Fragile X

About Fragile X Syndrome

Fragile X Syndrome is a genetic condition and is the most common known cause of inherited learning disabilities. There have been a number of studies aimed at determining the prevalence of FXS in males and females. The prevalence of FXS in males is approximately 1 in 3,600 to 4,000 and in females is approximately 1 in 4,000 to 6,000, and it occurs in all racial and ethnic groups. Disruption of the FMR1 gene causes a range of developmental problems, including learning disabilities and cognitive impairment. Almost all boys with Fragile X suffer from learning disabilities to varying degrees. Girls usually have milder learning disabilities than boys. Other symptoms include anxiety and hyperactive behaviour, and frequently autistic like behaviours such as avoiding eye contact, anxiety in social situations and insistence on familiar routines. Some children develop epilepsy. Speech and language are usually delayed, with continuing communication difficulties.

Sign, Symptom or Morbidity M F
Developmental Delay or Intellectual Disability 96% 64%
Attention Problems 84% 67%
Anxiety 70% 56%
Hyperactivity 66% 30%
Autism 46% 16%
Self Injury 41% 16%
Aggressiveness 38% 14%
Seizures 18% 7%
Depression 12% 22%

Data from the Center for Disease Control and Prevention, US.

AUT00206 for the treatment of Fragile X Syndrome

Autifony announced in July 2017 that the U.S. Food and Drug Administration (FDA) has granted AUT00206 an Orphan Drug Designation for the treatment of Fragile X Syndrome.

The Orphan Drug Designation was founded on positive results in a range of preclinical studies exploring the efficacy of AUT00206 in a genetic model of Fragile X in mice. In mice with a targeted knockout of the FMR1 gene, AUT00206 treatment for 21 days improved both cognitive and behavioral abnormalities that are similar to those that occur in children with Fragile X syndrome. This work was supported by the FRAXA Research Foundation, a charity which encourages and funds research into Fragile X Syndrome. Dr Mike Tranfaglia, Medical Director and Chief Scientific Officer of FRAXA Research Foundation, said: “We are excited about the potential of AUT00206 as a treatment for Fragile X. With its novel mechanism of action, this compound has demonstrated its ability to rescue many disease-relevant phenotypes in Fragile X animal models. AUT00206 has the potential to be a disease-modifying therapy for people with Fragile X, and we are looking forward to clinical trials in Fragile X patients.”

Kv3 Modulators for the treatment of Fragile X Syndrome

The Fragile X mental retardation protein (FMRP) regulates the expression of Kv3.1 ion channels (Strumbos et al. 2010. J. Neuroscience, 30(31):10263-10271), which may contribute to symptoms of FXS, including hypersensitivity to sound and cognitive deficits. Furthermore, parvalbumin-positive GABA interneurons, which specifically express Kv3 channels, are implicated in the neuropathology of FXS (Selby et al. 2007, 412(3):227-232; Cea-Del Rio. 2007. Neural and Synaptic Defects in Autism Spectrum Disorders. 125)

FMRP is predominantly expressed in neurons and interacts with the coding region of mRNA transcripts encoding pre- and postsynaptic proteins. FMRP level has a profound effect on higher brain function. FMRP regulates the expression and function of a wide range of neuronal proteins, with complex consequences. FMRP has been shown to regulate the expression and function of Kv3.1 voltage-gated potassium channels. For example, altered expression of Kv3.1 channels by auditory neurons may contribute to hypersensitivity to sound that is a common symptom in FXS.

Summarising the above, modulation of Kv3.1 channels by AUT00206 is a novel potential treatment for Fragile X Syndrome, which is supported by the following evidence:

  1. FMRP regulates the expression and function of Kv3.1 potassium channels. Loss of regulation of these channels could contribute to a number of the core symptoms of FXS patients, in particular:
    1. Hypersensitivity to sound and altered sensory processing
    2. Cognitive deficits
  2. Parvalbumin-positive GABAergic interneurons have been implicated in the neural pathology that underpins the development and expression of Fragile X. Kv3.1 channels are specifically expressed on these neurons and are essential for their normal function. Modulation of Kv3.1 channels by AUT00206 has been shown to influence the function of these interneurons and can reverse cognitive and social deficits in relevant animal models (Autifony, data on file).
  3. Empirical evidence from young adult Fmr1 knockout (Fmr1-KO) mice showing that AUT00206 can rescue different aspects of the mouse phenotype.

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