Exploring Novel Treatments for Rett Syndrome

Editor's Notes

• #10: Rett syndrome: Revised diagnostic criteria and nomenclature
• #13: From Wien Med Wochenschr (2016) 166:325–332 The etiology of RTT was considered by many to be genetic, based on the exclusive occurrence, at least at that time, of RTT in females, suggesting an X-linked, dominant disorder. However, the efforts to identify a biochemical or metabolic fingerprint greatly hampered further understanding. At Baylor, Dr. Zoghbi was then engaged in training in molecular genetics and was encouraged to pursue studies into a molecular etiology for RTT. Interestingly, the presence of an autosome–X chromosome translocation in one of the first children evaluated allowed a large portion of the X-chromosome to be excluded [19]. Gradually, the area of interest was narrowed to Xq28 by a series of studies from the rare instances of familial involvement [20, 21]. In this regard, the general failure of recurrence in families and the X-linked dominant nature suggested that a mutation, if one could be identified, would result from a germline de novo mutation in the father [22]. Although this idea was questioned by some [23], the molecular search continued and in 1999 a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, located at Xq28, was identified by Ruthie Amir [24] working in the Zoghbi laboratory. Subsequently, these findings were confirmed inmultiple laboratories throughout the world [25–28].
• #14: Shahbazian et al. (2002) investigated the spatial and temporal distribution of the Mecp2 protein during mouse and human development. By Western blot analysis, they found that Mecp2 in the adult mouse is high in the brain, lung, and spleen, lower in heart and kidney, and barely detectable in liver, stomach, and small intestine.  Tropea: While MeCP2 target genes have been difficult to identify (15) the best characterized target of MeCP2 regulation is BDNF (16), which is generally known to trigger neuronal and synaptic maturation (17). Furthermore, reduced BDNF expression in the brainstem correlateswith respiratory dysfunction in MeCP2 mutant mice, and enhancing BDNF expression ameliorates respiratory symptoms (19). Unfortunately, the therapeutic utility of BDNF is hampered by its poor efficiency at crossing the blood–brain barrier. Nevertheless, a therapeutic intervention in humans might thus arise from identifying an agent similarly capable of stimulating synaptic maturation.
• #16: Percy 2016 paper Definite genotype–phenotype correlations are noted with important caveats [63–65]. For both classic and atypical RTT, R133C, R294X, R306C, and 3’-truncations result in less severity than other common mutations (R106W, R168X, R255X, R270X, deletions/ insertions, and splice site mutations). Overall, clinical severity tends to increase slowly with age as the result of scoliosis, dystonia, and rigidity. Those who ambulate, maintain some hand function, and have a later age at onset also tend to be less severely impacted. However, markedly different clinical patterns or outcomes can be seen in two females with exactly the same genotype. These are most likely related to differences in X-chromosome inactivation (XCI), differing genetic backgrounds, environmental factors, and the clonal distribution of normal and abnormal X-chromosomes throughout the brain. From a relatively small study in blood involving 183 participants in the NHS (Friez et al., unpublished work), significant skewing of XCI was noted, including 11% that were highly skewed and 26% were moderately skewed. Overall, 51% were random and 12% were uninformative. Of the 11% who were highly skewed, this was evenly divided between the normal and the abnormal X-chromosome and, thus, conferred an exclusive advantage in neither direction.
