Fragile X Syndrome

About Fragile X Syndrome

Fragile X syndrome (FXS) is a rare, serious, life-long genetic disorder caused by alterations in the Fragile X gene (FMR1). It is the leading single gene cause of intellectual disability. FXS affects about one in 2,500–4,000 males and about one in 7,000–8,000 females. Females are typically less severely affected than males. Most boys and approximately 30 per cent of girls with FXS will have significant intellectual disability across their lifespan.

Figure 1 The genetic mutation that causes FXS is located within the X chromosome. As females have two X chromosomes, the prevalence is lower and they tend to have milder symptoms compared to males.

A Serious Genetic Condition

FXS is characterised by a range of developmental problems, including learning disabilities, behavioural issues including autism features, cognitive impairment, speech and language deficits, sleep problems, anxiety, and severe difficulties with regulating stress and emotions 1. These core symptoms have a substantial impact on day-to-day functioning of patients and their carers. 

Following diagnosis, which typically occurs around three to five years of age, a patient may require treatment to help alleviate the behavioural challenges they experience. Currently, medications prescribed experimentally (not formally approved by regulators) and behavioural interventions developed for other conditions are used to help improve some of the symptoms, with no FXS specific treatments available.

FXS is caused by a mutation to the FMR1 gene located on the X chromosome. This gene controls the production of the FMR protein (FRMP), which is required for the normal development of neural connections. A mutation of the FMR1 gene prevents normal development of neural networks in the brain, disrupts nervous system functions, and leads to the symptoms of FXS.2

The protein produced by the FMR1 gene, known as FMRP, is essential for normal brain development

Figure 2 FMRP acts as a protein production regulator, ensuring that the protein building blocks necessary for normal neural connections are produced in the right quantity. In people with FXS, there is no FMRP to regulate protein production. This results in unregulated, over production of protein building blocks and prevents normal development of neural networks in the brain. The malformed neural connections disrupt nervous system function and leads to the symptoms of FXS.
1. Intellectual functioning and behavioural features associated with mosaicism in fragile X syndrome. Baker EK, Arpone M, Vera SA, Bretherton L, Ure A, Kraan CM, Bui M, Ling L, Francis D, Hunter MF, Elliott J, Rogers C, Field MJ, Cohen J, Maria LS, Faundes V, Curotto B, Morales P, Trigo C, Salas I, Alliende AM, Amor DJ, Godler DE. J Neurodev Disord. 2019 Dec 26;11(1):41. doi: 10.1186/s11689-019-9288-7.
2. Epigenetics of fragile X syndrome and fragile X-related disorders. Kraan CM, Godler DE, Amor DJ. Dev Med Child Neurol. 2019 Feb;61(2):121-127. doi: 10.1111/dmcn.13985. Epub 2018 Aug 7. Review. PMID: 30084485

Anxiety occurs in about 90% of individuals with FXS and represents a substantial unmet clinical challenge. Elevated levels of the stress hormone, cortisol, is also reported in FXS There has been significant clinical interest in evaluating Actinogen’s lead drug candidate, Xanamem, for medical conditions associated with raised levels of cortisol. Thus, Actinogen recognises the potential for anxiety and stress regulation in FXS to be pursued as a clinical development opportunity with Xanamem.

Xanamem may be eligible for orphan drug designation in FXS in key markets. Orphan drug designation provides significant potential regulatory, development and commercial advantages for Actinogen.

FXS is caused by a mutation to the FMR1 gene located on the X chromosome

Fragile X Syndrome Gene Silencing
Figure 3 At the start of this gene lies a DNA sequence, called the CGG triplet repeat (in yellow), that varies in length from one person to another. When this sequence of DNA falls within a range of length that would be considered ‘normal’ (<45 CGG repeats), there are normal levels mRNA and protein (FMRP) produced and neural development is normal. In some people, this sequence expands longer (55-199 CGG repeats) in what is known as a ‘premutation’. This causes more mRNA to be produced than normal which may result in RNA toxicity, and reduced levels of FMRP. When this sequence od DNA expands beyond a certain length (200 CGG repeats), the FMR1 gene is switched and no FMR1 mRNA or FMRP is produced. This is known as a ‘full mutation’ and results in FXS.

Fragile X Syndrome is a major disease Area

Fragile X occurs in approximately one in 2,500–4,000 males and about one in 7,000–8,000 females
There are approximately 74,000 Fragile X patients in the United States. About 16,000 are under the age of 18 years
Anxiety is a symptom that occurs in approximately 90 per cent of Fragile X patients
Estimated peak global sales revenues of ~A$350 million by 2031, with about A$180 million in sales in the US market

No Treatment or Cure for Fragile X SYNDROME

There are currently no approved drugs to treat FXS. 

The current standard of care for FXS includes speech and language therapy, special educational support, occupational therapy, and behavioural therapy. Care may also include the use of off-label pharmaceuticals such as stimulants, anti-depressants, anti-psychotics and anti-convulsants. Selective serotonin reuptake inhibitors (SSRIs) are effective approximately 50 per cent of the time in managing anxiety in FXS patients. However, FXS patients tend to be more sensitive to these drugs and side effects are common even at low doses. This reflects a substantial unmet medical need.

Currently, treatment options that focus specifically on the behavioural aspects of FXS are limited. Drugs registered for other indications and not approved for use in FXS are commonly used. However, these only minimise symptoms of the disorder.

