Renal ciliopathies: promising drug targets and prospects for clinical trials

Figures & data

Figure 1. Clinical phenotypes and molecular genetics of renal ciliopathies.

Note:Variability in the age of onset of KF and the median age of onset of clinical symptoms are shown as extended diamond bars. ADPKD mostly presents in adulthood (30-40 years of age) although a small proportion of cases reported in early life (1-10 years of age) due to biallelic or digenic or severe loss of function PKD1/PKD2 variants. The age of presentation for ARPKD varies with approximately one third of patients presenting before 1 year of age, one third between 1 and 20 years of age and one third after 20 years with mutations in PKHD1 being the most common cause. In juvenile NPHP, KF develops at a median age of 13 years whereas in adult form, which is clinically and histologically similar to the juvenile NPHP, KF develops after 15-20 years of age. Infantile NPHP is rare with KF appearing during first year of life. The current clinical trials with name of the drug, ClinicalTrials.gov identifier number and the age range of patients the study is recruiting is shown for ADPKD and ARPKD. There are currently no clinical trials in progress for NPHP. (Created using BioRender.com).

Figure 2. Renal ciliopathies and potential drug targets and prospects for clinical trials.

Note: Summary diagram showing the molecular pathways and the therapeutic targets studied in cell based and rodent models (highlighted in green) and those studied in human clinical trials (highlighted in blue) in renal ciliopathies. The drug names are shown in red. (Created using BioRender.com).

Table 1. Molecular targets, drug compounds, preclinical trials, and clinical trials for renal ciliopathies.

