Methods and compositions for treating 4-hydroxyphenylpyruvate dioxygenase-like (HPDL)-related diseases or disorders
Inventors
BANH, Robert • Pacold, Michael • SPILLIER, Quentin • Shi, Guangbin
Assignees
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Publication Number
US-12558329-B2
Publication Date
2026-02-24
Expiration Date
Abstract
Various methods and compositions of treating 4-hydroxyphenylpyruvate dioxygenase-like (HPDL)-related diseases or disorders are presented herein. Also presented herein are methods of increasing CoQ10 biosynthesis, and methods of determining whether a subject will benefit from a CoQ10 or CoQ10 alternative treatment. Also presented herein are pharmaceutical compositions and dosage forms comprising 4-hydroxymandelic acid (4-HMA), and/or its metabolites. Further presented herein are compounds that inhibit 4-hydroxyphenylpyruvate dioxygenase-like (HPDL). Further presented herein are methods of identifying and/or assessing modulators of HPDL. Yet further presented herein are example methods and systems for isotopic labelling in cells by metabolizing cells in the presence of gaseous isotopic tracer.
Core Innovation
The invention relates to treating 4-hydroxyphenylpyruvate dioxygenase-like (HPDL)-related disease or disorder using 4-hydroxymandelic acid (4-HMA), or a metabolite, pharmaceutically acceptable salt, prodrug, solvate, hydrate, or combinations thereof. The disclosure also includes administering an activator of HPDL, where the activator is vitamin C and pharmaceutically acceptable derivatives thereof. The treatment framework further includes enantioenriched or enantiopure (R)-4-HMA variants, as well as (S)-4-HMA for inhibiting expression of HPDL in a subject in need thereof.
A central aspect is determining whether a subject will benefit from treatment with 4-HMA by detecting one or more mutations in the HPDL gene and/or additional gene(s) involved in CoQ10 headgroup synthesis. The detected mutations are characterized as resulting in reduced or abolished activity and/or expression of the protein(s) produced by the involved gene(s). When the mutations are present, the subject will benefit from treatment and the treatment is administered; when the mutations are absent, the subject will not benefit and the treatment is not administered.
The disclosure also includes methods for treating or preventing diseases associated with dysregulation of HPDL in a subject. It further describes treatment selection and prognosis determination based on detecting mutations in a biological sample obtained from a subject, with the same mutation presence or absence framework used to guide administration of 4-HMA-based treatment or an HPDL activator.
Claims Coverage
The independent claims cover treatment using 4-HMA forms, treatment using an HPDL activator, mutation-based benefit prediction for 4-HMA treatment, mutation-guided conditional administration of 4-HMA, and inhibition of HPDL expression. Across these claims, the inventive features center on HPDL-related disease treatment, specific 4-HMA variants, mutation detection in HPDL and additional CoQ10 headgroup synthesis genes, and conditional administration based on mutation presence or absence.
Administering 4-HMA for HPDL-related disease or disorder
A method of treating a 4-hydroxyphenylpyruvate dioxygenase-like (HPDL)-related disease or disorder by administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), or a metabolite, pharmaceutically acceptable salt, prodrug, solvate, hydrate, or combinations thereof.
Administering an HPDL activator
A method of treating a 4-hydroxyphenylpyruvate dioxygenase-like (HPDL)-related disease or disorder by administering to the subject a therapeutically effective amount of an activator of HPDL, where the activator is vitamin C or a pharmaceutically acceptable salt, prodrug, solvate, or hydrate thereof.
Mutation-based prediction of benefit from 4-HMA treatment
A method of determining whether a subject will benefit from treatment with 4-hydroxymandelic acid (4-HMA), or a metabolite, pharmaceutically acceptable salt, prodrug, solvate, hydrate, or combinations thereof, comprising detecting one or more mutations in the HPDL gene and/or additional gene(s) involved in CoQ10 headgroup synthesis, wherein the mutations result in reduced or abolished activity and/or expression of the protein(s), and determining benefit when the mutations are present and not benefit when the mutations are absent.
Mutation-guided conditional administration of 4-HMA
A method of treating an HPDL-related disease or disorder comprising detecting one or more mutations in the HPDL gene and/or additional gene(s) involved in CoQ10 headgroup synthesis, wherein the mutations result in reduced or abolished activity and/or expression, and then administering 4-hydroxymandelic acid (4-HMA), or a metabolite, pharmaceutically acceptable salt, prodrug, solvate, hydrate, or combinations thereof when the mutations are present, and not administering the same when the mutations are absent.
Inhibiting HPDL expression with (S)-4-HMA
A method of inhibiting expression of 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) in a subject by administering to the subject a therapeutically effective amount of (S)-4-HMA, or a metabolite, pharmaceutically acceptable salt, prodrug, solvate, hydrate, or combinations thereof.
The claims collectively cover HPDL-related disease treatment using 4-HMA, including metabolite and pharmaceutically acceptable derivative forms, treatment using an HPDL activator, mutation-based prediction and conditional administration guided by HPDL and additional CoQ10 headgroup synthesis genes, and inhibition of HPDL expression using (S)-4-HMA.
Stated Advantages
Enables determining whether a subject will benefit from treatment by detecting mutations in the HPDL gene and/or additional genes involved in CoQ10 headgroup synthesis and making a benefit or not benefit determination.
Supports conditionally administering therapy based on whether the one or more mutations are present or absent.
Provides enantiomer-specific modulation by specifying enantioenriched or enantiopure (R)-4-HMA for treatment and (S)-4-HMA for inhibiting HPDL expression.
Documented Applications
Treating a 4-hydroxyphenylpyruvate dioxygenase-like (HPDL)-related disease or disorder, including cerebral palsy and pancreatic cancer, including pancreatic ductal adenocarcinoma (PDAC), as described in the provided partial content.
Treating HPDL-related disease or disorder using an HPDL activator, with vitamin C described in the provided partial content.
Stratifying subjects for 4-HMA-based treatment by detecting HPDL gene mutations and/or mutations in genes involved in CoQ10 headgroup synthesis, and determining benefit versus no benefit, as described in the provided partial content.
Conditionally administering therapy based on mutation presence or absence, as described in the provided partial content.
Inhibiting expression of HPDL in a subject by administering (S)-4-HMA, as described in the provided partial content.
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