Research that is already underway will be necessary to confirm the safety and efficacy of this class of Rett syndrome therapies, and targeting IGF-1 may be a possibility for treating additional neurological disorders beyond Rett.
RETT SYNDROME (RTT) IS A RARE, debilitating, progressive neurodevelopmental disorder.1,2 Approximately 95% of RTT cases are associated with sporadic mutations in the X-linked MECP2 gene.3,4 Being caused by an X-linked dominant mutation, RTT affects female patients almost exclusively3; in fact, RTT is the second most common cause of intellectual disability in female patients.4 RTT is characterized by normal development for the first 6 to 18 months of life, followed by loss of purposeful hand movements; difficulties with walking, balance, and coordination; and loss of speech and social interaction.5 Patients with RTT may have seizures, slowed growth, autistic behaviors, breathing irregularity, gait abnormalities, and/or distinctive hand stereotypies.1,3,6,7 Physical, occupational, and speech therapies are effective strategies for managing these symptoms.6 There is a need for corrective interventions that could improve the lives of those with RTT. Experimental approaches under development include gene therapies leveraging adeno-associated virus vectors to deliver functional MECP2 to affected cells8,9 and drugs based on insulinlike growth factor 1 (IGF-1), which compensate for downregulation of PI3K/Akt/mTOR signaling in RTT.5,10 RTT remains a crucial area of research for scientists and medical investigators. Of the approaches listed above, only the IGF-1–based approaches are discussed further here.
Alterations in synaptic structure, density, function, and plasticity have been implicated in the development and progression of RTT.3 For example, loss of synapses in the cerebral cortex and hippocampus contributes to cognitive decline in Alzheimer disease.11 Degeneration of dopaminergic neurons causes the loss of striatal synapses that underlies motor control abnormalities in Parkinson disease.12 Altered brain connectivity in autism is correlated with deficits in social interaction and communication.13 In a mouse model of RTT, MECP2 dysfunction is implicated in the reduced connectivity among excitatory glutamatergic pyramidal neurons in the cortex.14 Significant decreases in dendrite number and length have been recorded in both MECP2-null mice and individuals with RTT.3,14 Additionally, the number of spines on the dendrites of glutamatergic neurons in the cortex and hippocampus is reduced in MECP2-null mice.3,7 The remaining dendritic spines exhibit changes in synaptic contacts, with decreased head size and increased neck length.3,7 Reversing and/or preventing synaptic dysfunction may thus represent a promising therapeutic strategy for RTT.3,9
MECP2 is a nuclear protein with a highly conserved methyl-CpG binding domain that binds to methylated CpG dinucleotides in the promoter regions of target genes.15 Its binding represses target gene transcription and reduces transcriptional noise by interacting with a repressor complex that includes histone deacetylases and the corepressor SIN3A.7,14 MECP2 also plays a role in transcriptional activation, mRNA splicing, and miRNA production, as supported by previous findings.7 Restoring MECP2 expression in MECP2-deficient mice is capable of improving RTT symptoms.7 Yet, selective deletion of MECP2 from specific neuron subtypes does not fully replicate the observed phenotypes in constitutive MECP2-null mice, indicating the necessity of broader loss of MECP2 for more profound RTT-like phenotypes; thus, RTT likely arises because of cumulative neurological dysfunction across various neurotransmitter systems and brain regions.7
Perturbations of IGF-1 signaling are increasingly associated with the abnormal brain development and synaptic plasticity characteristic of RTT.15 Patients with RTT have low levels of IGF-1 in the central nervous system.3 IGF-1 normally affects the PI3K/Akt/mTOR signaling pathway (FIGURE3) to promote maturation, formation, and plasticity of the developing cortex10 as well as the expression of synaptic pathway proteins, all processes that are dysregulated in RTT.3 IGF-1 functions in part to inhibit the expression and membrane targeting of FXYD domain–containing ion transport regulator 1 (FXYD1), also known as phospholemman, a transmembrane protein that regulates Na+/K+-adenosine triphosphatase activity and is normally suppressed by MECP2.3,16 In RTT, levels of IGF-1 expression are low and activation of the PI3K-Akt-mTOR pathway is reduced, which is correlated with overphosphorylation of FXYD1.3 IGF-1 treatment can increase the copy number of wild-type MECP2, which can improve RTT symptoms by decreasing the expression and phosphorylation of FXYD1.3
Importantly, IGF-1 is able to cross the blood-brain barrier.3 This suggests that it is possible to manage brain disorders with peripheral administration of IGF-1.3 Restoring the levels of IGF-1 and related neuropeptides may help repair brain deficits.15 Indeed, a synthetic analogue of the glycine-proline-glutamate (GPE) amino-terminal tripeptide of IGF-1, called trofinetide (Daybue; Acadia Pharmaceuticals), is a novel drug that has shown promise in the treatment of patients with RTT.17,18 Studies using animal models of RTT have shown that IGF-1 can increase the size and number of dendritic spines.4 IGF-1 reduced inflammation and improved cognitive, behavioral, and motor deficits in these models.3,9 Clinical trials of trofinetide have similarly demonstrated its efficacy in improving the symptoms of RTT.17,18
The ongoing phase 2/3 DAFFODIL trial (NCT04988867) is assessing trofinetide in 30 girls aged 2 to 5 years with classical RTT who either have not had any seizures or had seizures but with no significant changes in frequency or severity for at least 8 weeks before the screening.19 In an earlier, double-blind, placebo-controlled clinical trial of older patients (aged 16-44 years), trofinetide was deemed safe and was well tolerated.17 Although this trial, which is expected to complete in July 2023, was designed to assess safety and not efficacy, the findings suggest that trofinetide may be an effective treatment for RTT, despite the small sample size of this trial.17 LAVENDER (NCT04181723), a larger, randomized, double-blind, placebo-controlled, parallel-group phase 3 clinical trial, evaluated the safety and effectiveness of trofinetide.18,20 LAVENDER was completed in 2021, with 187 girls and young women aged 5 to 20 years with RTT.18 Participants were given twice-daily doses of either trofinetide or a placebo for 12 weeks.18 The 91 participants who received trofinetide showed significant improvements in RTT symptoms compared with those who received the placebo.2 IGF-1 led to a reduction in apnea episodes, improvements in anxiety and mood abnormalities, and improvements in electroencephalogram frontal asymmetry.2,4 Further analysis of these top-line results is required to confirm that the benefits of trofinetide treatment outweigh the risks of adverse effects. Trofinetide received approval from the FDA on March 10, 2023, for the treatment of RTT in individuals 2 years and older.21 The drug is expected to be available for commercial use by the end of April 2023.21
More research, which is already underway, is necessary to confirm the safety and efficacy of this class of RTT therapies.17,18 Targeting IGF-1 may be a possibility for treating additional neurological disorders beyond RTT.18
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Rutgers University, New Brunswick, NJ