majority of RTT patients display mutations in the gene that codes for the methyl-CpG-binding protein 2 (MeCP2). Clinical observations and neurobiological analysis of mouse models suggest that defects in the expression of MeCP2 protein compromise the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function, such as insulin-like growth factor 1 (IGF1), are good candidates for ameliorating the symptoms of RTT. IGF1 and its active peptide, (1–3) IGF1, cross the blood brain barrier, and (1–3) IGF1 ameliorates the symptoms of RTT in a mouse model of the disease; therefore they are ideal treatments for neurodevelopmental disorders, including RTT. We performed a pilot study to establish whether there are major risks associated with IGF1 administration in RTT patients. Six young girls with classic RTT received IGF1 subcutaneous injections twice a day for six months, and they were regularly monitored by their primary care physicians and by the unit for RTT in Versilia Hospital (Italy). This study shows that there are no risks associated with IGF1 administration.

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

“…Nonetheless, because hormonal levels were within normal ranges throughout the study, this issue deserves further investigation. In summary, at the doses used in this (240 μg·kg −1 ·d −1 ) and the previously published (200 μg·kg −1 ·d −1 ) trial (30), mecasermin is a safe treatment.…”

Placebo‐controlled crossover assessment of mecasermin for the treatment of Rett syndrome

“…The nonlinear kinetics of rhIGF‐1 also raises the possibility of long‐term effects that, in the case of crossover trials, could be manifested as carry forward effect. Conversely, Pini and colleagues reported improvements in breathing that extend for the latter half of the 6‐month treatment period that worsened after treatment cessation 36. Another possibility is continuous administration is not the best approach for rhIGF‐1's neurological effects.…”

β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome

“…The partial success of rhIGF1 in restoring numerous behavioral and organismal functions disrupted in Mecp2 KO mice (20), the safety and efficacy of rhIGF1 in clinical trials (25)(26)(27)(28), as well as the ability of rhIGF1 to rescue neuronal phenotypes in patientderived neurons (22,23) and astrocytes (24), prompted us to investigate whether Mecp2 knockdown can affect IGF1 expression, and look into additional drugs with potential to mechanistically rescue deficiencies in brain growth factor expression. Here, we show that, in addition to the known deficits in BDNF expression, IGF1 synthesis is reduced in the cerebellum of male Mecp2 KO mice, which is associated with a decreased level of miRNA-processing gene LIN28A and an up-regulation of LIN28A-regulated let-7f miRNA.…”

“…We thus cotreated animals with clenbuterol and rhIGF1, a drug that is in clinical trials for its therapeutic effects on RTT patients (25)(26)(27)(28).…”

“…Indeed, several studies have demonstrated that IGF1 can rescue molecular signaling, structural and physiological phenotypes in human induced pluripotent stem cell-derived neurons (22,23) and astrocytes (24), and clinical trials of recombinant human IGF1 for RTT have shown favorable safety (25), and safety plus efficacy (26,27) profiles.…”