Extracellular vesicle ribonucleic acid (RNA) cargo as a biomarker of hyperglycemia and type 1 diabetes
Inventors
Mirmira, Raghavendra G. • Evans-Molina, Carmella • Sims, Emily K.
Assignees
US Department of Veterans Affairs • Indiana University Bloomington
Publication Number
US-10738343-B2
Publication Date
2020-08-11
Expiration Date
2039-01-17
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Abstract
Methods and compositions are provided for detecting and/or determining a patient's risk of developing hyperglycemia or type 1 diabetes. The methods are directed to analyzing the miRNA content of extracellular vesicles recovered from said patient.
Core Innovation
The invention relates to methods and compositions for detecting and determining a patient's risk of developing hyperglycemia or type 1 diabetes by analyzing the microRNA (miRNA) content of extracellular vesicles recovered from said patient. The methods focus on detecting various forms of RNA, especially miRNAs, within extracellular vesicles such as exosomes, microvesicles, and apoptotic bodies isolated from patient samples like blood, serum, or plasma.
The background identifies a rising global incidence of type 1 diabetes, characterized by progressive pancreatic beta cell dysfunction and destruction leading to loss of functional beta cell mass at clinical presentation. Emerging evidence suggests that beta cells contribute to disease progression through intrinsic stress pathways exacerbating autoimmune destruction, highlighting the need for robust biomarkers of beta cell health. Existing approaches lack sufficient early detection methods to monitor beta cell dysfunction and permit earlier therapeutic interventions.
The disclosed invention addresses the need for improved biomarkers by providing detection methods centered on extracellular vesicle RNA, particularly miRNA cargo such as miR-21-5p, which exhibits selective enrichment in beta cell-derived exosomes following inflammatory cytokine exposure. The methodology includes isolating extracellular vesicles from patient samples using size-based centrifugation and extracellular vesicle markers like CD9 and CD63, followed by detecting specific miRNAs whose elevated levels correspond to susceptibility to hyperglycemia or onset of type 1 diabetes.
Claims Coverage
The patent includes two independent claims focusing on methods for treating patients susceptible to hyperglycemia by identifying elevated miRNA levels in isolated beta cell extracellular vesicles.
Method for identifying susceptibility to hyperglycemia by miRNA quantitation in beta cell extracellular vesicles
The method comprises obtaining a biological sample from a patient, isolating beta cell extracellular vesicles using vesicle markers CD9 and CD63, and quantitating two or more miRNAs selected from miR-21-5p, miR-21-3p, miR-217, and miR-193-3p. Elevated levels of these miRNAs identify the patient as susceptible to hyperglycemia.
Temporal comparison of miRNA levels for susceptibility identification
Elevated miRNA levels indicating susceptibility are determined by comparing miRNA quantities in two or more samples collected at different times from the same patient, with temporal spacings selectable from 1 day to 2 years, identifying an increase over time.
Use of plasma or serum samples for extracellular vesicle miRNA detection
The method uses plasma or serum samples from patients, isolates beta cell extracellular vesicles through CD9 or CD63 markers, and quantifies miR-21-5p, miR-21-3p, miR-217, and miR-193-3p. Detection of elevated levels of two or more miRNAs identifies susceptibility to hyperglycemia.
Treatment step following identification
Upon identification of susceptibility by elevated miRNA levels in beta cell extracellular vesicles, the method includes treating the patient using standard anti-diabetes therapies or administering insulin.
The independent claims collectively cover methods for identifying patients susceptible to hyperglycemia or type 1 diabetes by isolating beta cell extracellular vesicles marked by CD9 or CD63 from patient samples and quantitating multiple miRNAs, with optional temporal analysis of samples and subsequent treatment steps, emphasizing use of specific miRNAs including miR-21-5p, miR-21-3p, miR-217, and miR-193-3p.
Stated Advantages
Provides robust biomarkers of beta cell health for early identification and monitoring of beta cell dysfunction related to hyperglycemia and type 1 diabetes.
Enables detection of developing diabetes prior to clinical onset, allowing earlier administration of disease modifying therapies.
Selective enrichment of miR-21-5p and other miRNAs in extracellular vesicles offers a specific and sensitive approach for risk assessment.
Methods employ non-invasive sampling such as serum or plasma for extracellular vesicle isolation and RNA detection.
Documented Applications
Detecting and determining a patient's risk of developing hyperglycemia or type 1 diabetes by analyzing miRNA cargo in extracellular vesicles from patient blood samples.
Identification of subjects susceptible to hyperglycemia or type 1 diabetes by measuring levels of miRNAs such as miR-21-5p in beta cell extracellular vesicles isolated from serum or plasma.
Monitoring progression or risk of type 1 diabetes development through longitudinal analysis of extracellular vesicle RNA levels including multiple miRNAs over time.
Use of extracellular vesicle miRNA profiles as biomarkers for early diagnosis and therapeutic decision-making in type 1 diabetes management.
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