Principal Investigator Prof. Louise Gallagher
Research Title: “Molecular determinants of IGF1 action. A new avenue for treating Rett Syndrome and Autism Spectrum Disorders”
Meath Foundation Research funding awarded 2015
Patients with Rett Syndrome who responded to IGF-1 therapy showed a different pattern of gene expression assessed in peripheral blood, according to Meath Foundation research awarded to Prof Louise Gallagher and Dr. Daniela Tropea.
Prof. Gallagher, Professor Child & Adolescent Psychiatry at Trinity College, Dublin, was speaking on “Molecular determinants of IGFI action. A new avenue for treating Rett Syndrome and Autism Spectrum Disorders,” in a joint presentation with Dr Daniela Tropea, Assistant Professor in Functional Genomics, School of Medicine, TCD.
Rett Syndrome (RS) is a rare devastating neurodevelopmental disorder that affects one in 10,000 children, predominantly females. The onset of symptoms occurs in the first 6-18 months. First there is a period of developmental stagnation and social withdrawal, followed by a stage characterised by loss of language and motor skills. Thereafter seizures may develop and in the final stage of the condition there is severe motor impairment and mobility may cease. Some of the clinical symptoms of RS are also seen in autism, a more commonly occurring neurodevelopmental disorder.
RS is a genetic syndrome caused by mutations in the MeCP2 gene on the X-chromosome. MeCP2 protein turns off other genes in the genome and seems to be very important for the correct functioning of mature nerve cells. Animal models with MeCP2 mutations leading to loss of function of the protein have immature neurodevelopment. Many of the processes that go awry in RS, particularly in relation to how brain cells (neurons) communicate, are also implicated in autism. New therapies for RS may therefore have relevance for autism also.
Treatments targeting delayed maturation in RS animal models were previously studied by Dr. Tropea. Brain Derived Neurotrophic Factor (BDNF) was shown to promote maturation of the neurons. However BDNF is not translatable to humans as it does not cross the blood brain barrier (BBB). IGF-1 is a molecule that is similar to BDNF in terms of mechanisms of action and is smaller and consequently can cross the BBB.
In previous work, Dr. Tropea showed some functional recovery in mice treated with recombinant human IGF-1 (Mecasermin).
Subsequently, 10 human patients with RS were treated with Mecasermin in an open label study. Improvements in the RS International Severity Score were noted in 4 patient responders. They examined differential gene expression in the patients to determine if a profile could be identified that indicated response to Mecasermin. Patients that did not respond (Non-responders, n = 5) had greater differential expression of functioning genes. EEG data were obtained from patients and will be analysed as indicators of treatment response. This could inform future biomarker development. Both blood and EEG biomarkers have potential for indicating treatment response in patients that could be valuable in future approaches to care. Potentially these results could have relevance in autism in the context of clinical trials of Mecasermin.
Prof Gallagher, said a study of EEG biomarkers of treatment response was planned in a further study
RS is a rare syndrome and larger sample sizes and collaboration is necessary. However there are opportunities in Ireland for conducting clinical trials in Ireland, with both pharmaceutical companies and advocacy groups engaged around this.
“We need reliable, measurable and accessible biomarkers for patients’ stratification and measure of functional outcome. We need a patient registry to identify suitable patients for RCTs and we need an improved design and interpretation of clinical trials with better clinical and molecular endpoints,” Dr. Tropea concluded.