Treatment of kidney diseases associated with elevated AVP
Inventors
Kishore, Bellamkonda K. • Zhang, Yue • Carlson, Noel G.
Assignees
US Department of Veterans Affairs
Publication Number
US-11354990-B2
Publication Date
2022-06-07
Expiration Date
2038-01-31
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Abstract
Disclosed are methods for treating kidney disease including autosomal dominant polycystic kidney disease (ADPKD) in a subject, comprising the step of administering to the subject a composition comprising a therapeutically effective amount of ticagrelor or a derivative thereof, thereby treating ADPKD. Disclosed are methods of decreasing arginine vasopressin (AVP) production in a subject comprising the step of administering to the subject a composition comprising an effective amount of ticagrelor, thereby decreasing AVP production. Disclosed are methods for treating dilutional hyponatremia in a subject comprising the step of administering to the subject a composition comprising an effective amount of ticagrelor, thereby decreasing AVP production.
Core Innovation
The invention discloses methods for treating kidney diseases, particularly autosomal dominant polycystic kidney disease (ADPKD), in subjects by administering a therapeutically effective amount of ticagrelor or its derivatives. The treatment includes decreasing the production of arginine vasopressin (AVP) thereby lowering circulating levels of AVP, which is associated with the progression of kidney diseases linked to elevated AVP levels. The treatment with ticagrelor aims to reduce cyst number and/or size or prevent increase in kidney size, and also potentially ameliorate symptoms associated with these diseases.
The problem addressed is the lack of specific therapies for ADPKD, the most common inherited kidney disease characterized by cyst formation and progressive kidney function decline leading to end-stage renal disease. Current management controls blood pressure and symptoms but lacks effective treatments with sustainable long-term safety, and existing approaches to slow cyst growth have significant side effects. Importantly, elevated AVP levels contribute to ADPKD progression by stimulating cAMP production in renal collecting duct cells, promoting cyst growth. Thus, a treatment that safely reduces AVP production and activity is needed.
The invention identifies ticagrelor, previously used as an anti-clotting drug, as effective in reducing AVP production by the hypothalamus, thereby decreasing AVP-dependent signaling pathways implicated in kidney cyst growth. This approach differentiates from existing therapies like V2 receptor antagonists by decreasing AVP production itself, potentially offering a long-term treatment option with a known safety profile and more tolerable side effects. The methods can also include administering ticagrelor in combination with other therapeutics targeting different pathways.
Claims Coverage
The patent includes one independent claim focused on methods for lowering circulating AVP levels in subjects using ticagrelor. The claim covers multiple inventive features related to the treatment mechanism, target cells, and administration regimens.
Method for lowering circulating levels of AVP using ticagrelor
Administering to a subject an effective amount of a composition comprising ticagrelor to lower circulating levels of arginine vasopressin (AVP) in the subject.
Treatment of diseases associated with elevated AVP
Using ticagrelor to treat subjects with various diseases, including ADPKD, by lowering AVP, thereby reducing signaling through AVP-dependent V2 and V1 receptors, which in turn slows or reverses diseases associated with elevated AVP.
Targeting renal collecting duct cells to reduce cAMP
Lowering AVP levels reduces signaling in renal collecting duct cells, specifically principal cells, lowering cAMP levels, decreasing aquaporin protein expression and translocation (AQP2 and AQP3), leading to decreased water reabsorption and increased urine output.
Versatility and administration of ticagrelor
Applicable to multiple subject species, including humans and various mammals, including those diagnosed with kidney diseases. The method may include additional therapeutics and various administration routes, with a long-term treatment regimen of at least two weeks.
The claims comprehensively cover the use of ticagrelor to reduce circulating AVP levels in subjects, targeting biological mechanisms that reduce kidney disease progression, particularly ADPKD. The claims encompass treatment regimens, target cells, effects on AVP-dependent signaling, and flexible administration methods.
Stated Advantages
Ticagrelor offers a new treatment for kidney diseases associated with elevated AVP (such as ADPKD) with known long-term safety.
The methods potentially reduce cyst growth and kidney enlargement with fewer and tolerable side effects compared to current therapies like tolvaptan.
Ticagrelor decreases AVP production by the hypothalamus, reducing dependence on blocking V2 receptor directly, which may avoid compensatory AVP increases and associated unknown effects via other receptors.
Administration of ticagrelor provides added cardiovascular protection not offered by existing vasopressin V2 receptor antagonists.
Documented Applications
Treatment of autosomal dominant polycystic kidney disease (ADPKD) by reducing cyst number and/or size and stabilizing kidney size.
Treatment of diseases associated with elevated arginine vasopressin (AVP), including hypertension, preeclampsia, congestive heart failure, cardiorenal syndrome, cirrhosis of liver, diabetic ketoacidosis, post-traumatic stress disorder (PTSD), autism spectrum disorder, syndrome of inappropriate antidiuretic hormone secretion (SIADH), dilutional hyponatremia, and diseases associated with elevated AVP-V2 receptor-cAMP axis activity.
Decreasing AVP production in the hypothalamus and lowering circulating AVP levels to ameliorate associated symptoms.
Using ticagrelor in combination with other therapeutics such as mTOR inhibitors, somatostatin analogues, vasopressin V2 receptor antagonists, and epidermal growth factor receptor inhibitors.
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