What is Achondroplasia (ACH)?
 

Achondroplasia (ACH) is a common skeletal dysplasia characterized by disproportionate short stature, macrocephaly with frontal bossing, midface hypoplasia, and bowing of the tibiae. The incidence of ACH is approximately 1 in 15,000 to 25,000 live births.
 

Pathogenesis
 

The pathogenesis of achondroplasia is primarily associated with mutations in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene. Research indicates that over 97% of cases are caused by a missense mutation (p.G380R) in the transmembrane domain of the FGFR3 gene located on the short arm of chromosome 4. This mutation leads to constitutive activation of the FGFR3 receptor, releasing inhibitory signals that disrupt the process of endochondral ossification, ultimately resulting in rhizomelic (short-limbed) short stature.

Approximately 98% of ACH patients carry the FGFR3 gene variant c.1138G>A, with a minority having the c.1138G>C variant. Both variants result in the same amino acid change: p.Gly380Arg.
 

(Image: PubMed)

Gene Therapy
 

Viral Vector Gene Therapy: Utilizes viral vectors to deliver a normal copy of the FGFR3 gene into patients, aiming to replace the mutated gene and restore normal bone growth and development. This approach is still in the research and development phase.

mRNA Therapy: Employs mRNA technology to deliver mRNA encoding the normal FGFR3 protein into patients, enabling intracellular expression of the functional protein.

Gene Editing Technology: Aims to directly repair or modify the mutated FGFR3 gene within the patient's cells.

RNA Interference: Uses technologies like shRNA or siRNA to target and degrade the mutated FGFR3 mRNA, reducing the production of the abnormal protein.

Targeted Signaling Inhibition: Utilizes antisense oligonucleotides (ASOs) or small molecule drugs to inhibit the downstream overactivated MAPK signaling pathway of FGFR3.
 

Mouse Models
 

FGFR3-Gly380Arg Mice: Correspond to the most common human G380R mutation, modeling the pathological features of human achondroplasia. These mice exhibit significant growth retardation and skeletal deformities during bone development.

FGFR3−/− Mice: Reveal that FGFR3 is a negative regulator of bone growth under normal physiological conditions. Knockout of this gene leads to skeletal overgrowth in mice.

FGFR3 Y367C/+ Mice: The Y367C mutation in mice is often used to study the impact of ACH on craniofacial skeletal structures, such as the mandible.
 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various ACH mouse models according to client needs, such as FGFR3-Gly380Arg mice, FGFR3−/− mice, and FGFR3 Y367C/+ mice. We welcome inquiries!

 

References:

[1] Ornitz DM, Legeai-Mallet L. Achondroplasia: Development, pathogenesis, and therapy. Dev Dyn. 2017 Apr;246(4):291-309. doi: 10.1002/dvdy.24479. Epub 2017 Mar 2. PMID: 27987249; PMCID: PMC5354942.

[2] Zhang HQ, Tao DY, Zhang JJ, Niu HH, Luo JF, Cheng SQ. Clinical features and FGFR3 gene variation analysis in children with achondroplasia [Clinical features and FGFR3 mutations of children with achondroplasia]. Zhongguo Dang Dai Er Ke Za Zhi. 2022 Apr 15; 24(4):405-410. Chinese. doi: 10.7499/j.issn.1008-8830.2111039. PMID: 35527416; PMCID: PMC9044984.

[3] Wrobel, W.; Pach, E.; Ben-Skowronek, I. Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review. Int. J. Mol. Sci. 2021, 22, 5573. https://doi.org/10.3390/ijms22115573

[4] Lee YC, Song IW, Pai YJ, Chen SD, Chen YT. Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia. Sci Rep. 2017 Feb 23;7:43220. doi: 10.1038/srep43220. PMID: 28230213; PMCID: PMC5322349.

[5] Wang Y, Liu Z, Liu Z, Zhao H, Zhou X, Cui Y, Han J. Advances in research on and diagnosis and treatment of achondroplasia in China. Intractable Rare Dis Res. 2013 May;2(2):45-50. doi: 10.5582/irdr.2013.v2.2.45. PMID: 25343101; PMCID: PMC4204580.

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