WO2025199182A1 - Treatment with 4-hydroxybenzoic acid to augment coq10 production - Google Patents

Treatment with 4-hydroxybenzoic acid to augment coq10 production

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Publication number
WO2025199182A1
WO2025199182A1 PCT/US2025/020495 US2025020495W WO2025199182A1 WO 2025199182 A1 WO2025199182 A1 WO 2025199182A1 US 2025020495 W US2025020495 W US 2025020495W WO 2025199182 A1 WO2025199182 A1 WO 2025199182A1
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group
subject
hma
hpdl
disease
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WO2025199182A8 (en
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Michael Pacold
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New York University NYU
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New York University NYU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • CoQ10 is a lipophilic antioxidant critical for control of reactive oxygen species in biological membranes and for activity of the mitochondrial electron transport chain (FIG.10) (reviewed in(5)).
  • NEDSWMA is the latest addition to the family of primary CoQ10 deficiencies, a group of rare mitochondrial diseases caused by defects in CoQ10 biosynthesis. Patients with these conditions develop a variety of symptoms, with nearly all of them presenting with progressive encephalopathies. The overall success rate of treating patients with CoQ10 deficiencies with CoQ10 supplementation therapies is less than 30% (6). NEDSWMA is refractory to CoQ10 supplementation therapy.
  • Patients with mitochondrial diseases tend to present with incremental physical deterioration followed by rapid decompensation upon exposure to a stressor such as an infection.
  • HPDL 4-Hydroxyphenylpyruvate dioxygenase-like
  • 4- HMA is the first committed intermediate in the biosynthesis pathway for 4-hydroxybenzoate (4- HB), the immediate precursor of the Coenzyme Q10 (CoQ10) headgroup.
  • 4- HB 4-hydroxybenzoate
  • CoQ10 Coenzyme Q10
  • Hpdl -/- mice a model for NEDSWMA, develop spastic paresis and die by post-natal day 15 (P15).
  • No disease- modifying therapies for primary CoQ 10 deficiencies are currently available.
  • Hpdl -/- mouse pups have defects in cortical and cerebellar development consistent with mitochondrial disease. Labeled 4-HMA and 4-HB enter the brains of Hpdl -/- mice and are incorporated into CoQ 9 , the mouse equivalent of human CoQ 10 .
  • Oral treatment of Hpdl -/- pups with 4-HMA or 4-HB restores cerebellar architecture and Purkinje cell function, enables Hpdl -/- mice to live into adulthood, and substantially improves their motor function.
  • CoQ10, CoQ9, and soluble CoQ derivatives do not improve the overall survival of Hpdl -/- mice.
  • Our work suggests that 4-HMA and 4-HB treatment can modify the course of NEDSWMA and other diseases driven by loss of CoQ10 headgroup synthesis.
  • FIGS.1A-1H show that mammalian CoQ headgroup intermediates improve the survival of Hpdl -/- mice, and are incorporated into CoQ 9 in vivo.
  • FIG.1A shows the mammalian CoQ headgroup synthesis pathway. Tyrosine is deaminated to 4-hydroxyphenylpyruvate (4- 4 309005815v2 Attorney Docket No.: 243735.000414 HPPA). HPDL coverts 4-HPPA to 4-hydroxymandelate (4-HMA).4-HMA is converted to 4- hydroxybenzoate (4-HB), the immediate precursor of the CoQ headgroup.
  • FIG.1B is a graph showing that Hpdl -/- pups exhibit significant weight loss by post-natal day 10 (P10) relative to Hpdl +/+ and Hpdl +/- pups. Error bars represent median ⁇ interquartile range.
  • FIG.1C is a graph showing that Hpdl -/- pups die by P15. Hpdl +/+ and Hpdl +/- pups survive >1 year.
  • FIG.1D is a graph showing that all Hpdl -/- pups have observed seizures. No Hpdl +/+ or Hpdl +/- pups had observed seizures.
  • FIG.1E is a graph showing that Hpdl -/- pups have lower plasma 4-HMA than Hpdl +/+ or Hpdl +/- pups at P10. Error bars represent mean ⁇ standard deviation.
  • FIG.1F is a graph showing that oral supplementation with 4-HMA and 4-HB (10 mg/kg, once daily) improves the overall survival of Hpdl -/- pups. Oral supplementation of CoQ 9 , CoQ 10 and related compounds does not improve Hpdl -/- pup survival.
  • FIG.1G is a schematic showing the incorporation of 13 C from 13 C6-4-HMA and 13 C6-4-HB into mouse CoQ9.
  • FIGS.2A-2E show that 4-HMA supplementation restores the histologic appearances of the brains of Hpdl -/- mice.
  • FIG.2A shows representative electron micrographs of cortex (panels A-D) and cerebellum (panels E-H) in P11 Hpdl +/+ , Hpdl +/- , and Hpdl -/- mouse pups reveal minimal changes in cortical ultrastructure.
  • the mitochondria (marked by arrowheads) in Hpdl +/+ (panels A, E) and Hpdl +/- (panels B, F) mouse pups are intact, but the mitochondria in the cerebella of Hpdl -/- mouse pups (panel G) are fragmented.
  • FIG.2B shows quantitation of mitochondrial perimeter in electron micrographs of the cerebellum in P11 Hpdl +/+ , Hpdl +/- , and Hpdl -/- mouse pups, and Hpdl -/- mouse pups treated with 4-HMA.
  • Mitochondria in the Hpdl -/- mouse pups are smaller than in the Hpdl +/+ and Hpdl +/- pups.4-HMA treatment improves the size of the mitochondria in the Hpdl -/- pups, but not to the size of mitochondria in Hpdl +/+ pups.
  • FIG.2C shows that P11 Hpdl -/- pups exhibit marked cerebellar atrophy (panel C), with Purkinje cells (arrowheads) showing vacuolization and intracellular 5 309005815v2 Attorney Docket No.: 243735.000414 edema, thinning of the inner granular layer (IGL) and molecular layer, and compaction of the external granular layer (EGL) (panels G, K). These abnormalities are improved to near-wild-type pups by supplementation with 4-HMA (panels D, H, L).
  • FIG.2D shows quantitation of B. Hpdl -/- mouse pups have a thinner IGL than Hpdl +/+ or Hpdl +/- pups.
  • FIG.2E shows that P11 Hpdl -/- pups exhibit loss of normal cortical layers of the cerebral cortex (panels C, G, K), as well as edema, shrinking of the cortical neurons, and red neurons (marked by arrowheads).
  • FIGS 3A-3F show that 4-HMA supplementation improves the behavioral phenotypes of Hpdl -/- mice and electrophysiologic behavior of Purkinje cells from Hpdl -/- pups.
  • FIG.3A shows that patch-clamping of Purkinje cells in brain slices from P8-10 pups demonstrates increased input resistance and membrane capacitance in Purkinje cells from Hpdl -/- pups in comparison to Purkinje cells from Hpdl +/+ and Hpdl +/- pups.
  • Treatment of Hpdl -/- pups with 4-HMA decreases Purkinje cell input resistance and increases membrane capacitance to levels comparable to more mature Purkinje cells (FIG.6E).
  • FIG.3E shows that Hpdl -/- mice treated with 4-HMA have similar performance to Hpdl +/+ and Hpdl +/- mice in the transverse beam test, a measure of balance.
  • FIG.3F shows relative to Hpdl +/+ mice, forelimb grip strength is reduced in Hpdl +/- mice as well as Hpdl -/- mice treated with 4-HMA.
  • Hindlimb grip strength is identical in Hpdl +/+ , Hpdl +/- , and Hpdl -/- mice treated with 4-HMA from P3 until 4-6 weeks. Data presented are mean ⁇ standard deviation, as well as raw data.
  • FIG.4A shows lactate/pyruvate ratio in plasma from Hpdl +/+ , Hpdl +/- , and Hpdl -/- pups. Hpdl -/- pups have a higher lactate/pyruvate ratio than Hpdl +/+ and Hpdl +/- pups.
  • FIG.4B shows mouse dose-response of 4-HMA treatment in improving the survival of Hpdl -/- pups.4-HMA 6 309005815v2 Attorney Docket No.: 243735.000414 dosing of 10 mg/kg improves the 30-day survival of 90% of pups. Doses of 0.1 mg/kg or 1 mg/kg did not improve the overall survival of these.
  • FIG.4C shows MTD of 4-HMA and 4-HB, and half-life of 4-HMA and half-life of 4-HB dosed at treatment dose (10 mg/kg po), 500 mg/kg po, and 1 mg/kg IV. Data represent mean ⁇ standard deviation.
  • FIG.4D shows pharmacokinetic data for 4-HMA and 4-HB at 500 mg/kg po and 1 mg/kg IV.
  • FIG.4E shows treatment of Hpdl -/- pups with 4-HMA, the product of HPDL, and 4-HB, the immediate precursor of the CoQ headgroup, results in weight gain similar to Hpdl +/- pups. Error bars represent median ⁇ interquartile range.
  • FIG.4F shows Hpdl -/- pups are able to stand 3 days after supplementation with 4-HMA (10 mg/kg, oral administration).
  • FIG.4G shows effects of 4-HMA treatment on an Hpdl -/- pup. Two Hpdl -/- pups are on the right and two Hpdl +/- littermates are on the right.
  • FIG.4H shows CoQ 9 abundance and labeling from mouse brains following treatment with 13 C6-4-HMA starting at postnatal day 3.
  • 13 C6-4-HMA is incorporated into CoQ9 in Hpdl -/- mice, and increases brain CoQ9 relative to untreated mice.
  • 13 C6- 4-HMA is not incorporated into CoQ 9 in Hpdl +/+ mice and is incorporated into CoQ 9 at a lower fraction in Hpdl +/- mice. Significance was tested by two-way analysis of variance (ANOVA) followed by Tukey’s post-hoc test.
  • FIG.5A shows that P11 Hpdl -/- pups do not exhibit major changes in hippocampal histology in comparison to Hpdl +/+ pups, Hpdl +/- pups, and Hpdl -/- pups treated with 4-HMA.
  • FIGS.6A-6L show functional characteristics of Purkinje cells and additional behavioral and neurological tests of Hpdl +/+ , Hpdl +/- , Hpdl -/- and 4-HMA-treated Hpdl -/- mice.
  • FIG.6A shows that the I/V curves of Purkinje cells from P8-10 Hpdl -/- pups and 4-HMA-treated Hpdl -/- pups are significantly different from each other and from the I/V curves of Hpdl +/+ and Hpdl +/- pups, which are similar. P-values indicating statistical significance are listed.
  • the Hpdl -/- pups have a flatter I/V curve at hyperpolarized membrane potentials relative to the other curves due to a tighter grouping of currents at hyperpolarized membrane potentials (-100 to -60 mV) than the Hpdl +/+ and Hpdl +/- pups (see insert).
  • FIG.6B shows F/I curves of Purkinje cells from P8-10 Hpdl +/+ , Hpdl +/- , Hpdl -/- and 4-HMA-treated Hpdl -/- pups. There were no significant differences in the linear portions of each curve between each group.
  • the insert shows the simple firing 7 309005815v2 Attorney Docket No.: 243735.000414 pattern of an immature Purkinje cell.
  • FIG.6C shows peak frequency of Purkinje cells from P8- 10 Hpdl +/+ , Hpdl +/- , Hpdl -/- and 4-HMA-treated Hpdl -/- pups.
  • the 4-HMA treated Hpdl -/- group has higher peak frequency than any of the other groups. Differences in frequency were identified by two-way ANOVA followed by Dunnett’s multiple comparison test.
  • FIG.6D shows action potential characteristics of P8-10 Hpdl +/+ , Hpdl +/- , Hpdl -/- and 4-HMA-treated Hpdl -/- pups. An average action potential is shown in panel A and the phase plane diagram is shown in panel B.
  • FIG.6E shows that HPDL supplementation restores input resistance and membrane capacitance of Purkinje cells from Hpdl -/- pups to levels comparable to Hpdl +/+ and Hpdl +/- pups at P17-19.
  • FIG.6F shows that the I/V curves of Purkinje cells from P17-19 Hpdl +/+ , Hpdl +/- , and 4-HMA-treated Hpdl -/- pups are similar.
  • FIG.6G shows F/I curves of Purkinje cells from P17-19 Hpdl +/+ , Hpdl +/- , Hpdl -/- and 4-HMA-treated Hpdl -/- pups. There were no significant differences in the linear portions of each curve between each group.
  • the insert shows the simple firing pattern of a more mature Purkinje cell.
  • FIG.6H shows peak frequency of Purkinje cells from P17-19 Hpdl +/+ , Hpdl +/- , and 4-HMA-treated Hpdl -/- pups. The peak frequencies in all three groups are comparable.
  • FIG.6I shows action potential characteristics of P17-19 Hpdl +/+ , Hpdl +/- , and 4-HMA-treated Hpdl -/- pups. An average action potential is shown in panel A and the phase plane diagram is shown in panel B.
  • the spike threshold, spike amplitude, and spike half-width 8 309005815v2 Attorney Docket No.: 243735.000414 are comparable in all three groups.
  • FIG.6J shows that forelimb grip strength is decreased in 4-6-week-old Hpdl +/- (p ⁇ 0.0001) and 4-HMA-treated Hpdl -/- mice (p ⁇ 0.0001) relative to Hpdl +/+ mice. Grip strength of all limbs is similar in Hpdl +/+ , Hpdl +/- , and 4-HMA- treated Hpdl -/- mice.
  • FIG.6L shows metabolic phenotypes such as food and water intake, activity, O 2 consumption, CO 2 production, and energy expenditure are similar in 4-6-week-old Hpdl +/+ , Hpdl +/- , and 4-HMA-treated Hpdl -/- mice, as measured in metabolic cages. Differences were identified by two-way ANOVA followed by Dunnett’s multiple comparison test.
  • FIG.7 shows safety data sheet for 4-hydroxybenzoic acid.
  • FIG.8 shows product specification for 4-hydroxybenzoic acid.
  • FIG.9 shows certificate of analysis for 4-hydroxybenzoic acid.
  • FIG.10 shows the mammalian CoQ10 headgroup synthesis pathway. HPDL converts 4-hydroxyphenylpyruvate to 4-hydroxymandalate (4-HMA ⁇ .4-HMA is converted to 4- hydroxybenzoic acid (4-HB), the immediate precursor of the CoQ10 headgroup. The COQ2 prenyltransferase conjugates 4-HB to polyprenyl pyrophosphate to form the skeleton of CoQ10, followed by headgroup modification to form the active molecule (reviewed in (5)).
  • FIG.11A shows triplicate injections demonstrating the reproducibility of co-elution of 100 ⁇ M unlabeled 4-hydroxybenzoic acid (unlabeled) and 13C6-4-hydroxybenzoic acid internal standard (labeled). These standards and the frozen 4-HB were run simultaneously.
  • FIG.11B shows stability of frozen 4-HB stocks (frozen at -20 ⁇ C for 3 months). The peak height at 200 ⁇ M is 7.6E7, which is about four times the peak height of 50 ⁇ M fresh 4-HB (1.45E7; panel A).
  • FIG.12 shows that parabens are mainly metabolized through hydrolysis supported by esterases and through glucuronidation catalyzed by UDP-glucuronosyltransferases (UGT) using UDP-glucuronic acid (UDPGA). They can also produce sulfoconjugates by sulfotransferase (ST) using 3’-phosphoadenosine 5’-phosphosulfate (PAPS) as the sulfate donor substrate, or 4- hydroxyhippuric acid by amino acid transferase (AT) using glycine as the donor substrate.
  • FIG.13 is a survival plot for treatment of Hpdl-/- mice with a 4-HB suspension stored at room temperature.
  • FIG.14 shows regrowth of hair in shaved 90-week-old-mice following treatment with systemic 4-HMA at 100 mg/kg two weeks prior to treatment. After week 5, topical 4-HMA at 100 mg/kg was applied every other day.
  • FIG.15 shows regrowth of hair in shaved 90-week-old-mice following topical treatment with 4-HMA (100 mg/mL) every other day.
