Biomarkers of organic acidemias
Inventors
Venditti, Charles P. • Manoli, Irini
Assignees
US Department of Health and Human Services
Publication Number
US-11372004-B2
Publication Date
2022-06-28
Expiration Date
2038-09-06
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Abstract
Methods of using biomarkers in determining the efficacy of a treatment for an organic acidemia in a subject are disclosed herein. Methods of using biomarkers in determining the efficacy of a liver-directed treatment for an organic acidemia in a subject are likewise disclosed herein.
Core Innovation
The invention provides methods of using specific biomarkers to determine the efficacy of treatments for organic acidemias in subjects. These biomarkers include gene expression products of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). The methods involve detecting the levels of these biomarkers in biological samples from the subject prior to and after treatment. A decrease in biomarker levels after treatment compared to levels before treatment indicates treatment efficacy. These methods extend to liver-directed treatments and cover various therapeutic modalities including gene therapy, mRNA therapy, cell therapy, enzyme replacement, and genome editing, among others.
The problem addressed by the invention relates to the need for better therapies and methods to evaluate the efficacy of treatments for organic acidemias, such as methylmalonic acidemia (MMA) and propionic acidemia (PA). These inherited metabolic disorders disrupt amino acid metabolism leading to accumulation of toxic organic acids, causing severe metabolic instability and multiorgan complications that can be lethal even under current management strategies. Existing treatments, including dietary restrictions and organ transplantation, lack definitive curative options, and there is a need for sensitive, non-invasive biomarkers to monitor mitochondrial dysfunction, therapeutic response, and disease severity, particularly in hepatic tissues.
The invention solves the problem by identifying and validating reliable, non-invasive blood-based biomarkers, principally FGF21 and GDF15, to monitor hepatic mitochondrial dysfunction and treatment response in organic acidemias. These biomarkers provide a means to detect changes in hepatic enzyme activity associated with the disease and its treatment, enabling earlier and more accurate assessment of therapeutic efficacy. The methods also include diagnostic applications to detect hepatic mitochondrial dysfunction and utilize additional biomarkers such as Gadd45b, Gstm3, Pdk4, and others for expanded diagnostic and treatment monitoring purposes.
Claims Coverage
The patent includes several independent claims focused on methods for determining treatment efficacy, treating organic acidemias, improving hepatic enzyme activity, and diagnostic methods employing specific biomarkers. The main inventive features extract the novel use of defined biomarkers in these methods.
Use of specific biomarkers to determine treatment efficacy
A method for determining the efficacy of a treatment for an organic acidemia by detecting levels of FGF21 and/or GDF15 gene expression products in biological samples from a subject before and after treatment, where a decrease in biomarker levels post-treatment indicates efficacy, and adjusting treatment accordingly.
Treatment methods guided by biomarker levels
Methods of treating a subject for organic acidemia by measuring FGF21 and/or GDF15 levels pre- and post-treatment to improve hepatic enzyme activity, with the ability to alter or continue treatment based on biomarker changes.
Methods for improving hepatic enzyme activity
Administering treatment to improve compromised hepatic enzyme activity in subjects with organic acidemia guided by measuring FGF21 and/or GDF15 gene expression levels before and after treatment to assess and adjust treatment.
Diagnostic methods for hepatic mitochondrial dysfunction
Detecting increased levels of FGF21 and/or GDF15 gene expression products in biological samples as indicators of hepatic mitochondrial dysfunction in subjects with organic acidemia.
Expanded biomarker panels for efficacy assessment
Methods including detection of other gene expression products (e.g., Gadd45b, Gstm3, Pdk4, Rragd, Slc7A11, Asns, Abcc4, Fasn, and Hsd3b2) before and after treatment where decreases indicate treatment efficacy.
The claims collectively cover the use of FGF21, GDF15, and additional gene expression biomarkers as tools for diagnosing, monitoring, and guiding treatment of organic acidemias, especially focusing on hepatic mitochondrial dysfunction and liver-directed therapies.
Stated Advantages
Provides a non-invasive blood-based biomarker for monitoring mitochondrial dysfunction in organic acidemias, replacing invasive procedures like biopsies.
Offers a sensitive method to monitor clinical treatment responses before symptoms become apparent, particularly for hepatic mitochondrial function.
Enables monitoring the effects of diverse therapies including gene, mRNA, cell, small molecule, microbiome, enzyme replacement, and genome editing approaches.
Biomarker levels such as FGF21 are unaffected by renal function, allowing accurate treatment assessment even in patients with renal complications.
Documented Applications
Monitoring the efficacy of treatments for organic acidemias including methylmalonic acidemia (MMA) and propionic acidemia (PA).
Use in liver-directed treatments such as liver transplantation, combined liver-kidney transplantation, and liver-directed gene therapy.
Diagnosing hepatic mitochondrial dysfunction in subjects suffering from organic acidemias.
Monitoring metabolic crises and disease severity in MMA and PA patients through biomarker level changes.
Screening and treatment monitoring in cobalamin metabolic and transport disorders causing MUT deficiency.
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