Actinogen plans to initially target patients between 12-18 years of age who need help with the treatment of behavioural issues and who can potentially benefit from Xanamem. Once the safety of Xanamem has been confirmed in this population, longer term plans will see trials run in younger patient cohorts when the brain is more ‘plastic’ and subject to change.

Please note, Xanamem is still an investigational product.

High cortisol levels associated with Fragile X Syndrome

In children with FXS, raised cortisol levels are significantly associated with cognitive impairment and behaviour problems including social anxiety, hyperactivity, and social withdrawal3, 4. High levels of stress hormone may also impair neural circuits important for the regulation of these behaviours. 

Treatment options for behavioural problems represent a significant unmet clinical and medical need in FXS. Xanamem’s mechanism of action supports its use in the reduction of cortisol and as a potential treatment for the cognitive and behavioural symptoms associated with FXS.

Figure 4 In a normally developed brain there is a balance between excitatory and inhibitory signals that ensures nerve cells respond appropriately to incoming signals. This balance is crucial for the brain's response to stress. In FXS, the lack of FMRP leads to the loss of inhibitory (GABA) signals and this causes the brain to misinterpret normal neural signals as stressful. The chronically overactive stress response leads to dysfunction of the HPA-axis, elevated cortisol, and this is thought to contribute to the debilitating symptoms of FXS including anxiety, behavioural issues, and cognitive impairment. Xanamem, through the inhibition of cortisol production in the brain, provides a targeted strategy to lower cortisol and break the cycle that underlies some of the most debilitating symptoms of FXS.
3. Cortisol and social stressors in children with fragile X: a pilot study. Wisbeck JM1, Huffman LC, Freund L, Gunnar MR, Davis EP, Reiss AL. J Dev Behav Pediatr. 2000 Aug;21(4):278-82.
4.The neuroanatomy and neuroendocrinology of fragile X syndrome. Hessl D1, Rivera SM, Reiss AL. Ment Retard Dev Disabil Res Rev. 2004;10(1):17-24.

Xanamem could be a potential treatment for Fragile X

Xanamem is a novel therapeutic product specifically designed to inhibit the production of excess cortisol in the brain.  Xanamem is considered a potential therapy to decrease elevated cortisol and alleviate associated symptoms such as anxiety in FXS. Xanamem works by inhibiting the 11β-HSD1 enzyme in the brain, which blocks the production of the stress hormone, cortisol. 

The hypothalamic-pituitary-adrenal axis (HPA-axis) is responsible for maintaining normal levels of circulating cortisol. In FXS, the HPA-axis is impaired, cortisol is abnormally high, and this is thought to result in problems with stress regulation, anxiety as well as other debilitating symptoms including behavioural issues and cognitive impairment. By normalising HPA-axis function, Xanamem provides a targeted strategy that may alleviate the stress regulation difficulties that underlie some of the most debilitating symptoms in FXS.

External Links

Fragile X Association of Australia
https://www.fragilex.org.au/understanding-fragile-x/

US National Fragile X Foundation
https://fragilex.org/

‘Stuart X’ A short film about a Fragile X sufferer
https://www.youtube.com/watch?v=uKyGX-RJFiw&feature=youtu.be 

Publications

Publications
Intellectual functioning and behavioural features associated with mosaicism in fragile X syndrome

Baker, E. K., Arpone, M., Vera, S. A., Bretherton, L., Ure, A., Kraan, C. M., Bui, M., Ling, L., Francis, D., Hunter, M. F., Elliott, J., Rogers, C., Field, M. J., Cohen, J., Santa Maria, L., Faundes, V., Curotto, B., Morales, P., Trigo, C., Salas, I., Alliende, A. M., Amor, D. J. & Godler, D. E. 2019. Journal of Neurodevelopmental Disorders, 11, 15.

Biobehavioral composite of social aspects of anxiety in young adults with fragile X syndrome contrasted to autism spectrum disorder

Roberts, J. E., Ezell, J. E., Fairchild, A. J., Klusek, J., Thurman, A. J., Mcduffie, A. & Abbeduto, L. 2018. American Journal of Medical Genetics Part B-Neuropsychiatric Genetics, 177, 665-675.

Cortisol profiles differentiated in adolescents and young adult males with fragile X syndrome versus autism spectrum disorder

Matherly, S. M., Klusek, J., Thurman, A. J., Mcduffie, A., Abbeduto, L. & Roberts, J. E. 2018. Developmental Psychobiology, 60, 78-89.

Fragile X syndrome

Hagerman, R. J., Berry-Kravis, E., Hazlett, H. C., Bailey, D. B., Moine, H., Kooy, R. F., Tassone, F., Gantois, I., Sonenberg, N., Mandel, J. L. & Hagerman, P. J. 2017. Nature Reviews Disease Primers, 3, 19.

HPA axis function predicts development of working memory in boys with FXS

Scherr, J. F., Hahn, L. J., Hooper, S. R., Hatton, D. & Roberts, J. E. 2016. Brain and Cognition, 102, 80-90.

Cortisol and behavior in fragile X syndrome

Hessl, D., Glaser, B., Dyer-Friedman, J., Blasey, C., Hastie, T., Gunnar, M. & Reiss, A. L. 2002. Psychoneuroendocrinology, 27, 855-872.

Cortisol and social stressors in children with fragile X: A pilot study

Wisbeck, J. M., Huffman, L. C., Freund, L., Gunnar, M. R., Davis, E. P. & Reiss, A. L. 2000. Journal of Developmental and Behavioral Pediatrics, 21, 278-282.