  • the terms “about” or “approximately” for any numerical values or ranges indicate a suitable dimensional tolerance that allows the part or collection of components to function for its intended purpose as described herein. More specifically, “about” or “approximately” may refer to the range of values ⁇ 20% of the recited value, e.g. “about 90%” may refer to the range of values from 71% to 99%.
  • alkyl refers to an alkylene group.
  • certain compounds of the disclosure can be indicated to comprise “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
  • substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a substituent e.g., -B
  • the “pharmaceutically acceptable salts” include a subset of the “salts” described above which are conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Berge, SM et al, Journal of Pharmaceutical Science, 1977, 66, 1, 1-19.
  • pharmaceutically acceptable salts can comprise a suitable cation selected from aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamince, or zinc.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • prodrug as used herein includes a chemical which may be transformed in vivo to a pharmacologically active drug.
  • metabolite as used herein includes a chemical that a given agent is transformed into in vivo.
  • the enantiomeric excess, or “ee,” for a given pair of enantiomers is the percentage of the major enantiomer less the percentage of the minor enantiomer.
  • a “racemate” or “racemic mixture” is an equal mixture of two enantiomers and therefore has 0% ee.
  • enantiomerically enriched or “enantioenriched” as used herein includes compounds that are mixtures with one enantiomer's being present in excess over the other (ee >0% and ⁇ 100%). For example, a sample of 40% ee consists of 70% of the major enantiomer and 30% of the minor enantiomer.
  • enantiomerically pure or “enantiopure” as used herein includes compounds where the quantification of the minor enantiomer becomes difficult, e.g., with an ee of 99% or greater. Ideally, enantiopure compounds consist of a single enantiomer only.
  • sample includes any biological specimen obtained from a subject or patient.
  • Samples that can be used in the methods of the present disclosure include, without limitation, tumor sample, whole blood, plasma, serum, red blood cells, white blood cells (e.g., peripheral blood mononuclear cells (PBMC), polymorphonuclear (PMN) cells), ductal lavage fluid, nipple aspirate, lymph (e.g., disseminated tumor cells of the lymph node), bone marrow aspirate, saliva, urine, stool (i.e., feces), sputum, bronchial lavage fluid, tears, fine needle aspirate (e.g., harvested by random periareolar fine needle aspiration), any other bodily fluid, a tissue sample such as a biopsy (e.g., needle biopsy), and cellular extracts thereof.
  • PBMC peripheral blood mononuclear cells
  • PMN polymorphonuclear
  • the sample when the subject is a pregnant female, the sample may be a fetal DNA sample (e.g., cell-free fetal DNA (cffDNA)).
  • a fetal DNA sample e.g., cell-free fetal DNA (cffDNA)
  • the term “subject” or “patient” refers to mammals and includes, without limitation, human and veterinary animals. In a preferred embodiment, the subject is human.
  • the subject is a pediatric subject 0 to 18 years of age. In some embodiments, the subject is a child, including an unborn fetus, a newborn, an infant, or a toddler.
  • treating an unborn fetus using methods described herein may involve treating a pregnant female carrying the unborn fetus.
  • the subject is a pediatric subject 0 to 18 month of age, 0 to 2 years of age, 0 to 10 years of age, 0 to 18 years of age, or 0 to 21 years of age.
  • the subject is an adult. In some embodiments, the subject is an elderly adult. In some embodiments, the subject is 65 year old adult or older.
  • the subject is a male. In some embodiments, the subject is a male 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 55 years or older, 60 years or older, or 65 years or older.
  • the terms “treat” or “treatment” of a state, disorder or condition include: (1) preventing or delaying the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub- 13 309005815v2 Attorney Docket No.: 243735.000414 clinical symptoms.
  • an “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response, i.e., treating the state, disorder or condition.
  • the effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • reference to a component is intended also to include composition of a plurality of components.
  • References to a composition containing “a” constituent is intended to include other constituents in addition to the one named.
  • the terms “a,” “an,” and “the” do not denote a limitation of quantity, but rather denote the presence of “at least one” of the referenced item.
  • terminology will be resorted to for the sake of clarity. It is intended that each term contemplates its broadest meaning as understood by those skilled in the art and includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.
  • Such other materials not described herein can include, but are not limited to, materials that are developed after the time of the development of the invention, for example. Any dimensions listed in the various drawings are for illustrative purposes only and are not intended to be limiting. Other dimensions and proportions are contemplated and intended to be included within the scope of the invention.
  • Compounds of the Disclosure [0055] In one aspect, provided herein is a compound having the structure of Formula (I): R 3 O , wherein: R 1 is selected from the group ; R2 is selected from the group R3 is selected from the group consisting of H and C1-C3 alkyl, and R4 is selected from the group consisting of H , or pharmaceutically acceptable salt thereof. [0056] In one embodiment, R1 is H.
  • R 2 is H.
  • R 3 is H. 15 309005815v2 Attorney Docket No.: 243735.000414
  • R3 is methyl.
  • R4 is H.
  • R4 is H.
  • R4 is H.
  • R4 is H.
  • R4 is selected from one of Formula (I): or a pharmaceutically R1 is selected from the group R4 is selected from the group consisting of H .
  • the compound of the structure according to Formula (III): or a pharmaceutically R1 is selected from the group R4 is selected from the group consisting of H .
  • the compound having of Formula (I) is selected from the group consisting of: 16 309005815v2 Attorney Docket No.: 243735.000414 , [0067] In one embodiment, the compound having the structure of Formula (I) is selected from the group consisting of: a [0068] In one aspect, the present invention provides 2-hydroxy-2-(4-hydroxyphenyl)acetic acid (also known as 4-hydroxymandelic acid (4-HMA)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. .
  • 2-hydroxy-2-(4-hydroxyphenyl)acetic acid also known as 4-hydroxymandelic acid (4-HMA)
  • 4-HMA 4-hydroxymandelic acid
  • R- and the S- enantiomers of 4-HMA depicted below: 17 309005815v2 Attorney Docket No.: 243735.000414 .
  • the (R)-4-HMA is present with an enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.
  • 4-HMA is provided as the enantiopure R-enantiomer (R)-4- HMA.
  • 4-HMA is provided as an enantioenriched mixture of the S- enantiomer, i.e., (S)-4-HMA.
  • the (S)-4-HMA is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.
  • ee enantiomeric excess
  • the (S)-4-HMA is present with an enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.
  • 4-HMA is provided as the enantiopure S-enantiomer (S)-4- HMA.
  • compositions and Administration [0077]
  • the present invention also provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystals, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, R2, R3, and R4 are as defined above.
  • the present invention also provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystals, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
  • Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. 19 309005815v2 Attorney Docket No.: 243735.000414 [0081] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, 22 309005815v2 Attorney Docket No.: 243735.000414 magnesium hydroxide, aluminum hydroxide, al
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates of the invention are mixed with solubilizing agents such as CremophorTM, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof. 23 309005815v2 Attorney Docket No.: 243735.000414 [0098]
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, 24 309005815v2 Attorney Docket No.: 243735.000414 and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate,
  • encapsulating compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active ingredient can be in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, 25 309005815v2 Attorney Docket No.: 243735.000414 inhalants and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions.
  • Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers.
  • compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device 26 309005815v2 Attorney Docket No.: 243735.000414 comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non- ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • additional ingredients such as a liquid non- ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • Pharmaceutical compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • a flavoring agent such as saccharin sodium
  • a volatile oil such as a liquid oil
  • a buffering agent such as a liquid oil
  • a surface active agent such as methylhydroxybenzoate
  • a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the 27 309005815v2 Attorney Docket No.: 243735.000414 invention can be prepared, packaged, and/or sold in a formulation for buccal administration.
  • Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.
  • the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • the effective amount of the compound in the composition that may be used in accordance with the present disclosure may vary from about 0.0001 mg/kg to about 1000 mg/kg in one or more dose administrations for one or several days (depending on the mode of administration).
  • the compounds and compositions provided herein can be administered to a subject once a week, twice a week, three times a week, or four or more times a week.
  • the compounds and compositions provided herein can also be administered to a subject once every two weeks, once every three weeks, once a month, once every two month, once every three month, once every four month, once every five month, once every six month, once every seven month, once every eight month, once every nine month, once every ten month, once every eleven month, once a year, or once every two years.
  • the heart disease that can be treated include, but are not limited to, heart failure, high blood pressure, recovery post cardiac surgery, and statin-induced myopathy.
  • the neurodegenerative disease that can be treated include, but are not limited to, Parkinson’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS), and demyelinating and white matter disease.
  • the neurodevelopmental disease is cerebral palsy.
  • the pulmonary disease is chronic obstructive pulmonary disease (COPD) or asthma.
  • COPD chronic obstructive pulmonary disease
  • the muscle disease is muscular dystrophy.
  • the liver disease is characterized by toxicity due to statins or liver injury.
  • the pancreatic disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, and exocrine insufficiency. 33 309005815v2 Attorney Docket No.: 243735.000414
  • the oral disease is selected from the group consisting of tooth decay, periodontitis, and gum decay.
  • the ophthalmic disease is selected from the group consisting of macular degeneration, cataract formation, retinal detachment, and retinitis pigmentosa.
  • the hearing disease is hearing loss.
  • the disease of pregnancy is placental insufficiency or pre- eclampsia.
  • the disease of prematurity is selected from the group consisting of prematurity, retinopathy of prematurity, and cerebral palsy.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in improving wound healing in a subject.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a neurodevelopmental disorder with spastic paresis and brain white matter abnormalities.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a subject having a white matter abnormality.
  • the subject has 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) deficiency.
  • HPDL 4-hydroxyphenylpyruvate dioxygenase-like
  • the subject has a variant in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway.
  • the mutation is homozygous.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a subject having a variant in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in improving physical performance and energy production in a subject.
  • the treatment results in one or more of decreasing fatigue, increasing strength and stamina, increasing functional performance, and improving balance.
  • 34 309005815v2 Attorney Docket No.: 243735.000414
  • the compound(s) or pharmaceutical compositions of the present disclosure when used in combination with an antacid may be useful in treating a 4- hydroxyphenylpyruvate dioxygenase-like (HPDL)-related disease or disorder in a subject.
  • HPDL 4- hydroxyphenylpyruvate dioxygenase-like
  • Suitable antacid that can be used include, but are not limited to, aluminum, calcium, magnesium, and sodium salts.
  • the antacid is selected from the group consisting of aluminum hydroxide, magnesium hydroxide, sucrose/calcium carbonate, sodium citrate, citric acid, sodium bicarbonate, tartaric acid, and alginic acid.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a neurodegenerative or psychiatric disease.
  • the child when the subject being treated is a child, the child may be treated with the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), in utero, immediately after birth, or in postpartum days.
  • the method may involve treating a newborn or infant by administering the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), to the newborn or infant.
  • the method may involve treating an unborn fetus by administering the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 44-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), to the pregnant female.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in accelerating, promoting, or restoring hair growth in a subject.
  • the disclosed methods may be used to promote hair growth on any body surface of a subject where hair growth is desired, including, for example, the scalp, chest, and face (e.g., beard, eyebrows, scars, etc.).
  • hair growth over the entire body surface may be desired.
  • Particular methods involve growing hair on all or part of the scalp (such as, an area of premature balding or hair thinning) or in an area of alopecia-affected skin of a subject.
  • “Promoting hair growth” as used herein is intended to have its broadest possible meaning.
  • promoting hair growth is to decrease a rate of hair loss in an 35 309005815v2 Attorney Docket No.: 243735.000414 area that normally has hair such that (i) on-going hair loss occurs at a slower rate (e.g., retarded or slowed hair loss); (ii) hair loss is substantially stopped (e.g., the rate of hair loss is substantially the same as the rate of hair growth); or (iii) hair loss is reversed (e.g., the rate of hair loss is lower than the rate of hair growth) such that the area of interest exhibits a net increase in the amount of hair.
  • a slower rate e.g., retarded or slowed hair loss
  • hair loss is substantially stopped (e.g., the rate of hair loss is substantially the same as the rate of hair growth)
  • hair loss is reversed (e.g., the rate of hair loss is lower than the rate of hair growth) such that the area of interest exhibits a net increase in the amount of hair.
  • promoting hair growth is to induce hair growth on a substantially hairless surface capable of growing hair, such as a body surface that formerly had, but has lost substantially all, hair.
  • promoting hair growth includes inducing or stimulating hair growth on a hair-containing surface that is not experiencing hair loss; for example, increasing the rate at which hair-growing cells grow hair and/or increasing the number of hair-growing cells (e.g., increasing the number of hair follicles or the number of follicles in the anagen phase). Such latter method embodiments may be useful to increase hair density or length.
  • Promotion of hair growth also includes decreased shedding (either at the roots or by breaking/fragility) measured, for example, by hair pull tests.
  • the promotion of hair growth can be measured using any method known in the art or any of the methods disclosed herein, for example, quantitative and qualitative comparison of treated areas or subjects to controls.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful for treating hair loss in a subject.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful for treating a condition or disorder affecting hair growth in a subject, such as baldness, alopecia, or scarring.
  • the compound(s) or pharmaceutical compositions of the present disclosure maybe administered in combination with one or more additional therapeutic agents.
  • the treatment further comprises detecting in a biological sample obtained from the subject the presence of the one or more variants in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway prior to said administration.
  • the treatment further comprises detecting plasma 4-HMA concentration in a biological sample obtained from the subject prior to said administration.
  • Suitable biological sample can comprise peripheral blood mononuclear cells or a biopsy specimen. 36 309005815v2 Attorney Docket No.: 243735.000414
  • the subject is a pregnant female and the biological sample is a fetal DNA sample.
  • the fetal DNA sample can be obtained, for example, by circulating fetal DNA isolation, chorionic villus sampling, or amnioscentesis.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful for treating a 4-hydroxyphenylpyruvate dioxygenase-like (HPDL)- related disease or disorder in a subject.
  • the method includes detecting in a biological sample obtained from the subject the plasma 4-HMA concentration; and administering to the subject having a reduced plasma 4-HMA concentration ( ⁇ 20 nM) a therapeutically effective amount of the compound(s) or pharmaceutical compositions of the present disclosure.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful for increasing CoQ10 biosynthesis in a subject.
  • the method includes detecting in a biological sample obtained from the subject the plasma 4-HMA concentration; and administering to the subject having a reduced plasma 4-HMA concentration a therapeutically effective amount of the compound(s) or pharmaceutical compositions of the present disclosure.
  • EXAMPLES [00171] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments. [00172] Hpdl -/- mice recapitulate the symptoms of patients with NEDSWMA.
  • Hpdl -/- pups initially are identical in appearance to wild-type animals, but by post-natal day 5 (P5) Hpdl -/- pups develop movements consistent with spastic paresis and epileptic seizures, and stop gaining weight 19 . By P15, all Hpdl -/- pups are dead. In contrast, Hpdl +/- pups uniformly reach adulthood. [00173] Disease-modifying treatments for mitochondrial diseases, including NEDSWMA and other primary CoQ 10 deficiencies, remain an unmet medical need.
  • CoQ 10 supplementation can improve myositis, lactic acidosis, and other peripheral symptoms of primary CoQ10 deficiencies
  • CoQ10 supplementation controls the neurological symptoms of primary CoQ10 deficiency or other mitochondrial diseases less than 30% of the time 28 . It is not clear if correction of the underlying biochemical defects in primary CoQ10 deficiencies can modify the course of these diseases effectively or robustly. Specifically, the capacity of 4-HMA and 4-HB to restore CoQ synthesis and relieve the symptoms of HPDL loss in intact organisms is unknown. [00174] It was assumed that treatment of Hpdl -/- mice with 4-HMA would bypass loss of the CoQ10 headgroup biosynthesis and enable CoQ10 synthesis in situ.
  • the present disclosure shows 37 309005815v2 Attorney Docket No.: 243735.000414 that Hpdl -/- mice with 4-HMA, the product of HPDL, and 4-HB, the immediate precursor of the CoQ headgroup, near-uniformly live to adulthood and have motor phenotypes indistinguishable from Hpdl +/- littermates. 13 C-labeled 4-HMA and 4-HB were incorporated into CoQ 9 in the brains of treated mice. These experiments demonstrate that 4-HMA and 4-HB are physiologically important for CoQ10 synthesis during development and suggest that 4-HMA or 4-HB treatment may treat patients with NEDSWMA and SPG83 associated with HPDL variants.
