PYC-003

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a severe disease that leads to kidney failure

The most prevalent known monogenic disease

Affects 1 in every 1,000 people¹
There are ~160,000 patients in the US alone (qualifying as an orphan disease)
~80% of ADPKD cases are caused by mutations in one copy of the PKD1 gene²
Leading to insufficient PC1 protein expression in the renal tubular epithelial cells

Symptoms of ADPKD

It is a severe, progressive disease characterized primarily by the development and enlargement of fluid-filled renal cysts
The average size of a healthy kidney is a human fist. Polycystic kidneys can get much larger, reaching the size of a football.
50% of patients develop end-stage renal disease (ESRD) by age 60³
The average age of kidney failure for PKD1 patients is 55

ADPKD is caused by insufficient expression of one gene (PKD1) in the renal tubular epithelial cells of the kidney

Unaffected individual	ADPKD PATIENT		Genetic mechanism underlying disease pathology
		PKD1 DNA	80% of ADPKD cases are caused by mutations in one copy of the PKD1 gene¹
		PKD1 RNA	The mutation leads to an unstable RNA message that is rapidly degraded
		PC1 Protein	This leads to renal tubule epithelial cells of the kidney having half as much PC1 protein as they require to function normally – this protein is the rate-limiting modulator of cystic disease⁴


		Kidney Phenotype	Driving the formation of fluid filled cysts, ultimately leading to destruction of kidney function & architecture

PYC-003 is designed to increase PC1 expression to address the root cause of ADPKD

Unaffected
individual

PKD1 DNA
PKD1 RNA
PC1 Protein

Functional PC1 expression = 100%

2 ‘healthy’ copies of PKD1 results in functional PC1 protein expression

ADPKD
patient

PKD1 DNA
PKD1 RNA
PC1 Protein

Functional PC1 expression = ~50%-70%

80% of ADPKD patients have a mutation in one copy of the PKD1 gene¹, leading to insufficient PC1 protein expression (the rate limiting modulator of cystic disease⁴)

ADPKD patient treated
with PYC-003

PKD1 DNA
PKD1 RNA
PC1 Protein

Restoration of PC1 expression towards 100%

PYC-003 increases expression of the remaining healthy copy of PKD1 RNA to compensate for the PC1 protein insufficiency and reverse cyst formation

Treatment with PYC-003 results in decreased frequency and area of cysts in a 3D model of PKD derived from patients with late-stage disease

Untreated 3D cyst model

PYC-003 treated 3D cyst model

Treatment with PYC-003 results in decreased frequency and area of cysts in a 3D model of PKD derived from patients with late-stage disease. Images captured 7 days after treatment. Mock control samples treated with 5% H2O. Data are presented as mean+S.D (N=1 biological replicate with 4-6 technical replicates). Statistical significance was analyzed using Student’s t-test. *p=0.05, **p=0.01, ***p=0.005, ****p0.0001 . See https://www.crownbio.com/hubfs/WRCrownbio2021%20Assets/Resources/FactSheet/Crown-Bioscience-Factsheet-Cyst-Swelling-Assay-for-ADPKD.pdf for details of model and ASX release of 13 November 2023.

References

1. Willey et al. Analysis of Nationwide Data to Determine the Incidence and Diagnosed Prevalence of Autosomal Dominant Polycystic Kidney Disease in the USA: 2013-2015. Kidney Dis (Basel). 2019;5(2):107-17.
2. Cordido et al. The Genetic and Cellular Basis of Autosomal Dominant Polycystic Kidney Disease-A Primer for Clinicians. Front Pediatr. 2017;5:279.
3. Cloutier et al. The societal economic burden of autosomal dominant polycystic kidney disease in the United States. BMC Health Serv Res. 2020;20(1):126.
4. Lee SH, Somlo S. Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease. Kidney Res Clin Pract. 2014;33(2):73-8.
5. https://www.niddk.nih.gov/health-information/kidney-disease/polycystic-kidney-disease/what-is-pkd

Autosomal Dominant Polycystic Kidney Disease (ADPKD)