• #20: Percy 2016: As a result, the Rare Disease Clinical Research Network was formed and initial funding became available in the early 2000s. This resulted in the funding of a natural history study (NHS) regarding RTT that has been refunded twice and now, in its third iteration, is addressing RTT, MECP2 duplication disorders, and other RTT-related disorders including CDKL5, FOXGL, and individuals with MECP2 mutations, both females and males, who do not meet the diagnostic criteria for RTT. To date, data from more than 1200 participants evaluated in the first 11 years of the NHS have been published and several additional topics are being analyzed for submission. One of the initial outcomes of the NHS was validation of the revised consensus criteria of 2010 following the convening of an international panel of clinicians [52, 53]. These modifications simplified the criteria and provided a distinction for their application in classic and variant or atypical RTT (Table 1)
• #22: Tarquinio: Overall, 1205 individuals were enrolled in the Rett Natural History Study; the final analysis focused on 778 with classic Rett syndrome followed longitudinally for up to 9.0 years (median 5.5 years, IQR 3.2–7.5 years) and a median of five visits each, for a total of 3939 personyears. Of the original 1205, diagnosis or date of birth could not be verified in 22. Due to scarcity, only summary statistics are provided for epilepsy in males with Rett syndrome or MECP2 mutation without Rett syndrome, participants with MECP2 duplication and the two individuals with atypical severe Rett syndrome due to CDKL5 mutation (Table 1). These individuals were excluded from regression analyses. The remaining cohort of 1123 female participants included 922 with classic Rett syndrome, 78 with atypical mild Rett syndrome, 81 with atypical severe Rett syndrome, and 42 with a pathogenic mutation in MECP2 but without clinical Rett syndrome. Median age of diagnosis in classic Rett syndrome was 2.7 years (IQR 2.0–4.1). Further details were published previously (Tarquinio et al., 2015b). Some subjects were only seen once (cross-sectional cases with retrospective data only), but most (87.7%, n = 985) were followed longitudinally, including 84.4% (n = 778) of those with classic Rett syndrome. None born after 1997 lived in a group home or institution. The proportion of those older than 18 years who lived in a group home was 7.3%, and in an institution was 1.2%. Fifty-two of the total cohort died before the end of the study (4.6%). Most deaths were due to cardiorespiratory issues, and survival for both classic and atypical Rett syndrome was 470% at 45 years (Tarquinio et al., 2015a).
• #25: Online polling recorded the demographics of the meeting attendees showing that approximately 86% were from the US, 94% represented females with Rett syndrome, 68% represented pediatric individuals, and 99% had a variant in the MECP2 gene. Full results are presented in Appendix 1.
• #30: Unfortunately, the blood brain barrier penetrance of BDNF is low, making its application as a therapeutic challenging. Insulin-like growth factor 1 (IGF1), however, confers similar effects on neuronal survival and maturation through overlapping signaling pathways and crosses the blood brain barrier, especially through its metabolite glycine-prolineglutamate (GPE).192–194
• #31: Key inclusion and exclusion criteria. Inclusion criteria • Girls and women, aged 5–20 years • Weight ≥12 kg • Classic/typical RTT • Documented disease-causing mutation in MECP2 gene • At least 6 months post regression at screening (i.e., no loss or degradation in ambulation, hand function, speech, nonverbal communicative or social skills within 6 months of screening) • Rett Syndrome Clinical Severity Scale rating of 10–36 • CGI-S score of ≥4 • Stable pattern of seizures, or has had no seizures, within 8 weeks of screening Exclusion criteria • Current clinically significant cardiovascular, endocrine (such as hypo- or hyperthyroidism, type 1 diabetes, or uncontrolled type 2 diabetes), renal, hepatic, respiratory, or gastrointestinal disease (such as celiac disease or inflammatory bowel disease), or major surgery planned during the study • Known history or symptoms of long QT syndrome • QTcF interval >450 ms, history of risk factor for torsades de pointes or clinically significant QT prolongation deemed to increase risk • Treatment with insulin, IGF-1, or growth hormone within 12 weeks of baseline
• #32: Key inclusion and exclusion criteria. Inclusion criteria • Girls and women, aged 5–20 years • Weight ≥12 kg • Classic/typical RTT • Documented disease-causing mutation in MECP2 gene • At least 6 months post regression at screening (i.e., no loss or degradation in ambulation, hand function, speech, nonverbal communicative or social skills within 6 months of screening) • Rett Syndrome Clinical Severity Scale rating of 10–36 • CGI-S score of ≥4 • Stable pattern of seizures, or has had no seizures, within 8 weeks of screening Exclusion criteria • Current clinically significant cardiovascular, endocrine (such as hypo- or hyperthyroidism, type 1 diabetes, or uncontrolled type 2 diabetes), renal, hepatic, respiratory, or gastrointestinal disease (such as celiac disease or inflammatory bowel disease), or major surgery planned during the study • Known history or symptoms of long QT syndrome • QTcF interval >450 ms, history of risk factor for torsades de pointes or clinically significant QT prolongation deemed to increase risk • Treatment with insulin, IGF-1, or growth hormone within 12 weeks of baseline