  • Hpdl -/- pups develop symptoms of neurodevelopmental disease and have low plasma 4- HMA concentrations.
  • 4-HMA is an intermediate in a non-canonical tyrosine catabolism pathway required for the synthesis of the CoQ 10 headgroup in mammals (FIG.1A). It was hypothesized that deletion of Hpdl would result in decreased plasma concentrations of 4-HMA in Hpdl -/- pups relative to Hpdl +/- or Hpdl +/+ pups.
  • Hpdl +/- mice C57BL/6NCrl- Hpdlem1(IMPC)Mbp /Mmucd
  • KOMP/MMRRC Knockout Mouse Project / Mutant Mouse Resource & Research Center
  • Hpdl -/- pups initially have the same weight as wild-type pups, but do not gain weight following birth (FIG. 1B)
  • Hpdl -/- pups develop seizures, lose weight, and die by P15 (FIGS. 1C-1D).
  • Hpdl -/- pups have lower plasma [4-HMA] than Hpdl +/+ or Hpdl +/- pups (FIG.1E) and a higher plasma lactate/pyruvate ratio (Fig.4A).
  • Oral treatment with 4-HMA or 4-HB improves the lifespan of Hpdl -/- pups
  • 4-HMA the product of HPDL, or 4-HB, the immediate precursor of the CoQ 10 headgroup
  • Hpdl -/- pups treated with 4-HMA or 4-HB uniformly lived to ages of 12 months or more (FIG. 1F).
  • oral treatment of Hpdl -/- pups with CoQ 9 , CoQ 10 , the CoQ analog Idebenone, and mitochondrially targeted antioxidant MitoTEMPO 30-32 did not improve their survival (FIG.1F).
  • 4-HMA and 4-HB are incorporated into mouse brain CoQ9 38 309005815v2 Attorney Docket No.: 243735.000414 [00180]
  • Hpdl +/+ , Hpdl +/- , and Hpdl -/- pups with 13 C 6 -4-HB and 13 C 6 -4-HMA at 10 mg/kg from P3 to P20 and measured the incorporation of 13 C into CoQ9 in the brain by liquid chromatography-mass spectrometry (FIG.1G).
  • Hpdl +/+ and Hpdl +/- mice were derived from 4-HMA or 4-HB, but Hpdl -/- pups derived 50% of CoQ 9 from exogenously administered 13 C 6 -4-HB and 13 C 6 -4-HMA (FIG. 1H).
  • No CoQ 9 was labeled in P12 Hpdl -/- pups that were not fed 13 C 6 -4-HB or 13 C 6 -4-HMA.
  • Hpdl -/- pups not fed 13 C6-4-HMA exhibited reduced CoQ9 relative to Hpdl -/- pups fed 13 C6-4-HMA (FIG.4H).
  • Hpdl -/- pups There also was loss of normal architecture of the cerebellar Purkinje cell layer (EGL) (FIG.2C). Hpdl -/- pups also had decreased inner granular layer (IGL) thickness (FIG.2D). These findings are consistent with decreased proliferation of cerebellar granule cells and a failure of granule cells to successfully establish the IGL. Cortical neurons in Hpdl -/- pups also show vacuolation, decreased nuclear area, and loss of normal cortical architecture with neuronal microcolumns, edema and neuronal shrinking in the cortex relative to Hpdl +/- pups (FIG. 2E).
  • the P8-10 group contained Hpdl +/+ , Hpdl +/- , Hpdl- /- pups, and Hpdl -/- pups treated with 4-HMA.
  • the P17-19 group did not have untreated Hpdl -/- pups as these animals die by P15.
  • there was a significant increase in input resistance (Ri) and significant reduction in membrane capacitance (Cm) in cerebellar Purkinje cells in Hpdl -/- mice in comparison to Hpdl +/+ and Hpdl +/- mice (FIGS. 3A-3B, Table 1).
  • Cerebellar Purkinje cells from Hpdl -/- pups had a tighter grouping of currents at hyperpolarized membrane potentials (-100 to -60 mV) relative to the Hpdl +/+ group 40 309005815v2 Attorney Docket No.: 243735.000414 (FIGS.6A-6B, insets). This grouping resulted in a flatter I/V curve at hyperpolarized membrane potentials that was significantly different from the I/V curves of cerebellar Purkinje cells from Hpdl +/+ and Hpdl +/- pups (FIG. 6A).
  • the I/V curve of cerebellar Purkinje cells in Hpdl -/- pups treated with 4-HMA was steeper than the curves of the Hpdl +/+ , Hpdl +/- , and Hpdl -/- pups, and closer in slope and magnitude to the I/V curves of P17-19 cerebellar Purkinje cells.
  • the I/V curve of cerebellar Purkinje cells from 4-HMA-treated Hpdl -/- pups was indistinguishable from curves from Hpdl +/+ and Hpdl +/- pups (FIGS.6F-6G).
  • Cerebellar Purkinje cells from Hpdl -/- pups treated with 4-HMA had a higher firing rate than Hpdl +/+ and Hpdl +/- cerebellar Purkinje cells. These differences were consistent with immaturity of Hpdl -/- cerebellar Purkinje cells relative to Hpdl +/+ and Hpdl +/- pups, and with accelerated maturation of 4-HMA-treated Hpdl -/- cerebellar Purkinje cells. These differences disappeared by P17-19 (FIGS.6F-6G). Hpdl loss and 4-HMA rescue did not affect the F/I curves of cerebellar Purkinje cells (FIGS. 6C-6D).
  • Hpdl -/- mice are comparable to Hpdl +/- mice following 4-HMA treatment
  • 4-HMA treatment improves the neurological symptoms and metabolic physiology of Hpdl -/- mice
  • Hpdl -/- mice treated with 4-HMA had decreased gait periodicity (FIG.3C), but had identical performance on the pole test and transverse beam tests of cerebellar function (FIGS. 3D-3E). Both female and male Hpdl +/- mice and Hpdl -/- mice treated with 4-HMA had decreased forelimb grip strength relative to Hpdl +/+ mice, but did not have differences when the strength of all limbs was measured (FIG. 3F; FIGS. 6G, 6J). We did not observe differences in Rotarod latency between Hpdl +/+ mice, Hpdl +/- mice, and Hpdl -/- mice treated with 4-HMA (FIG. 6K).
  • non-neuronal symptoms of primary CoQ 10 deficiencies can respond to CoQ 10 or short- chain CoQ supplementation 41,42 , consistent with at least some bioavailability of CoQ10 to non- CNS organs.
  • 4-HMA or 4-HB supplementation may be of benefit in patients with HPDL variants that cause loss of HPDL function, or who have other defects in CoQ 10 headgroup synthesis. Because patients with HPDL variants appear normal at birth 19-26 , loss of HPDL function or other CoQ10 headgroup synthesis deficiencies ideally would be identified by newborn screening for reduced plasma 4-HMA, as we observed in our patients, or by sequencing so that supplementation with CoQ 10 headgroup intermediates can begin before symptoms develop.
  • Hpdl knockout does not significantly inhibit cellular development and that 4-HMA treatment accelerates maturation of Hpdl -/- Purkinje cells at P8-10.
  • 4-HMA treatment accelerates maturation of Hpdl -/- Purkinje cells at P8-10.
  • the electrophysiological characteristics of Hpdl +/+ , Hpdl +/- , and Purkinje cells from 4-HMA-treated Hpdl -/- pups have indistinguishable electrophysiological properties. 43 309005815v2 Attorney Docket No.: 243735.000414
  • Purkinje cell death induced by Hpdl loss would lead to loss of Purkinje function and cell axonal guidance signals, which may alter migration of granule cells from the EGL to the IGL.
  • HPDL loss may contribute to decreased numbers of cerebellar granule cells in the EGL, which reduces the population of cerebellar granule cells available to enter the IGL and form synapses with Purkinje cells and mossy fibers. The failure of these latter neurons to find their targets would lead to degeneration and the neurodevelopmental and neurodegenerative phenotypes that we observe in Hpdl -/- mice and patients with HPDL variants.
  • 4-HMA rescue substantially improves the overall survival of Hpdl -/- mice, but 4-HMA- treated Hpdl -/- mice have grip strength and weight comparable to Hpdl +/- mice.
  • the partial rescue of neurological phenotypes by 4-HMA could be due to inadequate dosing of 4-HMA or inability to import sufficient 4-HMA for CoQ10 synthesis. Alternately, inadequate production of 4-HMA during the late stages of embryogenesis, when granule cells start proliferating 46 , or peripheral nervous system defects could be responsible for these residual symptoms.
  • a proposed treatment is administration of 4-HB as an oral solution at a concentration of 5 mg/mL in water.
  • An example NEDSWMA patient might weigh approximately 30 kg. Said patient will be treated initially with 1 mg/kg 4-hydroxybenzoate (30 mg), corresponding roughly to the HED of the effective dose of 10 mg/kg studied in mice. If this dose is tolerated, the dose will increase to 10 mg/kg (300 mg) on the second day.
  • the dose will increase to 33 mg/kg (1000 mg) on the third day. If this dose is tolerated, the dose will increase to 100 mg/kg (3,000 mg) on the fourth day. This dose will be administered over 30-60 minutes if necessary to enable full dosing (the 3,000 mg dose will be equivalent to 600 ml of 4-HB DP solution at 5 mg/kg). The duration of dosing could be from 30 years to months or years, or potentially lifelong treatment.
  • a patient’s weight Prior to treatment, at days 3, 6, 15, and 30 after the first dose of 4-HB, and at 3, 6, 9, and 12 months after the end of the study, a patient’s weight will be measured, carry out neurological exams, and collect urine for organic acid analysis (malate, fumarate, lactate and pyruvate), a measure of mitochondrial disease (8). Also, pastic paraplegia rating scale (9), timed 10-meter walk test (10), 9-hole peg test (11), and the modified Ashworth scale (12) will be used to measure a patient’s neurological outcomes prior to, during, and after treatment. Brain and spine MRI/MRS, and video recording of the clinical exam will also be performed.
  • 4-HB is a natural mammalian metabolite. 4-HB is also the primary product of paraben catabolism in mammalians.
  • Parabens are simple esters of 4-HB widely used a food additives and 45 309005815v2 Attorney Docket No.: 243735.000414 preservatives and classified by the FDA as Generally Recognized as Safe (GRAS) (13). 4-HB is also found in high concentrations in natural foods (14-16). Based on this, acute toxicities are not anticipated from the proposed 4-HB treatment.
  • 4-Hydroxybenzoate has been tested in mice at doses of up to 500 mg/kg without observable toxicity. Toxicity would most likely be esophagitis or gastritis following administration of 4-hydroxybenzoic acid, as it has a pH of 4 in water (comparable to orange juice, which has a pH of 3.5).
  • a patient will be treated with aluminum hydroxide/magnesium hydroxide (Maalox/Mylanta), or with sucrose/calcium carbonate. If other toxicities are observed, the dose will be reduced by 20% and treatment will continue. If toxicity is observed a second time, the dose will be reduced by an additional 20%. If toxicity is observed after this point, the dose will be reduced to 1000 mg/day. If toxicity is observed after this point, the dose will be reduced to 300 mg/day. If toxicity is observed after this point, treatment will be discontinued.
  • the drug product to be used to treat a patient is 4-hydroxybenzoic acid in the form of white power prepared as a monophasic solution in water for oral use.
  • 4-HMA is converted to 4-hydroxybenzoic acid (4- HB).4-HB is the immediate precursor of the headgroup of Coenzyme Q10 (CoQ10), a lipophilic antioxidant critical for control of reactive oxygen species in biological membranes and for activity of the mitochondrial electron transport chain (FIG.10) (reviewed in(5).
  • CoQ10 Coenzyme Q10
  • FIG.10 mitochondrial electron transport chain
  • Biallelic HPDL variants cause a disease called NEDSWMA (Neurodevelopmental disorder with spastic paresis and brain white matter abnormalities; OMIM 619026) (1-4). This is a progressive, uniformly lethal pediatric encephalopathy. Patients with NEDSWMA present in childhood with progressive spasticity and neurodevelopmental delay.
  • spastic paraplegia-83 Patients with non-truncating HPDL variants present with a milder form of spastic paraplegia called spastic paraplegia-83 (OMIM 619027). 48 309005815v2 Attorney Docket No.: 243735.000414 [00216]
  • 4-HB the immediate precursor of the CoQ10 headgroup, should enter the brain and be incorporated into Coenzyme Q.
  • 4-HB is not detectable in plasma, but 4-HMA is detectable in the plasma of mice and patients.
  • Hpdl -/- mice have lower plasma levels of 4-HMA than wild-type mice (FIG.1E). Both 4- HMA and 4-HB at 10 mg/kg, dosed orally once daily, improve the survival of Hpdl -/- mice from 0% at 15 days to >90% at 300 days (FIG.1F). CoQ10 treatment does not improve the survival of mice lacking Hpdl (FIG. 1F).
  • Hpdl -/- mice must be treated with at least 10 mg/kg 4-HMA to improve their overall survival (FIG. 1F).
  • Hpdl -/- mice have cerebellar atrophy with Purkinje cell vacuolization and do not form the internal granular layer (IGL) of the mature cerebellum (FIG. 2C, panels C, G, K). These developmental defects are restored to near wild-type appearance by 4- HMA treatment (FIG.2C, panels D, H, L).
  • 4-HMA and 4-HB enter the brains of Hpdl -/- mice and account for half of the CoQ9 (the mouse equivalent of human CoQ10) synthesized in the brain (FIG.1H).
  • the 4-HB used for these studies came from a different source than the data in FIG.3A, and enabled all treated mice to survive to postnatal day 20, the time of sacrifice.
  • 4-HB would be administered as a suspension at a concentration of >10 mg/m, or as a pill, a lozenge, or a capsule. Consideration would need to be made for administration of this compound to neonates and infants who present with the more severe form of HPDL encephalopathy.
  • 4-HB will be prepared as a monophasic solution in water for oral use.4-HB will be added to distilled water to a concentration of 5 mg/mL with gentle stirring followed by sonication.
  • the solution will be vacuum filtered through a 0.2 ⁇ m PES membrane into a sterile bottle.
  • the solution has a sour taste and is palatable. Storage will be at 4 ⁇ C.
  • Formulated compound should be consumed within 24 hours of preparation or frozen at -20 ⁇ C immediately after formulation. [00227]
  • the purity and concentration of 4-HB will be measured by liquid chromatography-mass spectrometry.
  • the LC-MS method will use an Atlantis BEH Z-HILIC column mounted on a Dionex Ultimate 3000 UPLC coupled to a Thermo Q Exactive HF Orbitrap MS for detection.4- 50 309005815v2 Attorney Docket No.: 243735.000414 HB will be identified by retention time in comparison to unlabeled standards and a 13 C6-4-HB internal standard, MS1 accurate mass, and MS2 fragmentation. Concentration will be determined by comparison to a standard curve with a 13 C 6 -4-HB internal standard. Purity will be determined by measurement of the area under the 4-HB peak in comparison to the TIC. We will accept concentrations within 15% of the target concentration and purity of >80%, to account for high amounts of 13 C 6 -4-HB internal standard.
  • the final product will be packaged in a polypropylene bottle with tamper-evident packaging to be delivered to the patient.
  • Solutions can be made and frozen at -20 ⁇ C for at least a month without loss of efficacy in treating mice.4-HB is stable after storage at -20 ⁇ C in distilled water for 3 months (FIG.11B). Once the solution has been thawed, it must be brought to room temperature to ensure that all 4- HB has dissolved prior to use, and used within 24 hours.
  • Drug Components and Drug Product 51 309005815v2 Attorney Docket No.: 243735.000414 thawed, it will be mixed well to ensure that the 4-HB is dissolved and used with 24 hours.
  • LD 50 Mouse oral 2200 mg/kg (Lewis, R.J.
  • Parabens are simple ester precursors of 4- hydroxybenzoic acid (also known as para-hydroxybenzoic acid). Parabens are stable in air and resist hydrolysis in acidic medium and under conditions of sterilization. They have been used as preservatives in foods, cosmetics, and pharmaceutical additives for over five decades.
