IPA as a therapeutic agent, as a protective agent, and as a biomarker of disease risk
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Publication Number
US-9744155-B2
Publication Date
2017-08-29
Expiration Date
Abstract
Indole-3-propionic acid as a marker and for treatment for Huntington Disease.
Core Innovation
The invention discloses indole-3-propionic acid (IPA, also referred to as I3PA) as a bioactive metabolite and biomarker related to oxidative stress in disease. Low IPA levels are reported in Huntington disease (HD) and other neurodegenerative diseases including Alzheimer’s disease (AD), mild cognitive impairment (MCI), lower motor neuron disease (LMND), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD), and oxidative-stress-related biomarker behavior is also reported for hypertension, stroke, and ischemic heart disease.
The document states that individual-specific and genetically influenced patterns of IPA are observed and that IPA is proposed as a protective antioxidant. It describes that IPA suppresses protein aggregation and can cross the blood-brain barrier (BBB), while gut microbiome production of IPA is implicated. The document discusses modifying gut microbiota and/or supplementing IPA in connection with therapy and risk reduction.
A core aspect is evaluating oxidative stress by detecting oxidation products after a Fenton reaction in the presence of ubiquitin. The approach uses LC-EC and mass spectrometry (MS) to analyze reacted biological samples for oxidation products of indole-3-propionic acid bound to ubiquitin and/or oxidation products of indole lactic acid bound to ubiquitin, including using a ratio of these oxidation products, and comparing the result to a standard from an individual known to be suffering from the disease.
The document also provides support for an IPA-focused LC-EC/MS identification and quantification workflow and biomarker use for drug development monitoring and compliance. It connects oxidative degradation of IPA to reactive intermediates such as kynuric acid and describes evidence of oxidation products binding proteins including ubiquitin. It further reports in vivo mouse data using multiple HD models and discusses a microbiome footprint separation and intervention effects in the context of these biomarker measures.
Claims Coverage
The partial content provided contains one independent claim. The claim includes oxidative-stress evaluation by reacting a biological sample via a Fenton reaction in the presence of ubiquitin, analyzing LC-EC and MS signals for ubiquitin-bound oxidation products of indole-3-propionic acid and indole lactic acid, optionally using a ratio, and comparing the result to a standard from an individual suffering from the disease.
Fenton reaction in presence of ubiquitin for oxidative stress evaluation
Obtaining a biological sample from an individual known to be suffering from a disease and subjecting the biological sample to a Fenton reaction in the presence of ubiquitin.
LC-EC and MS analysis of ubiquitin-bound oxidation products
Using LC-EC and MS, analyzing the reacted biological sample for an oxidation product of indole-3-propionic acid bound to ubiquitin, an oxidation product of indole lactic acid bound to ubiquitin, or a ratio of an oxidation product of indole-3-propionic acid bound to ubiquitin/an oxidation product of indole lactic acid bound to ubiquitin.
Comparison to a disease standard
Comparing the analysis to a standard from an individual known to be suffering from the disease.
Across the provided claim set, oxidative stress is evaluated by generating ubiquitin-associated oxidation products via a Fenton reaction, detecting indole-3-propionic acid-derived and indole lactic acid-derived oxidation products using LC-EC and MS, and comparing the detected pattern to a disease-associated standard from affected individuals.
Stated Advantages
Documented Applications
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