Novel therapy for alcoholic liver disease-associated hepatorenal syndrome

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Novel therapy for alcoholic liver disease-associated hepatorenal syndrome Abstract Alcoholic liver disease (ALD) results in over 400,000 hospitalizations each year in the US, with a portion of these patients developing hepatorenal syndrome with acute kidney injury (HRS-AKI). There are no current therapeutic options that specifically address the cellular dysfunction and systemic inflammatory response that leads to progressive organ failure mediated by mitochondrial dysfunction and oxidative stress by direct alcohol-mediated toxicity. This leads to impaired hepatocyte and renal function, worsening organ failure, and the need for protective renal and hepatic therapies with the goal of improving clinical outcomes for patients who develop HRS-AKI. Nicotinamide adenine dinucleotide (NAD+) is a hallmark of aging-related disease for the liver and kidney. Decreased levels and impaired synthesis of NAD+ are found in ALD accompanied by increased de novo lipogenesis and impaired mitochondrial oxidation made possible by the role of alcohol in NAD+ depletion and impaired cellular function. NAD+ supplementation with the NAD+ precursor nicotinamide riboside (NR) reverses alcohol-induced changes by increasing NAD+ levels in tissue culture, enhancing mitochondrial oxidation, mitochondrial biogenesis, and gene expression. In animal models, NAD+ supplementation with NR has been shown to improve liver histology, reduce liver injury and protect the kidneys against ischemic injury and DNA damage preventing progressive worsening of renal injury. 2,4 dihydronicotinamide riboside (NRH), , a recently identified highly potent NAD+ precursor, consistently increases intracellular NAD+ levels to a greater extent than NR in liver and kidney, is stable in serum, and in addition acts as a highly potent immune modulator to dampen the systemic inflammatory state. Given the significant depletion in NAD+ levels in both liver and kidney in patients with ALD, NRH has the potential to reverse or prevent progression of HRS-AKI in ALD patients in combination with the standard of care. In this Fast Track study, we will complete IND-enabling studies of our proprietary intravenous formulation of NRH, MP04, followed by a Phase 1 clinical trial to investigate its safety and tolerability in humans. The outcome of this work will be a novel therapeutic for ALD-associated HRS.