  • ⁇ Methyl and propyl paraben have been affirmed as Generally Recognized as Safe (GRAS) for direct addition to food at concentrations up to 0.1% and by prior sanction for indirect addition via packaging materials.
  • 52 309005815v2 Attorney Docket No.: 243735.000414
  • Methyl-, propyl- and butyl-paraben have been approved as synthetic flavoring substances and adjuvants for addition to beverages at minimum quantity, in amounts not to exceed 20 ppm.
  • ⁇ Methyl-, propyl- and butyl-paraben can also be used as direct food additives for use as preservatives in synthetic flavoring substances and adjuvants.
  • mice, rat, rabbit, and dog models showed that parabens are practically non-toxic by various routes of administration. Toxicities for these compounds are >1 g/L in large animal models.
  • a summary of acute toxicity data is provided in the Table 2. Table 2. Acute oral toxicity of parabens in mice, rats, rabbits, and dogs. lethal assay, and host-mediated assay indicated that parabens are not genotoxic.
  • mice were treated with topical 100 mg/kg 4-HMA in water. 4-HMA was applied directly to the skin using Q-tip every other day (week 5-week 12). Regrowth of hair in shaved 90-week-old-mice following treatment was observed (FIG.14). [00246] 90-Week-old mice (JAX C57/BL6 mice) were shaved and the shaved area was treated topically with 4-HMA (no systemic 4-HMA was provided).

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Abstract

The present disclosure is directed to a method of treating a disease or disorder selected from the group consisting of heart disease, neurodegenerative disease, migraine headache, neurodevelopmental disease, infertility, pulmonary disease, muscle disease, liver disease, pancreatic disease, oral disease, ophthalmic disease, hearing disease, diseases of pregnancy, diseases of prematurity, aging disorders, movement disorders, infectious disease, and any disease in which Coenzyme Q declines, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), or a compound of Formula (I); where R1, R2, R3, and R4 are as described herein. The present disclosure is also directed to a method of improving wound healing in a subject and a method of treating a neurodevelopmental disorder with spastic paresis and brain white matter abnormalities.

Description

Attorney Docket No.: 243735.000414 TREATMENT WITH 4-HYDROXYBENZOIC ACID TO AUGMENT COQ10 PRODUCTION CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the priority benefit of U.S. Provisional Patent Application Serial No.63/567,290, filed March 19, 2024, which is hereby incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] This invention was made with government support under R35 GM147119 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION [0003] The present disclosure relates to a treatment with 4-hydroxybenzoic acid to augment COQ10 production. BACKGROUND [0004] Coenzyme Q (CoQ), or ubiquinone, is the sole endogenously synthesized lipophilic antioxidant found in biological membranes across all kingdoms of life1. CoQ consists of a benzoquinone headgroup conjugated to a polyisoprene tail that anchors the redox-active quinone headgroup in the membrane. In mice, the tail has 9 isoprene units (CoQ9) and in humans the tail has 10 isoprene units (CoQ10). Coenzyme Q10 (CoQ10) is essential for activity of the mitochondrial electron transport chain that generates ATP2 and quenches reactive oxygen species in membranes3. [0005] Primary CoQ10 deficiencies induced by variants in the CoQ10 synthesis genes result in heterogeneous symptoms, including myopathy, encephalopathy, nephropathy, and cerebellar ataxia during development4. By current clinical consensus, all patients with primary CoQ10 deficiencies are offered CoQ10 supplements5. Surprisingly, neurological symptoms only improve in about half of CoQ10-treated patients, potentially due to the intrinsically refractory response of neuronal electron transport chain activity to CoQ10 supplementation6, poor CoQ10 uptake and 1 309005815v2 Attorney Docket No.: 243735.000414 pharmacokinetics7-10, and an incomplete understanding of mammalian CoQ10 synthesis and trafficking11-13. There have been attempts to use CoQ10 precursors to treat primary CoQ10 deficiencies, but these trials required very high doses to improve symptoms14-16. There are no disease-modifying treatments for primary CoQ10 deficiencies. [0006] The biosynthesis pathways for the CoQ10 isoprenoid tail have long been known17, but the metabolic reactions required for synthesis of the CoQ10 headgroup in mammals have been elusive until recently18. Mammalian CoQ10 headgroup synthesis begins with the transamination of the aromatic amino acid tyrosine by the tyrosine aminotransferase (TAT) to yield 4- hydroxyphenylpyruvic acid (4-HPPA). It has been shown that the mitochondrial iron and O2- dependent dioxygenase 4-hydroxyhenylpyruvate dioxygenase-like (HPDL) oxidatively decarboxylates 4-HPPA to generate 4-hydroxymandelic acid (4-HMA).4-HMA is the first committed intermediate in the mammalian CoQ10 headgroup biosynthesis pathway.4-HMA is converted, through a set of uncharacterized steps, into 4-hydroxybenzoate (4-HB), the immediate precursor of the CoQ10 quinone headgroup (Fig.1A). [0007] Homozygous or compound heterozygous truncating HPDL variants that induce complete loss of HPDL function are associated with an infantile and childhood NEurodevelopmental Disorder with Spastic paresis and brain White Matter Abnormalities (NEDSWMA)19-27. Children with NEDSWMA present prior to the age of 2 with multiple progressive neurological symptoms including cortical and cerebellar atrophy, epilepsy, developmental delay with poor to absent language skills, and spastic tetraplegia, and die early in life. Biallelic variants in HPDL are associated with a less severe disorder, autosomal recessive Spastic Paraplegia 83 (SPG83), which presents with progressive lower limb spasticity, myalgia, mild dysarthria, and no other neurologic abnormalities22. [0008] NEDSWMA (NEurodevelopmental Disorder with Spastic paresis and brain White Matter Abnormalities; OMIM 619026) is an ultra-rare, progressive, uniformly lethal pediatric mitochondrial encephalopathy (1-4). NEDSWMA is caused by biallelic variants of 4- hydroxyphenylpyruvate dioxygenase-like (HPDL), a dioxygenase that converts 4- hydroxyphenylpyruvate into 4-hydroxymandelate (4-HMA), the first committed precursor in the mammalian Coenzyme Q10 (CoQ10) headgroup biosynthesis pathway.4-HMA is eventually converted into 4-hydroxybenzoic acid (4-HB), the immediate precursor of the CoQ10 Headgroup. HPDL deficiency results in reduced levels of CoQ10 due to the inability to 2 309005815v2 Attorney Docket No.: 243735.000414 synthesize the CoQ10 headgroup. CoQ10 is a lipophilic antioxidant critical for control of reactive oxygen species in biological membranes and for activity of the mitochondrial electron transport chain (FIG.10) (reviewed in(5)). [0009] NEDSWMA is the latest addition to the family of primary CoQ10 deficiencies, a group of rare mitochondrial diseases caused by defects in CoQ10 biosynthesis. Patients with these conditions develop a variety of symptoms, with nearly all of them presenting with progressive encephalopathies. The overall success rate of treating patients with CoQ10 deficiencies with CoQ10 supplementation therapies is less than 30% (6). NEDSWMA is refractory to CoQ10 supplementation therapy. [0010] Patients with mitochondrial diseases tend to present with incremental physical deterioration followed by rapid decompensation upon exposure to a stressor such as an infection. After day 7, Hpdl-/- mice, the accepted preclinical model of NEDSWMA (2) deteriorate rapidly and irreversibly to an obtunded state and death. Patients with HPDL variants experience a similar slow decline followed by sudden and unpredictable decompensation driven by the underlying encephalopathy and associated cardiomyopathy. The progressive encephalopathy and cardiomyopathy from mitochondrial diseases are often rapid and always lethal (7). [0011] As such, there is an unmet need for novel therapies to augment COQ10 production. SUMMARY OF THE INVENTION [0012] Primary CoQ10 deficiencies are inborn errors of metabolism driven by loss of function of the enzymes that make the critical antioxidant and electron carrier Coenzyme Q10 (CoQ10). Patients with primary CoQ10 deficiencies frequently have neurodevelopmental disease presenting with seizures, paresis, and profound neurodevelopmental delay. Surprisingly, the neurological symptoms of primary CoQ10 deficiencies rarely respond to CoQ10 supplementation. [0013] We recently described the first committed step in mammalian CoQ10 headgroup synthesis, in which the dioxygenase HPDL makes 4-hydroxymandelic acid (4-HMA). Patients with HPDL variants have a childhood neurodevelopmental disease presenting with spastic paresis, neurodevelopmental delay, and seizures, and Hpdl-/- mice recapitulate these symptoms. We find that Hpdl-/- mice have cerebellar atrophy with Purkinje and granular cell loss. Oral treatment of mice with 4-HMA and with 4-HB, the immediate precursor of the CoQ10 headgroup, restores cerebellar architecture and improves the survival of Hpdl-/- pups from 15 days to >300 days. Our work establishes the essential role of the 4-HMA CoQ10 headgroup synthesis pathway 3 309005815v2 Attorney Docket No.: 243735.000414 for neural development and offers proof of concept that CoQ10 headgroup intermediate supplementation could treat patients with loss-of-function HPDL variants. These data also suggest that CoQ10 levels could be increased by treatment with 4-HMA; this is a billion-dollar supplement market. This is the first disease-modifying therapy for primary CoQ10 deficiencies. [0014] 4-Hydroxyphenylpyruvate dioxygenase-like (HPDL) is an iron-dependent mitochondrial dioxygenase that synthesizes 4-hydroxymandelate (4-HMA). In mammals, 4- HMA is the first committed intermediate in the biosynthesis pathway for 4-hydroxybenzoate (4- HB), the immediate precursor of the Coenzyme Q10 (CoQ10) headgroup. Children with homozygous or compound heterozygous HPDL variants develop a lethal mitochondrial encephalopathy and primary CoQ10 deficiency called neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA). Hpdl-/- mice, a model for NEDSWMA, develop spastic paresis and die by post-natal day 15 (P15). No disease- modifying therapies for primary CoQ10 deficiencies are currently available. Here, we show that Hpdl-/- mouse pups have defects in cortical and cerebellar development consistent with mitochondrial disease. Labeled 4-HMA and 4-HB enter the brains of Hpdl-/- mice and are incorporated into CoQ9, the mouse equivalent of human CoQ10. Oral treatment of Hpdl-/- pups with 4-HMA or 4-HB restores cerebellar architecture and Purkinje cell function, enables Hpdl-/- mice to live into adulthood, and substantially improves their motor function. CoQ10, CoQ9, and soluble CoQ derivatives do not improve the overall survival of Hpdl-/- mice. Our work suggests that 4-HMA and 4-HB treatment can modify the course of NEDSWMA and other diseases driven by loss of CoQ10 headgroup synthesis. [0015] Our preclinical data have shown that (1) reductions in 4-HMA levels in Hpdl-/- mice and patients with HPDL variants are equivalent relative to wild-type mice and age-matched controls, respectively; (2) treatment of Hpdl-/- mice with 4-HB reverses cerebellar atrophy and dramatically improves overall survival; and (3) 4-HB incorporation into CoQ9, the murine equivalent of human CoQ10, is boosted by one order of magnitude in the brains of Hpdl-/- mice treated with 4-HB. BRIEF DESCRIPTION OF THE DRAWINGS [0016] FIGS.1A-1H show that mammalian CoQ headgroup intermediates improve the survival of Hpdl-/- mice, and are incorporated into CoQ9 in vivo. FIG.1A shows the mammalian CoQ headgroup synthesis pathway. Tyrosine is deaminated to 4-hydroxyphenylpyruvate (4- 4 309005815v2 Attorney Docket No.: 243735.000414 HPPA). HPDL coverts 4-HPPA to 4-hydroxymandelate (4-HMA).4-HMA is converted to 4- hydroxybenzoate (4-HB), the immediate precursor of the CoQ headgroup. FIG.1B is a graph showing that Hpdl-/- pups exhibit significant weight loss by post-natal day 10 (P10) relative to Hpdl+/+ and Hpdl+/- pups. Error bars represent median±interquartile range. FIG.1C is a graph showing that Hpdl-/- pups die by P15. Hpdl+/+ and Hpdl+/- pups survive >1 year. FIG.1D is a graph showing that all Hpdl-/- pups have observed seizures. No Hpdl+/+ or Hpdl+/- pups had observed seizures. FIG.1E is a graph showing that Hpdl-/- pups have lower plasma 4-HMA than Hpdl+/+ or Hpdl+/- pups at P10. Error bars represent mean±standard deviation. FIG.1F is a graph showing that oral supplementation with 4-HMA and 4-HB (10 mg/kg, once daily) improves the overall survival of Hpdl-/- pups. Oral supplementation of CoQ9, CoQ10 and related compounds does not improve Hpdl-/- pup survival. FIG.1G is a schematic showing the incorporation of 13C from 13C6-4-HMA and 13C6-4-HB into mouse CoQ9. Incorporation of 13C-labeled 4-HMA and 4- HB increases the mass of CoQ9 by 6 Da (m6). FIG.1H shows fractional labeling of bulk brain CoQ9 in mice fed 13C6-4-HMA and 13C6-4-HB (10 mg/kg, once daily) from P3-P20. Both 13C6-4- HMA and 13C6-4-HB are incorporated into 13C6-CoQ9 (m6) in Hpdl-/- mice. Data presented are mean±standard deviation. Significance was tested by two-way analysis of variance (ANOVA) followed by Tukey’s post-hoc test. p values are presented on the plot, with ns=not significant. Survival data were analyzed with the log-rank test. [0017] FIGS.2A-2E show that 4-HMA supplementation restores the histologic appearances of the brains of Hpdl-/- mice. FIG.2A shows representative electron micrographs of cortex (panels A-D) and cerebellum (panels E-H) in P11 Hpdl+/+, Hpdl+/-, and Hpdl-/- mouse pups reveal minimal changes in cortical ultrastructure. The mitochondria (marked by arrowheads) in Hpdl+/+ (panels A, E) and Hpdl+/- (panels B, F) mouse pups are intact, but the mitochondria in the cerebella of Hpdl-/- mouse pups (panel G) are fragmented. Supplementation of Hpdl-/- mice with 10 mg/kg 4-HMA restores mitochondrial ultrastructure in the cerebellum (panel H). FIG.2B shows quantitation of mitochondrial perimeter in electron micrographs of the cerebellum in P11 Hpdl+/+, Hpdl+/-, and Hpdl-/- mouse pups, and Hpdl-/- mouse pups treated with 4-HMA. Mitochondria in the Hpdl-/- mouse pups are smaller than in the Hpdl+/+ and Hpdl+/- pups.4-HMA treatment improves the size of the mitochondria in the Hpdl-/- pups, but not to the size of mitochondria in Hpdl+/+ pups. FIG.2C shows that P11 Hpdl-/- pups exhibit marked cerebellar atrophy (panel C), with Purkinje cells (arrowheads) showing vacuolization and intracellular 5 309005815v2 Attorney Docket No.: 243735.000414 edema, thinning of the inner granular layer (IGL) and molecular layer, and compaction of the external granular layer (EGL) (panels G, K). These abnormalities are improved to near-wild-type pups by supplementation with 4-HMA (panels D, H, L). FIG.2D shows quantitation of B. Hpdl-/- mouse pups have a thinner IGL than Hpdl+/+ or Hpdl+/- pups. The thickness of the IGL in Hpdl-/- mouse pups is restored by 4-HMA supplementation. Error bars represent median±interquartile range. FIG.2E shows that P11 Hpdl-/- pups exhibit loss of normal cortical layers of the cerebral cortex (panels C, G, K), as well as edema, shrinking of the cortical neurons, and red neurons (marked by arrowheads). These histological findings are partially restored by supplementation with 4-HMA (panels D, H, L). Raw data and means are presented. Significance was tested by two-way analysis of variance (ANOVA) followed by Tukey’s post-hoc test. [0018] FIGS 3A-3F show that 4-HMA supplementation improves the behavioral phenotypes of Hpdl-/- mice and electrophysiologic behavior of Purkinje cells from Hpdl-/- pups. FIG.3A shows that patch-clamping of Purkinje cells in brain slices from P8-10 pups demonstrates increased input resistance and membrane capacitance in Purkinje cells from Hpdl-/- pups in comparison to Purkinje cells from Hpdl+/+ and Hpdl+/- pups. Treatment of Hpdl-/- pups with 4-HMA decreases Purkinje cell input resistance and increases membrane capacitance to levels comparable to more mature Purkinje cells (FIG.6E). FIG.3B shows that 4-HMA treatment partially restores the weight of male Hpdl-/- mice and rescues the weight of Hpdl-/- female mice. Hpdl+/- mice have comparable weights to Hpdl+/+ mice. FIG.3C shows that Hpdl-/- mice treated with 4-HMA exhibit similar gait to Hpdl+/- mice. FIG.3D shows that Hpdl-/- mice treated with 4-HMA have similar performance to Hpdl+/+ and Hpdl+/- mice in the pole test, a measure of motor coordination. FIG.3E shows that Hpdl-/- mice treated with 4-HMA have similar performance to Hpdl+/+ and Hpdl+/- mice in the transverse beam test, a measure of balance. FIG.3F shows relative to Hpdl+/+ mice, forelimb grip strength is reduced in Hpdl+/- mice as well as Hpdl-/- mice treated with 4-HMA. Hindlimb grip strength is identical in Hpdl+/+, Hpdl+/-, and Hpdl-/- mice treated with 4-HMA from P3 until 4-6 weeks. Data presented are mean±standard deviation, as well as raw data. Significance