Molecular target	Pathway	Renal Ciliopathy Disease	Drug Compound	Preclinical Studies	Clinical trials	References
Transmembrane Channels
Vasopressin receptor 2 (VR2)	VR2 activation increases cAMP and PKA, promoting AQP2 localisation to membrane and increased water reabsorption and fluid secretion.	Upregulated in ADPKD, ARPKD and NPHP, increasing epithelial cell proliferation and fluid secretion promoting cystogenesis.	Tolvaptan (AV2R inhibitor)	PCK rat (ARPKD), pcy mouse (NPHP), Pkd1 mouse (ADPKD)	ADPKD, ARPKD	[45,131–135]
			Lixivaptan (AV2R inhibitor)	MCD4 cells, PCK rat (ARPKD).	ADPKD	[136,137]
Cystic fibrosis transmembrane conductance regulator (CFTR)	Channels contribute to increased chloride secretion in renal tubules.	Upregulated in ADPKD, contributing to increased chloride transport and fluid secretion, promoting cystogenesis.	CFTR inhibitors (CFTR inhibitor) (Tetrazolo-CFTR-172, Ph-GlyH-101)	Pkd1 mouse (ADPKD)	N/A	[138]
			Lumacaftor (CFTR corrector and potentiator)	Pkd1 mouse (ADPKD)	N/A	[139]
Transmembrane protein 16 A (TMEM16A)			Niclosamide (CFTR inhibitor)	Pkd1 (ADPKD)	N/A	[140]
			Benzbromarone (CFTR inhibitor)	Pkd1 (ADPKD)	N/A	[140]
			Ani9 (CFTR inhibitor)	Pkd1 (ADPKD)	N/A	[140]
Peroxisome proliferator-activator receptor gamma (PPARγ)	PPARγ inhibits the synthesis of CFTR and ERK signaling.		Pioglitazone (PPARγ inhibitors)	MDCK-C7, PCK rat (ARPKD), Pkd1 (ADPKD)	ADPKD	[141–146]
			Rosiglitazone (PPARγ inhibitors)	MDCK-C7, Han:SPRD rat (NPHP)	N/A	[142,145]
Lipids
Hydroxy-3-methylglutarylCoA reductase	Statins are Hydroxy-3-methylglutarylCoA reductase inhibitors which modulate lipids and effect AMPK activation.		Lovastatin (HMG-CoA inhibitors)	Han:SPRD rat (NPHP)	N/A	[147]
			Simvastatin (HMG-CoA inhibitors)		ADPKD	[148]
			Pravastatin (HMG-CoA inhibitors)		ADPKD	[149]
Glycosphingolipids	Components of ciliary membrane and effectors of ciliary signaling.	Glycosphingolipids accumulate in PKD models.	Genz-123346	Pkd1 mice (ADPKD), jck mice, pcy mice (NPHP)	N/A	[150]
			Venglustat (Glucosylceramide synthase inhibitor)		ADPKD	[151]
Inflammation
Cyclooxygenase 2 (COX2)	COX2 is a prostaglandin metaboliser, and contributes to inflammation.	COX2 is upregulated in PKD and NPHP disease models.	Celecoxib (COX2 inhibitors)	Pkd2 mouse (ADPKD), Han:SPRD rat (NPHP)	N/A	[152–154]
			Flax-oil diet	pcy mouse (NPHP)	N/A	[155]
Nuclear factor erythroid 2 like-2 (NFR2)	NFR2 promotes antioxidant activity, and negatively regulates primary ciliogenesis and Hh signaling.		Bardoxolone (promote NFR2 activation)		ADPKD, PKD patents	[156–159]
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB)	NF-KB is a pro-inflammatory cytokine		Triptolide (NF-KB inhibitor)	Pkd1 mouse (ADPKD)	N/A	[160]
Cellular Metabolism
Mammalian target of Rapamycin (mTOR) complex 1	mTOR pathway is a central regulator of cellular metabolism, protein translation, growth and cell cycle regulation, integrating other pathways including IGF and AMPK.	mTOR pathway is aberrantly activated in renal ciliopathies, stimulating uncontrolled cell growth and proliferation, driving cystogenesis.	Rapamycin/Sirolimus (mTORC1 inhibitor)	Orpk mouse (ADPKD), Bpk mouse (ARPKD), Pkd1 mouse (ADPKD) Pkd2 (ADPKD), pcy mouse (NPHP), Han:SPRD rat (NPHP), NPHP zebrafish models, Lpk rat (NPHP)	ADPKD	[27,28,161–170]
			TORKi (mTORC1 inhibitor)	Pkd1 mouse (ADPKD)	N/A	[171]
			Everolimus	Han:SPRD rat (NPHP)	ADPKD	[172,173]
c-Src	Epidermal growth factor (EGF) signaling activates RAF/MEK pathways to drive cellular proliferation and cystogenesis. C-Src phosphorylates and activates the EGF receptor.	EGF is upregulated in PKD/	Tesevatinib (multikinease inhibitor of c-Src)	Bpk mice (ARPKD)	ADPKD, ARPKD	[132,174,175]
			Bosutinib (multikinease inhibitor of c-Src)	Bpk mice (ARPKD), PCK rat (ARPKD), Pkd1 mouse (ADPKD)	ADPKD	[176–178]
			EGF inhibitors	Bpk mice (ARPKD), Han:SPRD rat (NPHP)	N/A	[174,179]
			Sorafenib (multi-kinase inhibitor of c-Src)	Human ADPKD cells	N/A	[180]
