About Fragile X syndrome
Fragile X syndrome (FXS) is an X-chromosome linked genetic disorder and is the most common known cause of autism and inherited learning disabilities worldwide.
Autifony is working closely with FRAXA to progress the development of AUT00206 for Fragile X Syndrome.
Fragile X is caused by a fault in the FMR1 (Fragile X messenger ribonucleoprotein 1) gene which is responsible for making a protein (FMRP1) that is required for normal neural activity and brain development.
The prevalence of FXS is approximately 1 in 4,000 in males and 1 in 6,000 – 8,000 in females; however, the exact frequency is still being determined.
More than 1.4 million people could be affected by FXS worldwide.
FXS occurs in all racial and ethnic groups.
More specifically, Fragile X syndrome is caused by up to 200 CGG repeats in the FMR1 gene leading to its expansion. This results in reduced expression of the FMR1 protein, which is a mRNA-binding translational repressor, and leads to 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.
| Sign, Symptom or Morbidity | M | F |
|---|---|---|
| Development 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 % |
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.
AUT00206 clinical candidate – designed to fulfil the high unmet medical need in FXS
There are currently no approved medicines for FXS. We are driven to develop novel therapies that target the pathophysiology of this disease such that symptoms in adults will be reduced and the course of the disorder will be changed in young children.
Profile and development status
Clinical stage: Poised to commence Phase 2 clinical trials
Proprietary novel molecule: Orally active small molecule available in tablet format.
Mechanism of action: Positive allosteric modulator specific for the potassium ion channels Kv3.1 and Kv3.2.
Safe and well tolerated: as shown by Phase I testing in healthy volunteers and patients with schizophrenia
Orphan Drug Designation was granted by the U.S. Food and Drug Administration (FDA) for the treatment of Fragile X syndrome in July 2017. View press release.
Human CNS effect and target engagement: as demonstrated in multiple Phase I biomarker studies in healthy volunteers and patients with schizophrenia.
View scientific posters:
AUT00206 significantly reduces the ketamine-induced BOLD response in healthy volunteers
Preclinical results
Orphan Drug Designation for the treatment of Fragile X syndrome was awarded to AUT00206 by the FDA based on positive results from a range of preclinical studies examining the efficacy of the drug in a genetic mouse model of Fragile X Syndrome*.
Mice with a targeted knock out of the fmr1 gene treated with AUT00206 for 15 days or 6 weeks demonstrated improved cognitive function and reduced behavioural abnormalities, similar to the symptoms of children with FXS.
AUT00206 shows a broad spectrum of efficacy to rescue the phenotype of fmr1 knockout mice. View poster
* These studies were supported by the FRAXA Research Foundation, a charity which encourages and funds research into Fragile X syndrome.
AUT00206 – Rationale for targeting Kv3 channels to treat Fragile X syndrome
Fragile X syndrome is caused by a decreased level of FMRP1 protein in the brain. FMRP1 plays a critical role in brain development and function into adulthood. Reduced FMRP1 impacts the development and function of an important class of nerve cells, known as parvalbumin-positive interneurons1,2,3,4. These interneurons are responsible for coordinating the activity of networks of brain cells rather like the clock in a computer chip (see Figure 1).
Figure 1: 40Hz EEG “gamma” synchrony is a biomarker of parvalbumin interneuron activity that is enhanced by AUT00206
The reduced coordination (or “synchronisation”) of these neural networks explains the symptoms observed in people with Fragile X syndrome such as increased excitability (leading to a susceptibility to seizures), sensory hypersensitivity (e.g. hyperacusis), and cognitive problems.
Consistent with the important role of Kv3 channels on parvalbumin interneurons, we have shown that modulating Kv3.1 and Kv3.2 channels with drugs such as AUT00206 can improve the range of behavioural and cognitive deficits observed in the fmr1 KO mouse.
Exploration of the downstream consequences of reduced FMRP1 also identified Kv3.1 channels themselves as targets5 . In mouse models, reduced FMRP1 was linked to altered expression and function of Kv3.1, leading to hyperexcitability of auditory neurons in the brainstem 6. Modulation of Kv3.1 channels with Autifony compounds was able to can reverse this dysfunction 7.
In clinical studies, we have shown that AUT00206 can enhance the synchronisation of cortical network activity, consistent with improvements in parvalbumin interneuron function, and improve hearing performance. View poster
AUT00206 is being developed specifically to treat the pathophysiology associated with Fragile X syndrome and has the potential to improve the broad range of symptoms experienced by patients with this disorder.
References
- Selby et al. 2007. Neuroscience Lett. 412(3): 227-232
- Goel et al. 2018. Nat Neuroscience. 21: 1404 -1411
- McCullagh et al. 2020. FASEB J. 34(3): 3501 – 3518
- Nomura, T. 2021. Cells. 10: 3390- 3404
- Darnell et al 2001 Cell. 107(4): 489-499
- Strumbos et al. 2010. J. Neuroscience. 30(31): 10263-10271
- El Hassar et al. 2019. J. Neuroscience. 39(24): 4797-4813