was tested by two-way analysis of variance (ANOVA) followed by Tukey’s post-hoc test. [0019] FIG.4A shows lactate/pyruvate ratio in plasma from Hpdl+/+, Hpdl+/-, and Hpdl-/- pups. Hpdl-/- pups have a higher lactate/pyruvate ratio than Hpdl+/+ and Hpdl+/- pups. FIG.4B shows mouse dose-response of 4-HMA treatment in improving the survival of Hpdl-/- pups.4-HMA 6 309005815v2 Attorney Docket No.: 243735.000414 dosing of 10 mg/kg improves the 30-day survival of 90% of pups. Doses of 0.1 mg/kg or 1 mg/kg did not improve the overall survival of these. FIG.4C shows MTD of 4-HMA and 4-HB, and half-life of 4-HMA and half-life of 4-HB dosed at treatment dose (10 mg/kg po), 500 mg/kg po, and 1 mg/kg IV. Data represent mean±standard deviation. FIG.4D shows pharmacokinetic data for 4-HMA and 4-HB at 500 mg/kg po and 1 mg/kg IV. Error bars represent mean±standard deviation for data from 3 mice. FIG.4E shows treatment of Hpdl-/- pups with 4-HMA, the product of HPDL, and 4-HB, the immediate precursor of the CoQ headgroup, results in weight gain similar to Hpdl+/- pups. Error bars represent median±interquartile range. FIG.4F shows Hpdl-/- pups are able to stand 3 days after supplementation with 4-HMA (10 mg/kg, oral administration). FIG.4G shows effects of 4-HMA treatment on an Hpdl-/- pup. Two Hpdl-/- pups are on the right and two Hpdl+/- littermates are on the right. The Hpdl-/- pup second from the right was treated with 10 mg/kg 4-HMA po with improvement in growth and motor function. The untreated Hpdl-/- pup died by P15. FIG.4H shows CoQ9 abundance and labeling from mouse brains following treatment with 13C6-4-HMA starting at postnatal day 3.13C6-4-HMA is incorporated into CoQ9 in Hpdl-/- mice, and increases brain CoQ9 relative to untreated mice.13C6- 4-HMA is not incorporated into CoQ9 in Hpdl+/+ mice and is incorporated into CoQ9 at a lower fraction in Hpdl+/- mice. Significance was tested by two-way analysis of variance (ANOVA) followed by Tukey’s post-hoc test. [0020] FIG.5A shows that P11 Hpdl-/- pups do not exhibit major changes in hippocampal histology in comparison to Hpdl+/+ pups, Hpdl+/- pups, and Hpdl-/- pups treated with 4-HMA. [0021] FIGS.6A-6L show functional characteristics of Purkinje cells and additional behavioral and neurological tests of Hpdl+/+, Hpdl+/-, Hpdl-/- and 4-HMA-treated Hpdl-/- mice. FIG.6A shows that the I/V curves of Purkinje cells from P8-10 Hpdl-/- pups and 4-HMA-treated Hpdl-/- pups are significantly different from each other and from the I/V curves of Hpdl+/+ and Hpdl+/- pups, which are similar. P-values indicating statistical significance are listed. The Hpdl-/- pups have a flatter I/V curve at hyperpolarized membrane potentials relative to the other curves due to a tighter grouping of currents at hyperpolarized membrane potentials (-100 to -60 mV) than the Hpdl+/+ and Hpdl+/- pups (see insert). The 4-HMA-treated Hpdl-/- pups have a steeper I/V curve similar to more mature Purkinje cells. FIG.6B shows F/I curves of Purkinje cells from P8-10 Hpdl+/+, Hpdl+/-, Hpdl-/- and 4-HMA-treated Hpdl-/- pups. There were no significant differences in the linear portions of each curve between each group. The insert shows the simple firing 7 309005815v2 Attorney Docket No.: 243735.000414 pattern of an immature Purkinje cell. FIG.6C shows peak frequency of Purkinje cells from P8- 10 Hpdl+/+, Hpdl+/-, Hpdl-/- and 4-HMA-treated Hpdl-/- pups. The 4-HMA treated Hpdl-/- group has higher peak frequency than any of the other groups. Differences in frequency were identified by two-way ANOVA followed by Dunnett’s multiple comparison test. FIG.6D shows action potential characteristics of P8-10 Hpdl+/+, Hpdl+/-, Hpdl-/- and 4-HMA-treated Hpdl-/- pups. An average action potential is shown in panel A and the phase plane diagram is shown in panel B. Significant action potential shape differences can be seen between Purkinje cells from Hpdl+/+ and 4-HMA-treated Hpdl-/- pups. Purkinje cells from 4-HMA-treated Hpdl-/- pups had a significantly lower spike threshold than the Hpdl+/+ (p=0.0076) and Hpdl-/- pups (p=0.0207; panel C). The spike threshold for Purkinje cells from the Hpdl+/- and 4-HMA-treated Hpdl-/- pups trended to difference but was not significant (p=0.0506), consistent with 4-HMA treatment rescuing Hpdl-/- pup grip strength to the level of Hpdl+/- mice (FIG.6J). The spike half-width of Purkinje cells from the 4-HMA-treated Hpdl-/- pups was significantly narrower than all three treatments (Hpdl+/+: p<0.0001; Hpdl+/-: p=0.0002; Hpdl-/-: p<0.0001; panel E). Finally, Purkinje cells from 4-HMA-treated Hpdl-/- pups had a shallower action half-potential (AHP) amplitude compared to Hpdl+/+and Hpdl-/- pups (WT: p=0.0008; KO: p=0.0461; panel F). The - HMA-treated Hpdl-/- pup statistics resemble the WT condition of the P17-19 group (Fig.6I). Differences in frequency were identified by two-way ANOVA followed by Dunnett’s multiple comparison test. FIG.6E shows that HPDL supplementation restores input resistance and membrane capacitance of Purkinje cells from Hpdl-/- pups to levels comparable to Hpdl+/+ and Hpdl+/- pups at P17-19. FIG.6F shows that the I/V curves of Purkinje cells from P17-19 Hpdl+/+, Hpdl+/-, and 4-HMA-treated Hpdl-/- pups are similar. The inset depicts an example Hpdl+/+ Purkinje cell current response to the voltage step commands, which is similar to the Hpdl+/- and 4-HMA-treated Hpdl-/- pup Purkinje cells responses. FIG.6G shows F/I curves of Purkinje cells from P17-19 Hpdl+/+, Hpdl+/-, Hpdl-/- and 4-HMA-treated Hpdl-/- pups. There were no significant differences in the linear portions of each curve between each group. The insert shows the simple firing pattern of a more mature Purkinje cell. FIG.6H shows peak frequency of Purkinje cells from P17-19 Hpdl+/+, Hpdl+/-, and 4-HMA-treated Hpdl-/- pups. The peak frequencies in all three groups are comparable. FIG.6I shows action potential characteristics of P17-19 Hpdl+/+, Hpdl+/-, and 4-HMA-treated Hpdl-/- pups. An average action potential is shown in panel A and the phase plane diagram is shown in panel B. The spike threshold, spike amplitude, and spike half-width 8 309005815v2 Attorney Docket No.: 243735.000414 are comparable in all three groups. The AHP for Purkinje cells from 4-HMA-treated Hpdl-/- pups was lower than for Hpdl+/+pups (p=0.0433). FIG.6J shows that forelimb grip strength is decreased in 4-6-week-old Hpdl+/- (p<0.0001) and 4-HMA-treated Hpdl-/- mice (p<0.0001) relative to Hpdl+/+ mice. Grip strength of all limbs is similar in Hpdl+/+, Hpdl+/-, and 4-HMA- treated Hpdl-/- mice. rotarod performance is similar in Hpdl+/+, Hpdl+/-, and 4- HMA-treated Hpdl-/- male and female mice. FIG.6L shows metabolic phenotypes such as food and water intake, activity, O2 consumption, CO2 production, and energy expenditure are similar in 4-6-week-old Hpdl+/+, Hpdl+/-, and 4-HMA-treated Hpdl-/- mice, as measured in metabolic cages. Differences were identified by two-way ANOVA followed by Dunnett’s multiple comparison test. [0022] FIG.7 shows safety data sheet for 4-hydroxybenzoic acid. [0023] FIG.8 shows product specification for 4-hydroxybenzoic acid. [0024] FIG.9 shows certificate of analysis for 4-hydroxybenzoic acid. [0025] FIG.10 shows the mammalian CoQ10 headgroup synthesis pathway. HPDL converts 4-hydroxyphenylpyruvate to 4-hydroxymandalate (4-HMA}.4-HMA is converted to 4- hydroxybenzoic acid (4-HB), the immediate precursor of the CoQ10 headgroup. The COQ2 prenyltransferase conjugates 4-HB to polyprenyl pyrophosphate to form the skeleton of CoQ10, followed by headgroup modification to form the active molecule (reviewed in (5)). [0026] FIG.11A shows triplicate injections demonstrating the reproducibility of co-elution of 100 µM unlabeled 4-hydroxybenzoic acid (unlabeled) and 13C6-4-hydroxybenzoic acid internal standard (labeled). These standards and the frozen 4-HB were run simultaneously. FIG.11B shows stability of frozen 4-HB stocks (frozen at -20^C for 3 months). The peak height at 200 µM is 7.6E7, which is about four times the peak height of 50 µM fresh 4-HB (1.45E7; panel A). [0027] FIG.12 shows that parabens are mainly metabolized through hydrolysis supported by esterases and through glucuronidation catalyzed by UDP-glucuronosyltransferases (UGT) using UDP-glucuronic acid (UDPGA). They can also produce sulfoconjugates by sulfotransferase (ST) using 3’-phosphoadenosine 5’-phosphosulfate (PAPS) as the sulfate donor substrate, or 4- hydroxyhippuric acid by amino acid transferase (AT) using glycine as the donor substrate. [0028] FIG.13 is a survival plot for treatment of Hpdl-/- mice with a 4-HB suspension stored at room temperature. This suspension has a concentration of 10 mg/mL, which is 2x the 9 309005815v2 Attorney Docket No.: 243735.000414 maximum solubility of 4-HB and is administered at a higher dose (25 mg/kg) than the 4-HB solution (5 mg/mL, 10 mg/kg). [0029] FIG.14 shows regrowth of hair in shaved 90-week-old-mice following treatment with systemic 4-HMA at 100 mg/kg two weeks prior to treatment. After week 5, topical 4-HMA at 100 mg/kg was applied every other day. [0030] FIG.15 shows regrowth of hair in shaved 90-week-old-mice following topical treatment with 4-HMA (100 mg/mL) every other day. DETAILED DESCRIPTION [0031] To facilitate an understanding of the principles and features of the various embodiments of the invention, various illustrative embodiments are explained below. Although exemplary embodiments of the invention are explained in detail, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the invention is limited in its scope to the details of construction and arrangement of components set forth in the following description or examples. The invention is capable of other embodiments and of being practiced or carried out in various ways. Also, in describing the exemplary embodiments, specific terminology will be resorted to for the sake of clarity. [0032] As used herein, the terms “about” or “approximately” for any numerical values or ranges indicate a suitable dimensional tolerance that allows the part or collection of components to function for its intended purpose as described herein. More specifically, “about” or “approximately” may refer to the range of values ±20% of the recited value, e.g. “about 90%” may refer to the range of values from 71% to 99%. [0033] As used herein, the term “alkyl” is given its ordinary meaning in the art and can include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 1–20 carbon atoms in its backbone (e.g., C1-20 for straight chain, C2-20 for branched chain), and alternatively, about 1–10 carbon atoms, or about 1 to 6 carbon atoms. In some embodiments, a cycloalkyl ring has from about 3–10 carbon atoms in their ring structure where such rings are monocyclic or bicyclic, and alternatively about 5, 6 or 7 carbons in the ring structure. In some embodiments, a cycloalkyl group is a cyclopropyl, a cyclobutyl, a cyclopentyl, or a cyclohexyl 10 309005815v2 Attorney Docket No.: 243735.000414 group. In some embodiments, an alkyl group can be a lower alkyl group, wherein a lower alkyl group comprises 1–4 carbon atoms (e.g., C1-4 for straight chain lower alkyls). When used in the context of a divalent alkyl group, it is to be understood that “alkyl” refers to an alkylene group. [0034] As described herein, in certain embodiments, certain compounds of the disclosure can be indicated to comprise “optionally substituted” moieties. When indicated, in general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [0035] As used herein, a substituent, e.g., -B, can be represented as , where denotes a point of attachment. [0036] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. [0037] The present application also includes pharmaceutically acceptable salts of the compounds described herein. The “pharmaceutically acceptable salts” include a subset of the “salts” described above which are conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Berge, SM et al, Journal of Pharmaceutical Science, 1977, 66, 1, 1-19. By way of an example, in an embodiment of the disclosure pharmaceutically acceptable salts can comprise 11 309005815v2 Attorney Docket No.: 243735.000414 a suitable anion selected from F−, Cl−, Br−, I−, OH−, −BF4, CF3SO3−, monobasic sulfate, dibasic sulfate, monobasic phosphate, dibasic phosphate, or tribasic phosphate, NO3−, PF6−, NO2−, carboxylate, CeFfSO3 −, (where e=2-10 and f=2e+1), acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, camsylate, carbonate, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollyalarsanilate, hexanoate, hydrabamine, hydroxynaphthoate, isthionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, mucate, napsylate, octanoate, oleate, oxalate, palmitate, pamoate, pantothenate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, tartrate, teoclate, tosylate, or triethiiodide. By way of another example, in an embodiment of the disclosure pharmaceutically acceptable salts can comprise a suitable cation selected from aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamince, or zinc. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0038] The term “prodrug” as used herein includes a chemical which may be transformed in vivo to a pharmacologically active drug. The term “metabolite” as used herein includes a chemical that a given agent is transformed into in vivo. [0039] The enantiomeric excess, or “ee,” for a given pair of enantiomers is the percentage of the major enantiomer less the percentage of the minor enantiomer. A “racemate” or “racemic mixture” is an equal mixture of two enantiomers and therefore has 0% ee. [0040] The term “enantiomerically enriched” or “enantioenriched” as used herein includes compounds that are mixtures with one enantiomer's being present in excess over the other (ee >0% and <100%). For example, a sample of 40% ee consists of 70% of the major enantiomer and 30% of the minor enantiomer. [0041] The term “enantiomerically pure” or “enantiopure” as used herein includes compounds where the quantification of the minor enantiomer becomes difficult, e.g., with an ee of 99% or greater. Ideally, enantiopure compounds consist of a single enantiomer only. 12 309005815v2 Attorney Docket No.: 243735.000414 [0042] The term “sample” as used herein includes any biological specimen obtained from a subject or patient. Samples that can be used in the methods of the present disclosure include, without limitation, tumor sample, whole blood, plasma, serum, red blood cells, white blood cells (e.g., peripheral blood mononuclear cells (PBMC), polymorphonuclear (PMN) cells), ductal lavage fluid, nipple aspirate, lymph (e.g., disseminated tumor cells of the lymph node), bone marrow aspirate, saliva, urine, stool (i.e., feces), sputum, bronchial lavage fluid, tears, fine needle aspirate (e.g., harvested by random periareolar fine needle aspiration), any other bodily fluid, a tissue sample such as a biopsy (e.g., needle biopsy), and cellular extracts thereof. In some embodiments, when the subject is a pregnant female, the sample may be a fetal DNA sample (e.g., cell-free fetal DNA (cffDNA)). [0043] As used herein, the term “subject” or “patient” refers to mammals and includes, without limitation, human and veterinary animals. In a preferred embodiment, the subject is human. [0044] In some embodiments, the subject is a pediatric subject 0 to 18 years of age. In some embodiments, the subject is a child, including an unborn fetus, a newborn, an infant, or a toddler. In some embodiments, treating an unborn fetus using methods described herein may involve treating a pregnant female carrying the unborn fetus. [0045] In some embodiments, the subject is a pediatric subject 0 to 18 month of age, 0 to 2 years of age, 0 to 10 years of age, 0 to 18 years of age, or 0 to 21 years of age. [0046] In some embodiments, the subject is an adult. In some embodiments, the subject is an elderly adult. In some embodiments, the subject is 65 year old adult or older. [0047] In some embodiments, the subject is a male. In some embodiments, the subject is a male 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 55 years or older, 60 years or older, or 65 years or older. [0048] The terms “treat” or “treatment” of a state, disorder or condition include: (1) preventing or delaying the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub- 13 309005815v2 Attorney Docket No.: 243735.000414 clinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician. [0049] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response, i.e., treating the state, disorder or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. [0050] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a state, disorder or condition or to delay or minimize one or more symptoms associated with the state, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. [0051] It must also be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. For example, reference to a component is intended also to include composition of a plurality of components. References to a composition containing “a” constituent is intended to include other constituents in addition to the one named. In other words, the terms “a,” “an,” and “the” do not denote a limitation of quantity, but