Fragile X Syndrome (FXS)
Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Our company is committed to driving forward the field of FXS research. With our exceptional team of accomplished researchers and scientists, we are at the forefront of pioneering advancements in the development of diagnostic tools and therapeutic drugs to effectively manage this complex disease. As your trusted partner in FXS research, we provide seamless and all-encompassing support to meet your scientific research needs.
Introduction to FXS
Fragile X Syndrome (FXS) is a complex genetic disorder that affects individuals worldwide. It is considered the leading cause of inherited intellectual disabilities, including autism spectrum disorder. FXS is characterized by physical abnormalities, behavioral issues, and a range of other health problems. The incidence of FXS in men is about 1/7,000, and the incidence in women is about 1/11,000. Women usually have milder symptoms than men.
Pathogenesis of FXS
Mutations in the FMR1 gene, located on the X chromosome, cause fragile X syndrome. The FMR1 gene is responsible for producing a protein called FMRP, which plays a crucial role in synaptic development. FMR1 mutations lead to an expansion of a DNA part called the CGG triplet repeat. In individuals with FXS, this repeat expands to more than 200 times, resulting in the silencing of the FMR1 gene. preventing the production of FMRP. This blocks the production of FMRP, affects synaptic development, and disrupts the normal function of the nervous system.
Fig.1 Diagram illustrating the main molecular mechanisms leading to fragile X syndrome and FMR1-associated disorders. (Quoted from Human Gene Mutation Database for FXS)Diagnostics Development of FXS
Gene Testing
FMR1 gene testing is an effective means of diagnosing FXS. The test usually takes a DNA sample from blood or other tissue to determine the length of the CGG triplet repeats. Techniques such as PCR and Southern blot analysis can be used to detect and quantify CGG repeat amplification.
Non-invasive Prenatal Testing
Non-invasive prenatal testing (NIPT) can detect FXS during pregnancy by analyzing fetal DNA in maternal blood samples. This significantly improves early identification of FXS, allowing for timely implementation of prenatal counseling and disease intervention.
Therapeutics Development of FXS
The therapeutics development for FXS focuses on targeting the underlying molecular and cellular mechanisms affected by the absence or reduction of the fragile X mental retardation protein (FMRP). Several potential drug targets are being investigated to address core features of FXS and ameliorate symptoms associated with the disease.
- Targets of FXS Therapy Development
| Target Name | Description |
|---|---|
| mGluR5 Pathway | The mGluR5 (metabotropic glutamate receptor 5) pathway is dysregulated in FXS, leading to abnormal synaptic signaling and neuronal function. Therapies targeting this pathway aim to normalize the signaling balance and improve cognitive and behavioral symptoms. Examples include mGluR5 antagonists, such as fenobam and mavoglurant (AFQ056). |
| GABAergic Modulators | GABA (gamma-aminobutyric acid) is an inhibitory neurotransmitter that plays a crucial role in regulating neuronal excitability. Therapies targeting GABAergic signaling aim to enhance inhibitory function and restore the excitatory-inhibitory balance disrupted in FXS. Medications like arbaclofen (STX209) and ganaxolone are being investigated. |
| Protein Translation Modulators | FMRP plays a key role in regulating protein synthesis at synapses. Therapies targeting protein translation aim to restore the balance of synaptic proteins affected in FXS. For instance, drugs such as minocycline and metformin have been investigated for their potential to modulate protein synthesis pathways. |
- Types of FXS Therapy Development
Gene therapy involves delivering functional copies of the FMR1 gene to restore normal protein production. Viral vectors, such as adeno-associated viruses (AAVs), have been used to deliver the therapeutic gene to the brain.
Small molecule compound therapy can target specific molecular pathways involved in FXS. For example, compounds that regulate the mGluR5 receptor, such as mavoglurant, have shown potential in preclinical studies by modulating synaptic plasticity.
Our Services
Our company has established a comprehensive platform for rare disease diagnostics and therapy development, encompassing small molecule drug, cell therapy, gene therapy, therapeutic antibody, therapeutic peptide, and therapeutic protein. Through our dedicated platforms, we are fully devoted to advancing the development of innovative diagnostic tools and therapeutics for FXS. Our focus on the AAV development platform specifically plays a crucial role in driving progress in gene therapy for FXS.
Recognizing the significance of animal disease models in the development of therapeutics for FXS, we offer our expertise in establishing FMR1 gene knockout rodent models (FMR1tm1Cgr and FMR1tm1.2Cidz) specifically tailored for FXS. These models serve as invaluable tools to facilitate safety evaluation and pharmacokinetics study of your drug candidates.
If you are interested in our services, please don't hesitate to contact us for more information and a detailed quotation regarding the specific services you require.
References
- Richter, Joel D., and Xinyu Zhao. "The molecular biology of FMRP: new insights into fragile X syndrome." Nature Reviews Neuroscience 22.4 (2021): 209-222.
- Kat, Renate, et al. "Translational validity and methodological underreporting in animal research: A systematic review and meta-analysis of the Fragile X syndrome (Fmr1 KO) rodent model." Neuroscience & Biobehavioral Reviews 139 (2022): 104722.
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