MAPK/ERK	MAPK/ERK pathways stimulate increased cellular proliferation and promote cystogenesis.		PD184352 (MAPK/ERK inhibitor)	pcy mice (NPHP), and inv mice (NPHP)	N/A	[181,182]
Somatostatin	Somatostatin is a growth factor negative regulator, and inhibitor of insulin and glucagon secretion, whilst lowering cAMP.		Lanreotide (somatostatin analogue)		ADPKD	[183–186]
			Octreotide (somatostatin analogue)	PCK rat (ARPKD) Nphp 2, 6, 8 KO spheroids	ADPKD	[183,187–190]
			Pasireotide (somatostatin analogue)	PCK rat (ARPKD), Pkd2 mouse (ADPKD)	ADPKD	[187,191]
AMP-activated protein kinase (AMPK)	AMPK signaling senses low ATP and mitochondrial function. It is negatively regulated by CFTR and mTOR.	PKD have impaired mitochondrial function and are prone to ER stress and increased ROS.	Metformin (AMPK activator)	Pkd1 (ADPKD), Zebrafish Pkd2 (ADPKD)	ADPKD	[149,192–196]
			Salsalate (AMPK inhibitor)	Pkd1 mouse (ADPKD)	N/A	[197]
Aerobic glycolysis	Conversion of glucose into pyruvate.	PKD models show shift in energy production from oxidative phosphorpylation to glycolysis.	2-deoxyglucose (glycolysis inhibitor)	Pkd1 mouse	N/A	[198]
Calmodulin-dependent protein kinase II (CaMKII)	Transducer of Ca2+ signaling, vital in mitochondrial function.	PKD have impaired mitochondrial function and are prone to ER stress and increased ROS.	CAMKII inhibitors	jck mice	N/A	[199]
Prostaglandin receptors	Prostaglandin signaling increases cAMP.	NPHP models sometimes show reduction in cAMP signaling.	PGE2 inhibitors	Nphp1 mice	N/A	[200]
Angiogenesis
VEGF Receptors	VEGF signaling promotes angiogenesis.	Increased angiogenesis is thought to promote cystogenesis.	VEGFR inhibitors	Han:SPRD rat (NPHP)	N/A	[201]
Ciliary signalling
Hedgehog (Hh)	Hh signaling is required for renal development, renal cell proliferation and has roles in fibrosis.	Hh signaling is dysregulated in renal ciliopathies.	Purmorphamine (Hh agonist)	Cep290 mouse model and human cells (NPHP)	N/A	[116]
			Gantb1 (Gli inhibitor)	Pkd1, jck, Ttc21b/Ift39 mouse (ADPKD, NPHP)	N/A	[202]
			Sant2 (Smo inhibitor)	Pkd1, jck, Ttc21b/Ift39 mouse (ADPKD, NPHP)	N/A	[202]
Cilium disassembly
Histone deacetylase 6 (HDAC6)	HDAC6 mediates cilium disassembly and is associated with heat shock protein 90 (HSP90).	In preclinical ADPKD models, HDAC6 and HSP90 are upregulated.	ACY-1215 (HDAC6 inhibitor)	PC1 (cells), PC1 (mouse)	N/A	[203]
			Tubacin (HDAC6 inhibitor)	MDCK cells, Pkd1 mouse (ADPKD)	N/A	[204]
			Trichostatin A (HDAC6 inhibitor)	Pkd2 zebrafish (ADPKD), Pkd2 mouse	N/A	[205,206]
			Valproic acid (VPA) (HDAC6 inhibitor)	Pkd2 zebrafish (ADPKD), Pkd1;Pkhd1 mouse (PKD)	N/A	[205]
			Nicotinamide (HDAC6 inhibitor)	Pkd1 mouse	ADPKD [175]	[175,207]
Heat shock protein 90 (HSP90)		HSP90 is increased in ADPKD models of disease	Ganetespib	Pkd1 mouse and Pkd2 mouse	N/A	[208]
			STA-2842	Pkd1 mouse (ADPKD)	N/A	[209]
Cell cycle regulation/DNA damage response
Cyclin dependent kinases (CDK)	CDK regulate the cell cycle and is used in DNA damage response (DDR) to arrest the cell cycle to remove damaged cells or allow for repair.	Cystogenesis is often driven by hyperproliferation of epithelial cells lining the cysts.	Roscovitine (CDK 1,2,5,7,9 inhibitor)	Pkd1 mouse (ADPKD), jck mouse (NPHP), Cpk mouse (ARPKD), Cep164 mouse (NPHP)	N/A	[30,210–213]
			CDK inhibitors	Cep290 mice and human cells	N/A	[214]
Cell division cycle 25 A (Cdc25A)	Cdc25A is involved in cell cycle regulation.	Cdc25A overexpressed in PKD mouse models.	Menadione (vitamin K3) (Cdc25A inhibitor)	Pkhd1 (ARPKD)	N/A	[215]
Genetic Therapies
MicroRNAs 17	Short-coding miRNA17 decreases PC1 and PC2 expression and affects mitochondrial function.	MicroRNA17s are upregulated in ADPKD murine models.	miR-17 inhibitors	Pkd1 (ADPKD)		[216]
			RGLS4326	Pkd2 (ADPKD)	ADPKD	[217,218]
The causative genetic mutation, targeted by ASOs.		The aim is to correct the causative genetic defect or modifier alleles, by binding to target mRNA to alter mRNA expression or splicing.	Cep290 ASOs	Cep290 mouse and human cells (NPHP)	N/A	[219]
			BSND ASOs	Cep290 mouse (NPHP)	N/A	[220]

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