rather denote the presence of “at least one” of the referenced item. [0052] Also, in describing the exemplary embodiments, terminology will be resorted to for the sake of clarity. It is intended that each term contemplates its broadest meaning as understood by those skilled in the art and includes all technical equivalents which operate in a similar manner to accomplish a similar purpose. [0053] It is also to be understood that the mention of one or more method steps does not preclude the presence of additional method steps or intervening method steps between those steps expressly identified. Similarly, it is also to be understood that the mention of one or more 14 309005815v2 Attorney Docket No.: 243735.000414 components in a composition does not preclude the presence of additional components than those expressly identified. [0054] The materials described hereinafter as making up the various elements of the present invention are intended to be illustrative and not restrictive. Many suitable materials that would perform the same or a similar function as the materials described herein are intended to be embraced within the scope of the invention. Such other materials not described herein can include, but are not limited to, materials that are developed after the time of the development of the invention, for example. Any dimensions listed in the various drawings are for illustrative purposes only and are not intended to be limiting. Other dimensions and proportions are contemplated and intended to be included within the scope of the invention. Compounds of the Disclosure [0055] In one aspect, provided herein is a compound having the structure of Formula (I): R3 O , wherein: R1 is selected from the group ; R2 is selected from the group R3 is selected from the group consisting of H and C1-C3 alkyl, and R4 is selected from the group consisting of H , or pharmaceutically acceptable salt thereof. [0056] In one embodiment, R1 is H. [0057] In one . [0058] In one [0059] In one embodiment, R2 is H. [0060] In one embodiment, R3 is H. 15 309005815v2 Attorney Docket No.: 243735.000414 [0061] In one embodiment, R3 is methyl. [0062] In one embodiment, R4 is H. [0063] In one R4 . [0064] In one of Formula (I) has the structure according to Formula (II): or a pharmaceutically R1 is selected from the group R4 is selected from the group consisting of H . [0065] In one embodiment, the compound of the structure according to Formula (III): or a pharmaceutically R1 is selected from the group R4 is selected from the group consisting of H . [0066] In one embodiment, the compound having of Formula (I) is selected from the group consisting of: 16 309005815v2 Attorney Docket No.: 243735.000414 , [0067] In one embodiment, the compound having the structure of Formula (I) is selected from the group consisting of: a [0068] In one aspect, the present invention provides 2-hydroxy-2-(4-hydroxyphenyl)acetic acid (also known as 4-hydroxymandelic acid (4-HMA)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. . [0069] In one of the R- and the S- enantiomers of 4-HMA, depicted below: 17 309005815v2 Attorney Docket No.: 243735.000414 . [0070] In of the R- enantiomer, - one - with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater. [0071] In one embodiment, the (R)-4-HMA is present with an enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%. [0072] In another embodiment, 4-HMA is provided as the enantiopure R-enantiomer (R)-4- HMA. [0073] In another embodiment, 4-HMA is provided as an enantioenriched mixture of the S- enantiomer, i.e., (S)-4-HMA. In one embodiment, the (S)-4-HMA is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater. [0074] In one embodiment, the (S)-4-HMA is present with an enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%. [0075] In another embodiment, 4-HMA is provided as the enantiopure S-enantiomer (S)-4- HMA. 18 309005815v2 Attorney Docket No.: 243735.000414 [0076] In one aspect, provided herein is 4-hydroxybenzoate (4-HB) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. Pharmaceutical Compositions and Administration [0077] The present invention also provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystals, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, R2, R3, and R4 are as defined above. [0078] The present invention also provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystals, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. [0079] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound(s) described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit. [0080] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. 19 309005815v2 Attorney Docket No.: 243735.000414 [0081] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient. [0082] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition. [0083] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof. [0084] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof. [0085] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, 20 309005815v2 Attorney Docket No.: 243735.000414 acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof. [0086] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof. [0087] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent. [0088] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. 21 309005815v2 Attorney Docket No.: 243735.000414 [0089] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. [0090] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. [0091] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. [0092] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. [0093] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. [0094] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, 22 309005815v2 Attorney Docket No.: 243735.000414 magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof. [0095] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof. [0096] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof. [0097] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents such as Cremophor™, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof. 23 309005815v2 Attorney Docket No.: 243735.000414 [0098] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [0099] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00100] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle. [00101] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient. [00102] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, 24 309005815v2 Attorney Docket No.: 243735.000414 and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (I) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent. [00103] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. [00104] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. [00105] Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, 25 309005815v2 Attorney Docket No.: 243735.000414 inhalants and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel. [00106] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable. [00107] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. [00108] A pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device 26 309005815v2 Attorney Docket No.: 243735.000414 comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form. [00109] Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non- ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient). [00110] Pharmaceutical compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers. [00111] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares. [00112] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition of the 27 309005815v2 Attorney Docket No.: 243735.000414 invention can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein. [00113] A pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention. [00114] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. [00115] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient 28 309005815v2 Attorney Docket No.: 243735.000414 employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. [00116] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). [00117] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). [00118] The effective amount of the compound in the composition that may be used in accordance with the present disclosure may vary from about 0.0001 mg/kg to about 1000 mg/kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.0001 mg/kg to about 1000 mg/kg, from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg. 29 309005815v2 Attorney Docket No.: 243735.000414 [00119] The compounds and compositions provided herein can be administered to a subject once a day, twice a day, three times a day, or four or more times a day. Alternatively, the compounds and compositions provided herein can be administered to a subject once a week, twice a week, three times a week, or four or more times a week. The compounds and compositions provided herein can also be administered to a subject once every two weeks, once every three weeks, once a month, once every two month, once every three month, once every four month, once every five month, once every six month, once every seven month, once every eight month, once every nine month, once every ten month, once every eleven month, once a year, or once every two years. [00120] The compounds and compositions provided herein can be administered to a subject for about a week, about two weeks, about three weeks, about four weeks, about a month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about one year, about two years, about three years, about four years, about five years, about six or more years, about ten or more years, or about twenty or more years. [00121] The compounds and compositions provided herein can be administered to a subject until the subject reaches the age of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 5 years, about 6 years, about 10 years, about 12 years, about 16 years, about 18 years, about 21 years, about 25 years, or about 30 years. [00122] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 10000 mg, about 0.0001 mg to about 9000 mg, about 0.0001 mg to about 8000 mg, about 0.0001 mg to about 7000 mg, about 0.0001 mg to about 6000 mg, about 0.0001 mg to about 5000 mg, about 0.0001 mg to about 4000 mg, about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 10000 mg, about 0.1 mg to about 5000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 100 mg, about 1 mg to about 10000 mg, about 1 mg to about 90000 mg, about 1 mg to about 8000 mg, about 1 mg to about 7000 mg, about 1 mg to about 6000 mg, about 1 mg to about 5000 mg, about 1 mg to about 4000 mg, about 1 mg to 30 309005815v2 Attorney Docket No.: 243735.000414 about 3000 mg, about 1 mg to about 2000 mg, about 1 mg to about 1000 mg, about 10 mg to about 90000 mg, about 10 mg to about 8000 mg, about 10 mg to about 7000 mg, about 10 mg to about 6000 mg, about 10 mg to about 5000 mg, about 10 mg to about 4000 mg, about 10 mg to about 3000 mg, about 10 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 90000 mg, about 100 mg to about 8000 mg, about 100 mg to about 7000 mg, about 100 mg to about 6000 mg, about 100 mg to about 5000 mg, about 100 mg to about 4000 mg, about 100 mg to about 3000 mg, about 100 mg to about 2000 mg, about 100 mg to about 1000 mg, about 1000 mg to about 90000 mg, about 1000 mg to about 8000 mg, about 1000 mg to about 7000 mg, about 1000 mg to about 6000 mg, about 1000 mg to about 5000 mg, about 1000 mg to about 4000 mg, about 1000 mg to about 3000 mg, or about 1000 mg to about 2000 mg or of a compound per unit dosage form. [00123] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 30 kg child may comprise about 0.0001 mg to about 10000 mg, about 0.0001 mg to about 9000 mg, about 0.0001 mg to about 8000 mg, about 0.0001 mg to about 7000 mg, about 0.0001 mg to about 6000 mg, about 0.0001 mg to about 5000 mg, about 0.0001 mg to about 4000 mg, about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 10000 mg, about 0.1 mg to about 5000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 100 mg, about 1 mg to about 10000 mg, about 1 mg to about 90000 mg, about 1 mg to about 8000 mg, about 1 mg to about 7000 mg, about 1 mg to about 6000 mg, about 1 mg to about 5000 mg, about 1 mg to about 4000 mg, about 1 mg to about 3000 mg, about 1 mg to about 2000 mg, about 1 mg to about 1000 mg, about 10 mg to about 90000 mg, about 10 mg to about 8000 mg, about 10 mg to about 7000 mg, about 10 mg to about 6000 mg, about 10 mg to about 5000 mg, about 10 mg to about 4000 mg, about 10 mg to about 3000 mg, about 10 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 90000 mg, about 100 mg to about 8000 mg, about 100 mg to about 7000 mg, about 100 mg to about 6000 mg, about 100 mg to about 5000 mg, about 100 mg to about 4000 mg, about 100 mg to about 3000 mg, about 100 mg to about 2000 mg, about 100 mg to about 1000 mg, about 1000 mg to about 90000 mg, about 1000 mg to about 8000 mg, about 1000 mg to about 7000 mg, about 1000 mg to about 6000 mg, about 1000 mg to about 5000 mg, about 1000 mg to 31 309005815v2 Attorney Docket No.: 243735.000414 about 4000 mg, about 1000 mg to about 3000 mg, or about 1000 mg to about 2000 mg or of a compound per unit dosage form. [00124] In certain embodiments, the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect. [00125] In certain embodiments, the compounds described herein may be administered at a concentration of about 1 mg/mL, about 2 mg/mL, about 5 mg/mL, about 7 mg/mL, about 10 mg/mL, about 15 mg/mL, or about 20 mg/mL. [00126] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. [00127] It will be also appreciated that a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). [00128] The compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) utilized in combination be 32 309005815v2 Attorney Docket No.: 243735.000414 utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. Methods of the Treatment and Uses [00129] The present invention also provides methods of using the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), for treating or preventing a disease or disorder. [00130] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a disease or disorder selected from the group consisting of heart disease, neurodegenerative disease, migraine headache, neurodevelopmental disease, infertility, pulmonary disease, muscle disease, liver disease, pancreatic disease, oral disease, ophthalmic disease, hearing disease, diseases of pregnancy, diseases of prematurity, aging disorders, movement disorders, infectious disease, and any disease in which Coenzyme Q declines. [00131] In some embodiments, the treatment results in one or more of reducing LDL cholesterol, improving insulin sensitivity, and decreasing diabetic or other neuropathy. [00132] In some embodiments, the treatment results in augmenting egg or sperm quality. [00133] The heart disease that can be treated include, but are not limited to, heart failure, high blood pressure, recovery post cardiac surgery, and statin-induced myopathy. [00134] The neurodegenerative disease that can be treated include, but are not limited to, Parkinson’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS), and demyelinating and white matter disease. [00135] In some embodiments, the neurodevelopmental disease is cerebral palsy. [00136] In some embodiments, the pulmonary disease is chronic obstructive pulmonary disease (COPD) or asthma. [00137] In some embodiments, the muscle disease is muscular dystrophy. [00138] In some embodiments, the liver disease is characterized by toxicity due to statins or liver injury. [00139] In some embodiments, the pancreatic disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, and exocrine insufficiency. 33 309005815v2 Attorney Docket No.: 243735.000414 [00140] In some embodiments, the oral disease is selected from the group consisting of tooth decay, periodontitis, and gum decay. [00141] In some embodiments, the ophthalmic disease is selected from the group consisting of macular degeneration, cataract formation, retinal detachment, and retinitis pigmentosa. [00142] In some embodiments, the hearing disease is hearing loss. [00143] In some embodiments, the disease of pregnancy is placental insufficiency or pre- eclampsia. [00144] In some embodiments, the disease of prematurity is selected from the group consisting of prematurity, retinopathy of prematurity, and cerebral palsy. [00145] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in improving wound healing in a subject. [00146] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a neurodevelopmental disorder with spastic paresis and brain white matter abnormalities. [00147] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a subject having a white matter abnormality. [00148] In some embodiments, the subject has 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) deficiency. [00149] In some embodiments, the subject has a variant in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway. [00150] In some embodiments, the mutation is homozygous. [00151] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a subject having a variant in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway. [00152] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in improving physical performance and energy production in a subject. [00153] In some embodiments, the treatment results in one or more of decreasing fatigue, increasing strength and stamina, increasing functional performance, and improving balance. 