Methods and compositions for detecting and diagnosing diseases and conditions
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Publication Number
US-12297502-B2
Publication Date
2025-05-13
Expiration Date
Abstract
The disclosure provides methods for detecting and diagnosing diseases and conditions associated with defects in cardiolipin remodeling. In some embodiments, the present technology relates to methods for detecting the presence or amount of cardiolipin isoforms and/or the presence or amount of enzymes involved in cardiolipin remodeling.
Core Innovation
The disclosure relates to cardiolipin-remodeling–based methods for monitoring and treating a subject for heart failure and for assessing mitochondrial dysfunction. The approach includes detecting levels of monolysocardiolipin acyltransferase (MLCL AT1) or acyl-CoA lysocardiolipin (ALCAT1) mRNA in a biological sample from the subject, and the detected MLCL AT1 or ALCAT1 mRNA level is compared to a normal control sample.
Subjects with elevated MLCL AT1 or ALCAT1 mRNA are selected for aromatic-cationic peptide treatment. The aromatic-cationic peptide is D-Arg-2′-Dmt-Lys-Phe-NH2 or a pharmaceutically acceptable salt thereof, and treatment increases the expression of TAZ1 in the myocardium of the subject.
The disclosure also frames cardiolipin isoforms and cardiolipin remodeling enzymes as monitoring readouts in connection with mitochondrial dysfunction and heart failure. It includes cardiolipin isoform measurement and comparison to normal controls, together with remodeling enzyme and mRNA expression assessments, and provides illustrative diagnostic examples using lipidomics and qPCR-based readouts.
Claims Coverage
The document provides one independent claim with multiple dependent claims that refine how mRNA and cardiolipin isoforms are detected, how subjects are selected, and how the aromatic-cationic peptide treatment is administered. Across the claim set, the inventive features focus on MLCL AT1/ALCAT1 mRNA detection, selection based on elevated mRNA relative to normal controls, and peptide administration to increase TAZ1 expression in the myocardium.
Monitoring and treating heart failure via MLCL AT1 or ALCAT1 mRNA detection
A method for monitoring and treating a subject for heart failure comprising detecting levels of MLCL AT1 or acyl-CoA lysocardiolipin (ALCAT1) mRNA in a biological sample from the subject.
Selecting subjects for aromatic-cationic peptide treatment based on elevated MLCL AT1 or ALCAT1 mRNA
Selecting the subject for aromatic-cationic peptide treatment where the level of MLCL AT1 or ALCAT1 mRNA in the biological sample from the subject is elevated about 2.5-fold compared to a normal control sample.
Administering D-Arg-2′-Dmt-Lys-Phe-NH2 or a salt to increase TAZ1 expression in myocardium
Administering to the subject a therapeutically effective amount of the aromatic-cationic peptide D-Arg-2′-Dmt-Lys-Phe-NH2 or a pharmaceutically acceptable salt thereof, wherein treatment increases the expression of TAZ1 in the myocardium of the subject.
Measuring MLCL AT1 or ALCAT1 mRNA using specific assay modalities
Detecting MLCL AT1 or ALCAT1 mRNA using RT-PCR, in situ hybridization, or Northern blotting.
Profiling cardiolipin isoform levels and comparing to normal controls
Detecting cardiolipin isoform levels in a biological sample from a subject and comparing them to levels in a normal control using chromatography, mass spectrometry, ELISA, Western blotting, immunodetection, or immunoprecipitation.
Daily peptide administration for at least 6 weeks
Administering the peptide daily for at least 6 weeks.
Permissible administration routes for the peptide
Administering the peptide via oral, topical, systemic, intravenous, subcutaneous, intraperitoneal, or intramuscular routes.
Optional co-administration of a selected cardiovascular agent
Administering a selected cardiovascular agent to the subject, where the agent is chosen from an enumerated set including anti-arrhythmia agents, vasodilators, anti-anginal agents, ACE inhibitors, angiotensin II antagonists, thrombolytic agents, calcium channel blockers, anti-platelet drugs, angiotensin-related classes, and other listed cardiovascular drug classes and formulations.
Overall, the claims cover monitoring heart failure by detecting elevated MLCL AT1 or ALCAT1 mRNA, optionally with specific mRNA assay modalities, selecting subjects based on an about 2.5-fold elevation relative to normal controls, and administering an aromatic-cationic peptide to increase TAZ1 expression in the myocardium. Dependent claims further include optional cardiolipin isoform profiling and specify additional treatment regimen and optional co-therapy aspects.
Stated Advantages
Documented Applications
Monitoring and treating a subject for heart failure using detection of MLCL AT1 or ALCAT1 mRNA in a biological sample and selecting subjects for aromatic-cationic peptide treatment where treatment increases TAZ1 expression in the myocardium.
Assessing mitochondrial dysfunction and heart failure by measuring cardiolipin isoforms and cardiolipin remodeling enzymes, including comparisons to normal controls and diagnostic examples using lipidomics and qPCR-based readouts.
Documented illustrative use in a dog heart failure model (coronary microembolization-induced HF) for cardiolipin/enzymes and related diagnostic examples.
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