GPCRs in kidney disease
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Kidney disease still has relatively low standards of care and has experienced massive underinvestment when compared to oncology, cardiovascular, and diabetes. Third Rock Ventures formed a platform company called Goldfinch Bio to sequence over 2000 kidney disease patients and develop organoids to identify new drug candidates. One of the most important and potentially lucrative kidney disease indications is autosomal dominant polycystic kidney disease (PKD). Classified just barely as a rare disease with a standard of care with severe side effects (i.e. Jynarque by Otsuka approved in April 2018). Any new drug for PKD will have a low bar to cross as well as have advantages of fast track development and as large of a patient population a rare disease can be. PKD is a genetic disorder characterized by formation of cysts within kidneys driven by two genes: polycystin-1 (PC-1 - 85% of all cases) and polycystin-2 (PC-2). In particular, PC-1 is a purported GPCR with a currently unknown mechanism-of-action. PKD eventually progresses to end stage renal disease leading to transplantation or dialysis. According to the NIH, patient with PKD develop end stage renal disease on average at 57 years of age and is responsible for 4.5% and 2.2% of all cases and new cases, respectively. For any company focused on drugging GPCRs, PC-1 as well as PC-2 are extremely attractive targets. An agonist against either target would bring higher quality of life for PKD patients by reducing cyst size from football size to a baseball.
Overview of PKD
Autosomal dominant polycystic kidney disease is the most common inherited disorder for kidneys (~90% of all PKD cases are dominant meaning that the disease often persists within a family for generations). It is the fourth leading cause of kidney failure and more than 50% of people with ADPKD will develop kidney failure by age 50. Symptoms (i.e. cysts) often appears around 30 or 40 and is usually diagnosed by kidney imaging studies with genetic testing for confirmation. Fluid-filled cysts develop and enlarge in both kidneys eventually leading to kidney failure - the average size of a typical kidney is a human fist; polycystic kidneys can get much large some growing as large as a football and weighing up to 30 pounds each.
ADPKD is a systemic disease, with cysts developing in other organs as well—most frequently, in the liver and pancreas. Additional extrarenal manifestations associated with ADPKD include cardiac disease and intracranial aneurysms. Progression of the disease leads to an increase in the number and volume of cysts and an increase in kidney volume, which lead to a decline in renal function, renal inflammation, fibrosis, and ESRD. By the time there is a decline in renal function, the enlarged kidney is distorted, with little recognizable parenchyma. Along with renal decline, disease complications include polycystic liver disease, cardiac disease, hypertension, hematuria, urinary tract infections, renal stones, and renal pain. ADPKD is a chronic disease that evolves over a lifetime. Mild symptoms in early stages typically go undiagnosed as ADPKD. The majority of cases are due to PKD1 mutations, and by definition, progress more rapidly. The symptoms caused by ADPKD contribute to substantial morbidity and impairment of quality of life, as well as costs to society, as these undiagnosed symptoms progress. Although few studies have investigated the impact of symptoms on quality of life in patients with ADPKD, chronic pain is evidently a significant complication; therefore, pain management is an important consideration in patients with ADPKD. A recent study of patients with early ADPKD from the Polycystic Kidney Disease Treatment Network (the HALT PKD Trial) demonstrated that symptoms relating to abdominal fullness and pain are greater in patients with more advanced disease, possibly due to organ enlargement. Similarly, little has been reported on the economic burden of ADPKD. In contrast, chronic kidney disease (CKD) has been investigated extensively and is recognized as a source of substantial morbidity and economic burden with clear associations between kidney dysfunction and adverse outcomes, leading to hospitalizations, resource utilization, and mortality. As ADPKD is both among the leading causes of ESRD and the leading heritable cause, it is important for US healthcare payers to understand this genetic disorder and the healthcare resource utilization and costs associated with it. Here we review the available ADPKD literature, published between 2003 and 2013, to characterize the impact of ADPKD on patients and healthcare systems, and to assess any current gaps in the available evidence that hinder either a better understanding of the disease or the need for effective therapies, as there is currently no treatment for ADPKD. Better understanding and earlier diagnosis of the disease may lead to improved treatment of complications.
ADPKD is a systemic disease with various renal and extra-renal manifestations, and it therefore confers a heavy burden on patients and caregivers, leading to increased healthcare resource utilization and costs. Despite this impact, there is a clear lack of studies in the literature directly evaluating the humanistic or economic burden of ADPKD. While pain is consistently reported by patients with ADPKD,11 no evidence was identified that established a definitive correlation between disease severity or progression and health-related quality of life. However, a recent report of the HALT-PKD trials showed that symptoms relating to abdominal fullness and pain are greater in patients with more advanced disease. Additionally, while a relationship between loss of kidney function and increasing healthcare costs has been shown, definitive cost-of-care data for patients with ADPKD has not been reported.
What are the symptoms of autosomal dominant PKD? The most common symptoms are pain in the back and the sides—between the ribs and hips—and headaches. The pain can be temporary or persistent, mild or severe. People with autosomal dominant PKD also can experience the following complications:
Urinary tract infections—specifically, in the kidney cysts
Hematuria—blood in the urine
Liver and pancreatic cysts
Abnormal heart valves
High blood pressure
Kidney stones
Aneurysms—bulges in the walls of blood vessels—in the brain
Diverticulosis—small pouches bulge outward through the colon
PC-1
PC-1 is an atypical GPCR with 11 transmembrane-spanning regions showing the capabilities to transmit physical cues from the external environment into the cell via cilia localization (i.e. mechanosensation). PC-1 selectively binds multiple classes of Gα subunits at a specific stretch of 20 amino acids in the COOH terminus. PC-1 also has a highly conserved autoproteolytic site, GPCR proteolysis site (GPS) within a GPCR-Autoproteolytic Inducing (GAIN) domain located on the NH2-terminal side of the first transmembrane span. GAIN domains are often found in cell adhesion GPCRs, a class overexpressed in main kidney diseases especially oncology, maintain tubular epithelial cell morphology. Likely, PC-1 is a ligand-independent GPCR.
More materials:
https://jasn.asnjournals.org/content/jnephrol/20/1/1.full.pdf
https://jasn.asnjournals.org/content/20/1/1
Other adhesion GPCRs (aGPCR) of interest
Out of the 33 human aGPCRs, 18 are overexpressed in kidney disease when compared to healthy counterparties with 12 cases have fold changes well over 3. With GPCRs have many roles in cell signalling, it is expected they have an important role in kidney disease where the key drivers are inflammation, ischemia, hypoxia, fibrosis, and metabolic waste accumulation.
Adgrb1 suppresses renal cell carcinoma angiogenesis
Adgrg2 promotes invasiveness in clear cell renal cell carcinoma
Adgrl2, Adgrl4, Adgre1, Adgre5, Adgrg2, and Adgrg6 all involved in lupus nephritis and diabetic nephropathy
Business models in drug development made a shift from blockbusters to rare disease candidates 2-3 decades ago. As a result, going after PC-1/2 is still a viable approach. Over time, new models around measuring value and reimbursement for outcomes will probably become more prevalent. For any company drugging GPCRs, both characterized and orphaned, going after targets with drugs that not only treat the disease but exceed the standard of care will become increasingly important. PC-1/2 fits these criteria as well.