34 309005815v2 Attorney Docket No.: 243735.000414 [00154] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure when used in combination with an antacid may be useful in treating a 4- hydroxyphenylpyruvate dioxygenase-like (HPDL)-related disease or disorder in a subject. [00155] Suitable antacid that can be used include, but are not limited to, aluminum, calcium, magnesium, and sodium salts. In some embodiments, the antacid is selected from the group consisting of aluminum hydroxide, magnesium hydroxide, sucrose/calcium carbonate, sodium citrate, citric acid, sodium bicarbonate, tartaric acid, and alginic acid. [00156] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a neurodegenerative or psychiatric disease. [00157] In some embodiments, when the subject being treated is a child, the child may be treated with the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), in utero, immediately after birth, or in postpartum days. [00158] In some embodiments, the method may involve treating a newborn or infant by administering the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), to the newborn or infant. [00159] In some embodiments, the method may involve treating an unborn fetus by administering the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 44-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), to the pregnant female. [00160] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in accelerating, promoting, or restoring hair growth in a subject. [00161] The disclosed methods may be used to promote hair growth on any body surface of a subject where hair growth is desired, including, for example, the scalp, chest, and face (e.g., beard, eyebrows, scars, etc.). In veterinary subjects, hair growth over the entire body surface (excluding eyes, mouth, nose and other typically hair-less regions) may be desired. Particular methods involve growing hair on all or part of the scalp (such as, an area of premature balding or hair thinning) or in an area of alopecia-affected skin of a subject. [00162] “Promoting hair growth” as used herein is intended to have its broadest possible meaning. Thus, in some examples, promoting hair growth is to decrease a rate of hair loss in an 35 309005815v2 Attorney Docket No.: 243735.000414 area that normally has hair such that (i) on-going hair loss occurs at a slower rate (e.g., retarded or slowed hair loss); (ii) hair loss is substantially stopped (e.g., the rate of hair loss is substantially the same as the rate of hair growth); or (iii) hair loss is reversed (e.g., the rate of hair loss is lower than the rate of hair growth) such that the area of interest exhibits a net increase in the amount of hair. In another example, promoting hair growth is to induce hair growth on a substantially hairless surface capable of growing hair, such as a body surface that formerly had, but has lost substantially all, hair. In still another example, promoting hair growth includes inducing or stimulating hair growth on a hair-containing surface that is not experiencing hair loss; for example, increasing the rate at which hair-growing cells grow hair and/or increasing the number of hair-growing cells (e.g., increasing the number of hair follicles or the number of follicles in the anagen phase). Such latter method embodiments may be useful to increase hair density or length. Promotion of hair growth also includes decreased shedding (either at the roots or by breaking/fragility) measured, for example, by hair pull tests. The promotion of hair growth can be measured using any method known in the art or any of the methods disclosed herein, for example, quantitative and qualitative comparison of treated areas or subjects to controls. [00163] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful for treating hair loss in a subject. [00164] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful for treating a condition or disorder affecting hair growth in a subject, such as baldness, alopecia, or scarring. [00165] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure maybe administered in combination with one or more additional therapeutic agents. [00166] In some embodiments, the treatment further comprises detecting in a biological sample obtained from the subject the presence of the one or more variants in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway prior to said administration. [00167] In some embodiments, the treatment further comprises detecting plasma 4-HMA concentration in a biological sample obtained from the subject prior to said administration. Suitable biological sample can comprise peripheral blood mononuclear cells or a biopsy specimen. 36 309005815v2 Attorney Docket No.: 243735.000414 [00168] In some embodiments, the subject is a pregnant female and the biological sample is a fetal DNA sample. The fetal DNA sample can be obtained, for example, by circulating fetal DNA isolation, chorionic villus sampling, or amnioscentesis. [00169] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful for treating a 4-hydroxyphenylpyruvate dioxygenase-like (HPDL)- related disease or disorder in a subject. The method includes detecting in a biological sample obtained from the subject the plasma 4-HMA concentration; and administering to the subject having a reduced plasma 4-HMA concentration (<20 nM) a therapeutically effective amount of the compound(s) or pharmaceutical compositions of the present disclosure. [00170] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful for increasing CoQ10 biosynthesis in a subject. The method includes detecting in a biological sample obtained from the subject the plasma 4-HMA concentration; and administering to the subject having a reduced plasma 4-HMA concentration a therapeutically effective amount of the compound(s) or pharmaceutical compositions of the present disclosure. EXAMPLES [00171] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments. [00172] Hpdl-/- mice recapitulate the symptoms of patients with NEDSWMA. Hpdl-/- pups initially are identical in appearance to wild-type animals, but by post-natal day 5 (P5) Hpdl-/- pups develop movements consistent with spastic paresis and epileptic seizures, and stop gaining weight19. By P15, all Hpdl-/- pups are dead. In contrast, Hpdl+/- pups uniformly reach adulthood. [00173] Disease-modifying treatments for mitochondrial diseases, including NEDSWMA and other primary CoQ10 deficiencies, remain an unmet medical need. Although CoQ10 supplementation can improve myositis, lactic acidosis, and other peripheral symptoms of primary CoQ10 deficiencies, CoQ10 supplementation controls the neurological symptoms of primary CoQ10 deficiency or other mitochondrial diseases less than 30% of the time 28. It is not clear if correction of the underlying biochemical defects in primary CoQ10 deficiencies can modify the course of these diseases effectively or robustly. Specifically, the capacity of 4-HMA and 4-HB to restore CoQ synthesis and relieve the symptoms of HPDL loss in intact organisms is unknown. [00174] It was assumed that treatment of Hpdl-/- mice with 4-HMA would bypass loss of the CoQ10 headgroup biosynthesis and enable CoQ10 synthesis in situ. The present disclosure shows 37 309005815v2 Attorney Docket No.: 243735.000414 that Hpdl-/- mice with 4-HMA, the product of HPDL, and 4-HB, the immediate precursor of the CoQ headgroup, near-uniformly live to adulthood and have motor phenotypes indistinguishable from Hpdl+/- littermates.13C-labeled 4-HMA and 4-HB were incorporated into CoQ9 in the brains of treated mice. These experiments demonstrate that 4-HMA and 4-HB are physiologically important for CoQ10 synthesis during development and suggest that 4-HMA or 4-HB treatment may treat patients with NEDSWMA and SPG83 associated with HPDL variants. [00175] Hpdl-/- pups develop symptoms of neurodevelopmental disease and have low plasma 4- HMA concentrations. [00176] 4-HMA is an intermediate in a non-canonical tyrosine catabolism pathway required for the synthesis of the CoQ10 headgroup in mammals (FIG.1A). It was hypothesized that deletion of Hpdl would result in decreased plasma concentrations of 4-HMA in Hpdl-/- pups relative to Hpdl+/- or Hpdl+/+ pups. Adult Hpdl+/- mice (C57BL/6NCrl-Hpdlem1(IMPC)Mbp/Mmucd) were obtained from the Knockout Mouse Project / Mutant Mouse Resource & Research Center (KOMP/MMRRC) at the University of California, Davis29. Hpdl-/- pups initially have the same weight as wild-type pups, but do not gain weight following birth (FIG. 1B) As previously described, Hpdl-/- pups develop seizures, lose weight, and die by P15 (FIGS. 1C-1D). Hpdl-/- pups have lower plasma [4-HMA] than Hpdl+/+ or Hpdl+/- pups (FIG.1E) and a higher plasma lactate/pyruvate ratio (Fig.4A). [00177] Oral treatment with 4-HMA or 4-HB improves the lifespan of Hpdl-/- pups [00178] It was hypothesized that treatment of Hpdl-/- pups with 4-HMA, the product of HPDL, or 4-HB, the immediate precursor of the CoQ10 headgroup, would prevent the development of neurological symptoms and extend the lifespan of mice. Both 4-HMA and 4-HB do not induce toxicity in mice at doses of 500 mg/kg and are orally bioavailable with half-lives of 2.8 and 0.35 hours, respectively (FIG. 4C). The half-life of both compounds is <1 hour following IV administration (FIG.4D). Hpdl-/- pups treated orally with 4-HMA and 4-HB at a minimum of 10 mg/kg once daily starting from P3 – P6 gained weight (FIGS. 4B, 4E) and mobility (FIGS. 4F- 4G). Following weaning, we treated Hpdl-/- pups with 1 mM 4-HMA or 4-HB in their drinking water until P30, after which we discontinued 4-HMA or 4-HB. Hpdl-/- pups treated with 4-HMA or 4-HB uniformly lived to ages of 12 months or more (FIG. 1F). In contrast, oral treatment of Hpdl-/- pups with CoQ9, CoQ10, the CoQ analog Idebenone, and mitochondrially targeted antioxidant MitoTEMPO 30-32 did not improve their survival (FIG.1F). [00179] 4-HMA and 4-HB are incorporated into mouse brain CoQ9 38 309005815v2 Attorney Docket No.: 243735.000414 [00180] To test if 4-HMA and 4-HB crossed the blood-brain barrier and were incorporated into CoQ9, the predominant Coenzyme Q species in mice, we treated Hpdl+/+, Hpdl+/-, and Hpdl-/- pups with 13C6-4-HB and 13C6-4-HMA at 10 mg/kg from P3 to P20 and measured the incorporation of 13C into CoQ9 in the brain by liquid chromatography-mass spectrometry (FIG.1G). Less than 15% of CoQ9 in Hpdl+/+ and Hpdl+/- mice was derived from 4-HMA or 4-HB, but Hpdl-/- pups derived 50% of CoQ9 from exogenously administered 13C6-4-HB and 13C6-4-HMA (FIG. 1H). No CoQ9 was labeled in P12 Hpdl-/- pups that were not fed 13C6-4-HB or 13C6-4-HMA. Hpdl-/- pups not fed 13C6-4-HMA exhibited reduced CoQ9 relative to Hpdl-/- pups fed 13C6-4-HMA (FIG.4H). These data show that 13C6-4-HB and 13C6-4-HMA cross the blood-brain barrier to restore CoQ9 synthesis during development. [00181] 4-HMA treatment improves histological phenotypes of Hpdl-/- pups [00182] Electron microscopy revealed abnormal mitochondrial morphology in the cerebellum, but not in the cortex, of Hpdl-/- pups (FIG.2A). The mitochondria in the cerebella of Hpdl-/- pups were smaller than mitochondria in Hpdl+/+ or Hpdl+/- mice, as measured by mitochondrial perimeter (FIG. 2B). Cerebellar mitochondrial size was restored by 4-HMA supplementation, although not to the same size as Hpdl+/+ pups (FIG. 2B). This finding is consistent with the mitochondrial morphology of CoQ8a-/- mice, which develop cerebellar ataxia33. Prior research showed that the brains of Hpdl-/- pups have higher numbers of cleaved caspase-3 positive cells, consistent with higher rates of apoptosis19. Histology of the brains of post-natal day 8 (P8) mouse pups revealed reduced cerebellar size, with compaction of the external granular layer (EGL) and an overt lack of granular cell expansion. There also was loss of normal architecture of the cerebellar Purkinje cell layer (EGL) (FIG.2C). Hpdl-/- pups also had decreased inner granular layer (IGL) thickness (FIG.2D). These findings are consistent with decreased proliferation of cerebellar granule cells and a failure of granule cells to successfully establish the IGL. Cortical neurons in Hpdl-/- pups also show vacuolation, decreased nuclear area, and loss of normal cortical architecture with neuronal microcolumns, edema and neuronal shrinking in the cortex relative to Hpdl+/- pups (FIG. 2E). These histological defects in Hpdl-/- pups are mostly resolved by 4-HMA supplementation (FIG.2A, panels D and H; FIG.2C, panels D, H, and L; FIG.2E, panels D, H, and L). In contrast, the hippocampus was largely unremarkable on H&E slides in Hpdl-/- pups (FIG.5A). 39 309005815v2 Attorney Docket No.: 243735.000414 [00183] These data demonstrate that 4-HMA-dependent CoQ synthesis is critical for cerebellar and cortical development and suggest that treatment with 4-HMA or 4-HB during infancy or childhood could improve the outcomes of patients with HPDL variants. [00184] Functional properties of Hpdl-/- Purkinje cells are improved following 4-HMA treatment Table 1. Passive Electrophysiological Characteristics of Cerebellar Purkinje cells Ri (M^) WT Het KO Rescued KO P17-19 172 ^ 043 186 ^ 237 208 ^ 196 - p . . . . . . ^ ^ ^ ^ o e e e p oss a ec e e u c o o u e ce s, a ese p ope ties could be improved by 4-HMA treatment, we carried out electrophysiological measurements by manual patch-clamping in cerebellar Purkinje cells in brain slices from Hpdl+/+, Hpdl+/-, and untreated and 4-HMA-treated Hpdl-/- mice. We analyzed two age brackets: P8-10 pups (during cerebellar development), and P17-19 pups (after cerebellar maturation was mostly completed). There were substantial electrophysiologic differences in Purkinje cell electrophysiology between the two groups due to cerebellar development. The P8-10 group contained Hpdl+/+, Hpdl+/-, Hpdl- /- pups, and Hpdl-/- pups treated with 4-HMA. The P17-19 group did not have untreated Hpdl-/- pups as these animals die by P15. In the P8-10 group, there was a significant increase in input resistance (Ri) and significant reduction in membrane capacitance (Cm) in cerebellar Purkinje cells in Hpdl-/- mice in comparison to Hpdl+/+ and Hpdl+/- mice (FIGS. 3A-3B, Table 1). These were reverted by 4-HMA treatment, which brings Ri and Cm closer to values of P17-19 Purkinje cells (FIG.6E). By P17-19, no difference was observed in the Ri and Cm of Hpdl+/+ pups, Hpdl+/- pups, and Hpdl-/- pups treated with 4-HMA (FIG.6E). These data are consistent with 4-HMA treatment normalizing the aberrant passive electrophysiologic characteristics of cerebellar Purkinje cells from Hpdl-/- pups. [00186] We next tested if partial or complete Hpdl loss affected the I/V curves of cerebellar Purkinje cells in mouse pups. Cerebellar Purkinje cells from Hpdl-/- pups had a tighter grouping of currents at hyperpolarized membrane potentials (-100 to -60 mV) relative to the Hpdl+/+ group 40 309005815v2 Attorney Docket No.: 243735.000414 (FIGS.6A-6B, insets). This grouping resulted in a flatter I/V curve at hyperpolarized membrane potentials that was significantly different from the I/V curves of cerebellar Purkinje cells from Hpdl+/+ and Hpdl+/- pups (FIG. 6A). The I/V curve of cerebellar Purkinje cells in Hpdl-/- pups treated with 4-HMA was steeper than the curves of the Hpdl+/+, Hpdl+/-, and Hpdl-/- pups, and closer in slope and magnitude to the I/V curves of P17-19 cerebellar Purkinje cells. The I/V curve of cerebellar Purkinje cells from 4-HMA-treated Hpdl-/- pups was indistinguishable from curves from Hpdl+/+ and Hpdl+/- pups (FIGS.6F-6G). These data are consistent with cerebellar Purkinje cells from Hpdl-/- pups having a higher sensitivity to inputs at hyperpolarized membrane potentials than Hpdl+/+ and Hpdl+/- Purkinje cells, and with reversion of these electrophysiological properties by 4-HMA treatment. [00187] The peak frequency of cerebellar Purkinje cells from P8-10 Hpdl-/- pups was lower than Hpdl+/+ and Hpdl+/- cerebellar Purkinje cells (FIG. 6C), although these differences resolved by P17-19 (FIG. 6H). Cerebellar Purkinje cells from Hpdl-/- pups treated with 4-HMA had a higher firing rate than Hpdl+/+ and Hpdl+/- cerebellar Purkinje cells. These differences were consistent with immaturity of Hpdl-/- cerebellar Purkinje cells relative to Hpdl+/+ and Hpdl+/- pups, and with accelerated maturation of 4-HMA-treated Hpdl-/- cerebellar Purkinje cells. These differences disappeared by P17-19 (FIGS.6F-6G). Hpdl loss and 4-HMA rescue did not affect the F/I curves of cerebellar Purkinje cells (FIGS. 6C-6D). Likewise, action potential parameters of Hpdl+/+, Hpdl+/-, and Hpdl-/- pups were similar (FIG. 6D). However, the action half potential (AHP) of cerebellar Purkinje cells from Hpdl-/- pups treated with 4-HMA were slightly less than cerebellar Purkinje cells from Hpdl+/+ pups (FIG. 6D, panel F). This finding persisted at P17-19 (FIG. 6I, panel F). [00188] These results demonstrate that homozygous Hpdl loss has a significant effect on the