Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD)

Area of Science:

• Nephrology
• Molecular Biology
• Genetics

Background:

• Autosomal-dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by progressive kidney cyst formation, enlargement, hypertension, and eventual end-stage renal disease.
• Mutations in PKD1 or PKD2 disrupt polycystin function, leading to the loss of a crucial cyst-repressive signal from the renal cilium, a structure essential for ADPKD pathogenesis.
• Heat shock protein 90 (HSP90) is implicated in the maintenance of ciliary proteins, making it a potential therapeutic target.

Purpose of the Study:

• To investigate the therapeutic potential of inhibiting HSP90 with ganetespib in ADPKD.
• To elucidate the mechanism by which HSP90 inhibition affects ciliary function and cystogenesis in ADPKD.

Main Methods:

• In vitro experiments assessed ganetespib's effect on NEK8, trichoplein, Aurora-A kinase, and ciliary integrity.
• Conditional mouse models of ADPKD were used for long-term in vivo dosing studies (10 or 50 weeks).
• Evaluated the impact of ganetespib on ciliary loss, cystic growth, and ADPKD-related symptoms, including combination therapy with 2-deoxy-d-glucose.

Main Results:

• Ganetespib inhibited proteasomal repression of NEK8 and trichoplein, leading to rapid Aurora-A kinase activation and in vitro ciliary loss.
• Long-term in vivo administration of ganetespib resulted in durable loss of cilia in ADPKD mouse models.
• HSP90 inhibition effectively controlled cystic growth and ameliorated symptoms in Pkd1 and Pkd2 loss-of-function models.
• Combination therapy with 2-deoxy-d-glucose did not enhance ganetespib's efficacy.

Conclusions:

• HSP90 inhibition represents a novel therapeutic strategy for ADPKD by disrupting ciliary function and limiting cystogenesis.
• Ganetespib demonstrates significant in vivo efficacy in controlling ADPKD progression in mouse models.
• These findings support a cilia-based mechanism for cyst repression and highlight HSP90 as a viable therapeutic target for ADPKD.