# Novel therapy for alcoholic liver disease-associated hepatorenal syndrome

> **NIH NIH U44** · MITOPOWER LLC · 2023 · $1,500,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10875889
- **Project number:** 4U44AA029833-03
- **Recipient organization:** MITOPOWER LLC
- **Principal Investigator:** Shyamasundaran Kottilil
- **Activity code:** U44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,500,000
- **Award type:** 4N
- **Project period:** 2021-09-25 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875889

## Citation

> US National Institutes of Health, RePORTER application 10875889, Novel therapy for alcoholic liver disease-associated hepatorenal syndrome (4U44AA029833-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10875889. Licensed CC0.

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