ACMSD inhibition offers potential benefit across a broad range of liver and kidney diseases
MENLO PARK, Calif.--(BUSINESS WIRE)--#OrsoBio--OrsoBio, Inc. (“OrsoBio” or “the Company”), a clinical-stage biopharmaceutical company developing treatments for obesity and obesity-associated disorders, together with a team of academic researchers from Europe, Japan, and the United States, published promising preclinical data regarding the potential of ACMSD inhibition in animal and cellular models of metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH). In addition to enhancing synthesis of NAD+, a key co-factor in diverse bodily processes, the researchers discovered that ACMSD inhibition prevents DNA damage and cellular redox stress, leading to significantly reduced inflammation and fibrosis due to MASH.
“We see tremendous therapeutic potential in ACMSD inhibitors across a spectrum of metabolic and inflammatory hepatic and renal diseases,” said Mani Subramanian, MD, PhD, Chief Executive Officer of OrsoBio. “The mechanism of action of ACMSD inhibition is highly complementary to our broader portfolio, including mitochondrial protonophores and an ACC2 inhibitor, as they target causal drivers of inflammation and fibrosis. Their potential therapeutic impact extends well beyond the obesity-associated diseases that are the focus of the rest of our pipeline.”
The study, published in the Journal of Hepatology, investigates the mechanistic role and therapeutic implications of inhibiting a key enzyme involved in cellular energy metabolism for the potential treatment of MASLD/MASH. Researchers found that inhibition of ACMSD (aminocarboxymuconate semialdehyde decarboxylase), an enzyme restricted to liver and kidney, enhances de novo NAD+ synthesis and significantly reduces DNA damage responses in liver, thereby preventing MASLD/MASH progression.1 These findings were reproduced in mouse models and in a human liver organoid (HLO) model of steatohepatitis.
“Enhancing NAD+ levels in hepatocytes represents an attractive yet underexplored area for preventing redox stress. We observed that inhibiting ACMSD in human hepatocytes, both ex vivo and in vivo, increases NAD+ levels, enhances mitochondrial respiration, and helps maintain genomic stability,” said Takanori Takebe, MD, PhD, Associate Professor at Cincinnati Children’s Hospital Medical Center and a scientific advisor to OrsoBio. “Here, we have reproduced our earlier findings from a study published in Cell that demonstrated the benefits of alternative approaches to cellular NAD+/redox/mitochondrial modulation in a MASH organoid model from human induced pluripotent stem cells (iPSCs).2 Importantly, ACMSD inhibition alleviated phenotypes found in MASH organoids even from iPSCs of genetically at-risk individuals.”
“Prevention and delayed progression of organ injury in the setting of acute and chronic liver and kidney diseases is a major unmet medical need,” said Johan Auwerx, MD, PhD, Professor at the École Polytechnique Fédérale de Lausanne (EFPL), Switzerland, and a scientific advisor to OrsoBio. “This research suggests that pharmacologic ACMSD inhibition could have a role in advanced disease where there is both metabolic and mitochondrial dysfunction leading to cellular redox mediated exacerbation of the DNA damage response, which sustains progressive inflammation and fibrosis. We look forward to continued collaboration with the OrsoBio team to evaluate the benefits of ACMSD inhibition as monotherapy and in combination with other mechanisms to better understand its therapeutic potential.”
A range of proprietary compounds within OrsoBio’s ACMSD inhibitor portfolio are currently being evaluated for their potential to replenish NAD+ and improve mitochondrial function in metabolic and inflammatory liver and kidney disorders. The company plans to complete lead optimization and IND-enabling activities in 2025.
About ACMSD
ACMSD (aminocarboxymuconate semialdehyde decarboxylase) is a key enzyme involved in the de novo synthesis of NAD+ from tryptophan. Enhancing NAD+ synthesis by silencing or inhibiting ACMSD improves mitochondrial function, increases the lifespan of C. elegans, and protects against liver and kidney injury in mice. OrsoBio’s preclinical portfolio of ACMSD inhibitors is being advanced for the treatment of a range of metabolic and inflammatory liver and kidney disorders.
About OrsoBio, Inc.
OrsoBio, Inc. is a privately held, clinical-stage biopharmaceutical company dedicated to developing therapies to treat obesity and obesity-associated disorders, including type 2 diabetes, MASH, and severe dyslipidemias. OrsoBio currently has four programs in clinical and preclinical development with first-in-class compounds that address central pathways in energy metabolism. For more information, please visit www.orsobio.com.
1 Liu YJ, et al. J Hepatol 2024 Aug 22:S0168-8278(24)02484-X. doi: 10.1016/j.jhep.2024.08.009. Available: https://www.journal-of-hepatology.eu/article/S0168-8278(24)02484-X/fulltext.
2 Kimura M, et al. Cell 2022;185(22):4216-4232.e16. doi: 10.1016/j.cell.2022.09.031. Available: https://www.cell.com/cell/fulltext/S0092-8674(22)01250-8.
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