Editors' ChoiceMEDICINE

Combined Treatment for Rett Syndrome

Sci. Signal.  15 Jul 2014:
Vol. 7, Issue 334, pp. ec190
DOI: 10.1126/scisignal.2005683

Mutations in methyl-CpG–binding protein 2 (MECP2), a gene located on the X chromosome, are responsible for the neurodevelopmental disorder Rett syndrome that occurs mostly in females. MECP2 regulates gene expression through multiple mechanisms, including altering the abundance of microRNAs that control the abundance of brain-derived neurotrophic factor (BDNF). Insulin-like growth factor 1 (IGF1) is another growth factor that is produced in the brain and the periphery and can cross the blood-brain barrier. Clinical trials for safety and efficacy of IGF1 in treating Rett syndrome are under way. Studies by Castro et al. and Mellios et al. showed the efficacy of recombinant human IGF1 (rhIGF1) and a β2-adrenergic receptor agonist, clenbuterol, in ameliorating Rett-like symptoms in a mouse model of Rett syndrome. Castro et al. found that circulating IGF1 was less in male Mecp2–/y mice than in wild-type mice and that daily intraperitoneal injection of rhIGF1 into these Mecp2–/y mice, starting at postnatal day 14 (P14), increased life span, improved respiratory patterns and heart rate, and increased locomotor activity. Additionally, the treated mice had improved social behaviors and reduced behaviors associated with anxiety. Delayed maturation of synapses and neuronal circuits may contribute to Rett syndrome symptoms, and female Mecp2–/+ mice exhibited an extended period of ocular dominance plasticity, which was corrected by treatment with rhIGF1. The density of postsynaptic spines in the visual cortex and miniature excitatory postsynaptic currents were also normalized in male Mecp2–/y mice following rhIGF1 treatment.

Mellios et al. investigated whether the deficits in adrenergic signaling associated with Rett syndrome and Mecp2-deficient mice could be therapeutically targeted. Clenbuterol is a β2-adrenergic receptor–specific agonist that can cross the blood-brain barrier and stimulate BDNF production. Male Mecp2–/y mice injected intraperitoneally, starting at P14 with clenbuterol with a 5-day injection followed by 2-day off regimen, had increased survival and improved respiratory function, motor coordination, and social behaviors. Clenbuterol also improved respiratory function, cognitive function, and motor coordination when administered to symptomatic female Mecp2–/+ mice (6 to 12 months old), suggesting that the symptoms of Rett syndrome may be at least partially reversed. Combined administration of clenbuterol and rhIGF1 to male Mecp2–/y mice produced a greater enhancement in life span than clenbuterol alone. Analysis of the cerebellum of male Mecp2–/y mice revealed a decrease in Bdnf expression and protein abundance, and clenbuterol treatment increased the amount of pCREB, the transcription factor that stimulates Bdnf expression, and Bdnf and Igf1 mRNAs in the cerebellum. One target of BDNF is the microRNA-processing protein LIN28A, which decreases the abundance of microRNAs of the let-7 family. In the cerebellum, LIN28A abundance was lower in Mecp2-deficient mice, and clenbuterol treatment normalized the abundance of LIN28A and let-7f that targets IGF1. Overexpression experiments in cultured cell lines indicated that LIN28A enhanced IGF1 production and that let-7f reduced IGF1 production and confirmed that let-7f could repress gene expression of a reporter with the 3′-untranslated region of Igf1 that contains a let-7f consensus site. Thus, one possible mechanism for the action of clenbuterol in ameliorating Rett syndrome–like phenotypes may be the activation of CREB to increase BDNF, which increases the abundance of LIN28A, thereby reducing the abundance of the microRNA let-7f and restoring IGF1 production.

J. Castro, R. I. Garcia, S. Kwok, A. Banerjee, J. Petravicz, J. Woodson, N. Mellios, D. Tropea, M. Sur, Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett syndrome. Proc. Natl. Acad. Sci. U.S.A. 111, 9941–9946 (2014). [Abstract] [Full Text]

N. Mellios, J. Woodson, R. I. Garcia, B. Crawford, J. Sharma, S. D. Sheridan, S. J. Haggarty, M. Sur, β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome. Proc. Natl. Acad. Sci. U.S.A. 111, 9947–9952 (2014). [Abstract] [Full Text]