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Therapeutic α-1-mic...
Therapeutic α-1-microglobulin ameliorates kidney ischemia-reperfusion injury.
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- Burmakin, Mikhail (author)
- Karolinska Institutet,Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, Huddinge, Sweden; Guard Therapeutics International AB, Stockholm, Sweden
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- Gilmour, Peter S (author)
- Guard Therapeutics International AB, Stockholm, Sweden
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- Gram, Magnus (author)
- Malmö universitet,Institutionen för biomedicinsk vetenskap (BMV),Biofilms Research Center for Biointerfaces,Pediatrics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Department of Neonatology, Skåne University Hospital, Lund, Sweden
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- Shushakova, Nelli (author)
- Renal Disease and Transplantation, Phenos GmbH, Hannover, Germany; Department of Nephrology, Hannover Medical School, Hannover, Germany
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- Sandoval, Ruben M (author)
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
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- Molitoris, Bruce A (author)
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
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- Larsson, Tobias E (author)
- Guard Therapeutics International AB, Stockholm, Sweden; Division of Nephrology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Sweden
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(creator_code:org_t)
- American Physiological Society, 2024
- 2024
- English.
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In: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 327:1, s. F103-F112
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- α-1-Microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme-binding, and mitochondrial protection properties. The investigational drug RMC-035, a modified therapeutic A1M protein, was assessed for biodistribution and pharmacological activity in a broad set of in vitro and in vivo experiments, supporting its clinical development. Efficacy and treatment posology were assessed in various models of kidney ischemia and reperfusion injury (IRI). Real-time glomerular filtration rate (GFR), functional renal biomarkers, tubular injury biomarkers (NGAL and KIM-1), and histopathology were evaluated. Fluorescently labeled RMC-035 was used to assess biodistribution. RMC-035 demonstrated consistent and reproducible kidney protection in rat IRI models as well as in a model of IRI imposed on renal impairment and in a mouse IRI model, where it reduced mortality. Its pharmacological activity was most pronounced with combined dosing pre- and post-ischemia and weaker with either pre- or post-ischemia dosing alone. RMC-035 rapidly distributed to the kidneys via glomerular filtration and selective luminal uptake by proximal tubular cells. IRI-induced expression of kidney heme oxygenase-1 was inhibited by RMC-035, consistent with its antioxidative properties. RMC-035 also dampened IRI-associated inflammation and improved mitochondrial function, as shown by tubular autofluorescence. Taken together, the efficacy of RMC-035 is congruent with its targeted mechanism(s) and biodistribution profile, supporting its further clinical evaluation as a novel kidney-protective therapy.NEW & NOTEWORTHY A therapeutic A1M protein variant (RMC-035) is currently in phase 2 clinical development for renal protection in patients undergoing open-chest cardiac surgery. It targets several key pathways underlying kidney injury in this patient group, including oxidative stress, heme toxicity, and mitochondrial dysfunction. RMC-035 is rapidly eliminated from plasma, distributing to kidney proximal tubules, and demonstrates dose-dependent efficacy in numerous models of ischemia-reperfusion injury, particularly when administered before ischemia. These results support its continued clinical evaluation.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Urologi och njurmedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Urology and Nephrology (hsv//eng)
Keyword
- A1M
- IRI
- kidney injury
- proximal tubules
Publication and Content Type
- ref (subject category)
- art (subject category)
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