• #33: Key inclusion and exclusion criteria. Inclusion criteria • Girls and women, aged 5–20 years • Weight ≥12 kg • Classic/typical RTT • Documented disease-causing mutation in MECP2 gene • At least 6 months post regression at screening (i.e., no loss or degradation in ambulation, hand function, speech, nonverbal communicative or social skills within 6 months of screening) • Rett Syndrome Clinical Severity Scale rating of 10–36 • CGI-S score of ≥4 • Stable pattern of seizures, or has had no seizures, within 8 weeks of screening Exclusion criteria • Current clinically significant cardiovascular, endocrine (such as hypo- or hyperthyroidism, type 1 diabetes, or uncontrolled type 2 diabetes), renal, hepatic, respiratory, or gastrointestinal disease (such as celiac disease or inflammatory bowel disease), or major surgery planned during the study • Known history or symptoms of long QT syndrome • QTcF interval >450 ms, history of risk factor for torsades de pointes or clinically significant QT prolongation deemed to increase risk • Treatment with insulin, IGF-1, or growth hormone within 12 weeks of baseline
• #34: Key inclusion and exclusion criteria. Inclusion criteria • Girls and women, aged 5–20 years • Weight ≥12 kg • Classic/typical RTT • Documented disease-causing mutation in MECP2 gene • At least 6 months post regression at screening (i.e., no loss or degradation in ambulation, hand function, speech, nonverbal communicative or social skills within 6 months of screening) • Rett Syndrome Clinical Severity Scale rating of 10–36 • CGI-S score of ≥4 • Stable pattern of seizures, or has had no seizures, within 8 weeks of screening Exclusion criteria • Current clinically significant cardiovascular, endocrine (such as hypo- or hyperthyroidism, type 1 diabetes, or uncontrolled type 2 diabetes), renal, hepatic, respiratory, or gastrointestinal disease (such as celiac disease or inflammatory bowel disease), or major surgery planned during the study • Known history or symptoms of long QT syndrome • QTcF interval >450 ms, history of risk factor for torsades de pointes or clinically significant QT prolongation deemed to increase risk • Treatment with insulin, IGF-1, or growth hormone within 12 weeks of baseline
• #35: Key inclusion and exclusion criteria. Inclusion criteria • Girls and women, aged 5–20 years • Weight ≥12 kg • Classic/typical RTT • Documented disease-causing mutation in MECP2 gene • At least 6 months post regression at screening (i.e., no loss or degradation in ambulation, hand function, speech, nonverbal communicative or social skills within 6 months of screening) • Rett Syndrome Clinical Severity Scale rating of 10–36 • CGI-S score of ≥4 • Stable pattern of seizures, or has had no seizures, within 8 weeks of screening Exclusion criteria • Current clinically significant cardiovascular, endocrine (such as hypo- or hyperthyroidism, type 1 diabetes, or uncontrolled type 2 diabetes), renal, hepatic, respiratory, or gastrointestinal disease (such as celiac disease or inflammatory bowel disease), or major surgery planned during the study • Known history or symptoms of long QT syndrome • QTcF interval >450 ms, history of risk factor for torsades de pointes or clinically significant QT prolongation deemed to increase risk • Treatment with insulin, IGF-1, or growth hormone within 12 weeks of baseline
• #36: Key inclusion and exclusion criteria. Inclusion criteria • Girls and women, aged 5–20 years • Weight ≥12 kg • Classic/typical RTT • Documented disease-causing mutation in MECP2 gene • At least 6 months post regression at screening (i.e., no loss or degradation in ambulation, hand function, speech, nonverbal communicative or social skills within 6 months of screening) • Rett Syndrome Clinical Severity Scale rating of 10–36 • CGI-S score of ≥4 • Stable pattern of seizures, or has had no seizures, within 8 weeks of screening Exclusion criteria • Current clinically significant cardiovascular, endocrine (such as hypo- or hyperthyroidism, type 1 diabetes, or uncontrolled type 2 diabetes), renal, hepatic, respiratory, or gastrointestinal disease (such as celiac disease or inflammatory bowel disease), or major surgery planned during the study • Known history or symptoms of long QT syndrome • QTcF interval >450 ms, history of risk factor for torsades de pointes or clinically significant QT prolongation deemed to increase risk • Treatment with insulin, IGF-1, or growth hormone within 12 weeks of baseline