Treatment of Diseases Associated with Aberrant Ciliary Function

REF. NO. 06-16


Defects in mammalian cell cilia lead to the development of a large number of genetic disorders such as polycystic kidney disease (PKD), Bardet-Biedl Syndrome, Alstrom syndrome and others, which affects many body systems and can be associated with obesity, retinitis, hypogonadism, and renal failure in some cases. Moreover, deregulation of cilia-associated pathways during cell transformation suggests that defective cilary signaling can also promote cancer. A number of cilia-associated genetic disorders and pathological conditions have very limited treatment options for patients. For example, there is no specific treatment for polycystic kidney disease other than dialysis and transplantation. Thus, new drugs for ciliary disorders will address both the efficacy of current treatment and quality of patients’ lives.

Summary of the Invention

The mammalian cell cilium protrudes from the apical surface of polarized cells, and acts as a sensor of extracellular stimuli to induce an intracellular response. On the organismal level, ciliary defects produce renal cyst, infertility, respiratory disorders, and predisposition to obesity, diabetes, and hypertension. However, the regulation of ciliary assembly and function has not been well understood. Researchers at the Fox Chase Cancer Center identified that the Aurora A kinase (AurA) and the scaffolding protein HEF1 affect formation and function of cilia. This discovery indicates a novel mechanism that impacts multiple signaling pathways and the strategy for the identification and assessment of compounds that modulate cilia. AurA is already regarded as a promising chemotherapeutic target, with agents inhibiting this protein in clinical trials. Thus, this study will lead to the creation of new therapeutic strategies by providing the basis to apply existing compounds in use and the development of new agents that treat ciliary genetic disorders, including PKD, and certain types of cancer.

Pugacheva E.N. et al. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell. 2007 Jun 29;129(7):1351-63.

Patent Status: US Patent # US 8,685,658 B2 issued April1, 2014

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