passive electrophysiologic characteristics of cerebellar Purkinje cells in vitro, and that these changes are treatable with 4-HMA treatment. Heterozygous Hpdl loss has no significant effect on in vitro cerebellar Purkinje cell electrophysiologic parameters. [00189] Motor phenotypes of Hpdl-/- mice are comparable to Hpdl+/- mice following 4-HMA treatment [00190] To test if 4-HMA treatment improves the neurological symptoms and metabolic physiology of Hpdl-/- mice, we carried out neurological tests and metabolic cage measurements of Hpdl+/+ and Hpdl+/- mice in comparison to Hpdl-/- mice treated with 4-HMA at 8 weeks of age. 41 309005815v2 Attorney Docket No.: 243735.000414 Male Hpdl-/- mice weighed less than their Hpdl+/+ or Hpdl+/- counterparts (FIG.3C), but exhibited no significant decreases in food or water consumption, activity, vO2, vCO2, or energy expenditure (FIG. 6I). Female Hpdl-/- mice treated with 4-HMA had indistinguishable weight from female Hpdl+/+ or Hpdl+/- mice (FIG.3C) and had no differences in food or water consumption, activity, vO2, vCO2, or energy expenditure (FIG.6I). Hpdl-/- mice treated with 4-HMA had decreased gait periodicity (FIG.3C), but had identical performance on the pole test and transverse beam tests of cerebellar function (FIGS. 3D-3E). Both female and male Hpdl+/- mice and Hpdl-/- mice treated with 4-HMA had decreased forelimb grip strength relative to Hpdl+/+ mice, but did not have differences when the strength of all limbs was measured (FIG. 3F; FIGS. 6G, 6J). We did not observe differences in Rotarod latency between Hpdl+/+ mice, Hpdl+/- mice, and Hpdl-/- mice treated with 4-HMA (FIG. 6K). These physiologic data are consistent with our histological data as Rotarod latency is a striatal phenotype34 and grip strength is mediated by cerebellar input35. [00191] The similarity of metabolic and neurological phenotypes in Hpdl+/- mice and Hpdl-/- mice treated with 4-HMA suggests that 4-HMA treatment could improve the neurologic symptoms of humans with NEDSWMA due to HPDL variants if treatment is started in infancy. [00192] Conclusions [00193] Here we demonstrate that orally administered 4-HMA, the product of HPDL, and 4-HB, the immediate precursor of the CoQ10 headgroup, efficiently rescue the phenotypes of Hpdl-/- mice. Ninety percent or more of the mice survive for up to a year following CoQ10 headgroup intermediate supplementation. Our data demonstrate direct resolution of mitochondrial disease due to a primary CoQ10 deficiency in a by supplementation of a missing metabolic intermediate. This work builds on prior mechanistic treatments or effective treatments for mitochondrial disease that compensate for underlying metabolic defects by other mechanisms38. [00194] CoQ9, CoQ10, MitoTEMPO, and idebenone do not improve the survival of Hpdl-/- pups, but 4-HMA and 4-HB do. Supplementation of downstream CoQ10 synthesis intermediates has restored CoQ10 levels14,39 at high doses, and partially rescued primary CoQ10 deficiency in mice15. We find that both 13C-4-HMA and 13C-4-HB are incorporated into 50% of the CoQ9 in the brains of Hpdl-/- mice, consistent with the ability of 4-HMA or 4-HB to cross the blood-brain barrier and restore CoQ synthesis in the brain efficiently in vivo. [00195] The neurological symptoms of primary CoQ10 deficiencies are often refractory to CoQ10 supplementation28,38, possibly due to poor CoQ10 absorption, distribution and metabolism; 42 309005815v2 Attorney Docket No.: 243735.000414 difficulty delivering CoQ10 to inner mitochondrial membrane in neuronal and other cells behind the blood-brain barrier; or the action of CoQ10 at sites in the cell other than the mitochondria40. However, non-neuronal symptoms of primary CoQ10 deficiencies can respond to CoQ10 or short- chain CoQ supplementation 41,42, consistent with at least some bioavailability of CoQ10 to non- CNS organs. We anticipate that 4-HMA or 4-HB supplementation may be of benefit in patients with HPDL variants that cause loss of HPDL function, or who have other defects in CoQ10 headgroup synthesis. Because patients with HPDL variants appear normal at birth19-26, loss of HPDL function or other CoQ10 headgroup synthesis deficiencies ideally would be identified by newborn screening for reduced plasma 4-HMA, as we observed in our patients, or by sequencing so that supplementation with CoQ10 headgroup intermediates can begin before symptoms develop. [00196] The motor symptoms associated with HPDL loss are correlated with Purkinje cell vacuolization and failure of cerebellar granule cells to form the inner granular layer, resulting in cerebellar cortical atrophy. The sequence of events that lead to decreased cerebellar size is not clear. One possibility is that loss of HPDL function resulting in decreased CoQ10 synthesis results in mitochondrial dysfunction comparable to cerebellar hypoxia, in spite of oxygen availability. Developing Purkinje cells are among the most hypoxia-sensitive cells in the brain43. We hypothesize that the sensitivity of Purkinje cells to hypoxia renders them disproportionately sensitive to loss of CoQ10 synthesis, which mimics hypoxic by depriving them of oxidative phosphorylation. [00197] Our electrophysiologic data demonstrate that Hpdl-/- cells in the P8-10 age group had significant defects in electrophysiological characteristics. A significant increase in Ri and significant decrease in Cm were found between the Hpdl-/- cells and the Hpdl+/+ cells. Both the higher Ri and lower Cm, are indicative of less mature cells1,3. The electrophysiological changes carried over to differences in the I/V curve between the Hpdl-/- cerebellar Purkinje cells and the Hpdl+/+ cerebellar Purkinje cells at hyperpolarized membrane potentials which indicates the KO cells are much more sensitive to synaptic input at this membrane potential range. [00198] We find that heterozygous expression of the Hpdl knockout does not significantly inhibit cellular development and that 4-HMA treatment accelerates maturation of Hpdl-/- Purkinje cells at P8-10. By P17-19, the electrophysiological characteristics of Hpdl+/+, Hpdl+/-, and Purkinje cells from 4-HMA-treated Hpdl-/- pups have indistinguishable electrophysiological properties. 43 309005815v2 Attorney Docket No.: 243735.000414 [00199] Purkinje cell death induced by Hpdl loss would lead to loss of Purkinje function and cell axonal guidance signals, which may alter migration of granule cells from the EGL to the IGL. In addition, cerebellar granule cells undergo a dramatic expansion at P8-944-46. Because HPDL is essential for CoQ10 headgroup synthesis and CoQ10 is essential for mitochondrial electron transport chain activity that enables cellular proliferation47,48, HPDL loss may contribute to decreased numbers of cerebellar granule cells in the EGL, which reduces the population of cerebellar granule cells available to enter the IGL and form synapses with Purkinje cells and mossy fibers. The failure of these latter neurons to find their targets would lead to degeneration and the neurodevelopmental and neurodegenerative phenotypes that we observe in Hpdl-/- mice and patients with HPDL variants. The timing and order of these phenotypes will best be addressed with tissue-specific, conditional knockouts of Hpdl. [00200] 4-HMA rescue substantially improves the overall survival of Hpdl-/- mice, but 4-HMA- treated Hpdl-/- mice have grip strength and weight comparable to Hpdl+/- mice. The partial rescue of neurological phenotypes by 4-HMA could be due to inadequate dosing of 4-HMA or inability to import sufficient 4-HMA for CoQ10 synthesis. Alternately, inadequate production of 4-HMA during the late stages of embryogenesis, when granule cells start proliferating46, or peripheral nervous system defects could be responsible for these residual symptoms. Treatment of mice with increased doses of 4-HMA, which is nontoxic in mice at doses >500 mg/kg (FIG.1E), as well as supplementation of mothers with 4-HMA will allow us to determine when HPDL activity is critical for brain and end-organ development. [00201] To our knowledge, this is the first small molecule, disease-modifying treatment of a mitochondrial disease that directly addresses the etiology of the disease and is administered at doses compatible with human therapy. Our data suggest that the HPDL encephalopathies NEDSWMA and SPG83, if detected early enough by sequencing and by decreased plasma 4-HMA concentrations, should respond to 4-HMA, 4-HB, or prodrug treatment. In addition to the HPDL encephalopathies, other diseases enabled by mitochondrial dysfunction and decreased CoQ10 synthesis may respond to mammalian CoQ10 headgroup intermediate supplementation that corrects underlying bioenergetic defects driven by inadequate CoQ10 synthesis. [00202] We propose a metabolite replacement therapy with 4-HB to support and boost endogenous CoQ10 synthesis in the cells of the pediatric NEDSWMA patient. 44 309005815v2 Attorney Docket No.: 243735.000414 [00203] At present, no treatments targeting disease mechanisms to improve or arrest disease progression are available for NEDSWMA or other HPDL-related encephalopathies, apart from standard-of-care treatments for spastic paresis such as baclofen and botulinum toxin to treat contractures. No treatment extends the lifespan of patients with NEDSWMA. A patient with NEDSWMA can weaken and become more spastic on a daily basis. Without treatment it is likely that a NEDSWMA patient’s neurodegenerative symptoms will rapidly progress. Children with known HPDL deficiency–induced NEDSWMA do not survive childhood beyond 8-10 years of age. [00204] A proposed treatment is administration of 4-HB as an oral solution at a concentration of 5 mg/mL in water. An example NEDSWMA patient might weigh approximately 30 kg. Said patient will be treated initially with 1 mg/kg 4-hydroxybenzoate (30 mg), corresponding roughly to the HED of the effective dose of 10 mg/kg studied in mice. If this dose is tolerated, the dose will increase to 10 mg/kg (300 mg) on the second day. If this dose is tolerated, then the dose will increase to 33 mg/kg (1000 mg) on the third day. If this dose is tolerated, the dose will increase to 100 mg/kg (3,000 mg) on the fourth day. This dose will be administered over 30-60 minutes if necessary to enable full dosing (the 3,000 mg dose will be equivalent to 600 ml of 4-HB DP solution at 5 mg/kg). The duration of dosing could be from 30 years to months or years, or potentially lifelong treatment. [00205] Prior to treatment, at days 3, 6, 15, and 30 after the first dose of 4-HB, and at 3, 6, 9, and 12 months after the end of the study, a patient’s weight will be measured, carry out neurological exams, and collect urine for organic acid analysis (malate, fumarate, lactate and pyruvate), a measure of mitochondrial disease (8). Also, pastic paraplegia rating scale (9), timed 10-meter walk test (10), 9-hole peg test (11), and the modified Ashworth scale (12) will be used to measure a patient’s neurological outcomes prior to, during, and after treatment. Brain and spine MRI/MRS, and video recording of the clinical exam will also be performed. [00206] Prior to treatment, at days 3, 6, 15, and 30 after the first dose of 4-HB, and at 3, 6, 9, and 12 months after the first dose, we will collect plasma. In addition to testing Chem10, CBC, liver function, lactate, and pyruvate, 4-HMA will be measured as a biomarker of HPDL deficiency and 4-HB to determine the PK of the DP. [00207] 4-HB is a natural mammalian metabolite. 4-HB is also the primary product of paraben catabolism in mammalians. Parabens are simple esters of 4-HB widely used a food additives and 45 309005815v2 Attorney Docket No.: 243735.000414 preservatives and classified by the FDA as Generally Recognized as Safe (GRAS) (13). 4-HB is also found in high concentrations in natural foods (14-16). Based on this, acute toxicities are not anticipated from the proposed 4-HB treatment. [00208] 4-Hydroxybenzoate has been tested in mice at doses of up to 500 mg/kg without observable toxicity. Toxicity would most likely be esophagitis or gastritis following administration of 4-hydroxybenzoic acid, as it has a pH of 4 in water (comparable to orange juice, which has a pH of 3.5). If adverse GI toxicity from 4-hydroxybenzoate treatment is observed, a patient will be treated with aluminum hydroxide/magnesium hydroxide (Maalox/Mylanta), or with sucrose/calcium carbonate. If other toxicities are observed, the dose will be reduced by 20% and treatment will continue. If toxicity is observed a second time, the dose will be reduced by an additional 20%. If toxicity is observed after this point, the dose will be reduced to 1000 mg/day. If toxicity is observed after this point, the dose will be reduced to 300 mg/day. If toxicity is observed after this point, treatment will be discontinued. [00209] The drug product to be used to treat a patient is 4-hydroxybenzoic acid in the form of white power prepared as a monophasic solution in water for oral use. 4-Hydroxybenzoic acid, 99% [00210] Dose and Exposure Formulation and 4-hydroxybenzoic acid will be prepared as a monophasic solution in 46 309005815v2 Attorney Docket No.: 243735.000414 water to a concentration of 5 mg/mL with gentle stirring followed by sonication. The solution will be vacuum filtered through a 0.2 µm rs t f e 47 309005815v2 Attorney Docket No.: 243735.000414 area of the peak to area under to total ion current peak. Concentration will be determined by comparison to a standard curve with a 13C6- d [00 ] Overv ew o rec n ca ata [00212] 4-HB supplementation therapy (10 mg/kg [HED approx. 1 mg/kg]) in Hpdl-/- mice reverses cerebellar atrophy and improves overall survival to >90%. [00213] Therapeutic effect is related to the high permeability of the brain for 4-HB compared to CoQ10 [00214] HPDL (4-hydroxyphenylpyruvate dioxygenase like) is a mitochondrial dioxygenase that makes 4-hydroxymandelate (4-HMA) (17). 4-HMA is converted to 4-hydroxybenzoic acid (4- HB).4-HB is the immediate precursor of the headgroup of Coenzyme Q10 (CoQ10), a lipophilic antioxidant critical for control of reactive oxygen species in biological membranes and for activity of the mitochondrial electron transport chain (FIG.10) (reviewed in(5). [00215] Biallelic HPDL variants cause a disease called NEDSWMA (Neurodevelopmental disorder with spastic paresis and brain white matter abnormalities; OMIM 619026) (1-4). This is a progressive, uniformly lethal pediatric encephalopathy. Patients with NEDSWMA present in childhood with progressive spasticity and neurodevelopmental delay. Patients with non-truncating HPDL variants present with a milder form of spastic paraplegia called spastic paraplegia-83 (OMIM 619027). 48 309005815v2 Attorney Docket No.: 243735.000414 [00216] To support the treatment of patients with HPDL variants with 4-HB, the following must hold: 1) 4-HMA, the product of HPDL, should be low in Hpdl-/- mice and in patients with HPDL variants; 2) Treatment of mice lacking Hpdl (Hpdl-/- mice) with 4-HB should improve their overall survival; and 3) 4-HB, the immediate precursor of the CoQ10 headgroup, should enter the brain and be incorporated into Coenzyme Q. [00217] 4-HB is not detectable in plasma, but 4-HMA is detectable in the plasma of mice and patients. Hpdl-/- mice have lower plasma levels of 4-HMA than wild-type mice (FIG.1E). Both 4- HMA and 4-HB at 10 mg/kg, dosed orally once daily, improve the survival of Hpdl-/- mice from 0% at 15 days to >90% at 300 days (FIG.1F). CoQ10 treatment does not improve the survival of mice lacking Hpdl (FIG. 1F). Hpdl-/- mice must be treated with at least 10 mg/kg 4-HMA to improve their overall survival (FIG. 1F). Hpdl-/- mice have cerebellar atrophy with Purkinje cell vacuolization and do not form the internal granular layer (IGL) of the mature cerebellum (FIG. 2C, panels C, G, K). These developmental defects are restored to near wild-type appearance by 4- HMA treatment (FIG.2C, panels D, H, L). [00218] Both 4-HMA and 4-HB enter the brains of Hpdl-/- mice and account for half of the CoQ9 (the mouse equivalent of human CoQ10) synthesized in the brain (FIG.1H). The 4-HB used for these studies came from a different source than the data in FIG.3A, and enabled all treated mice to survive to postnatal day 20, the time of sacrifice. Normal survival for untreated Hpdl-/- mice is less than 15 days (FIG.1F). [00219] A patient has bi-allelic variants in HPDL and is 8 years old. Sequencing revealed bi- allelic variants in HPDL. The patient grew up apparently normally. The patient’s neurological exam began to deteriorate. The patient became increasingly spastic and ataxic to the point of being unable to walk without falling, and used a wheelchair as a result. The patient’s symptoms were worsening on a daily basis. [00220] The patient received multiple doses of 4-hydroxybenzoic acid starting with a test dose of 1 mg/kg, followed by 10 mg/kg on the second day, followed by 33 mg/kg on the third day, followed by 100 mg/kg on the fourth day and at all subsequent doses (up to 30 doses). By day 15, the patient’s symptoms had stabilized. Following dose 22, the patient exhibited decreased spasticity and ataxia, increased energy, longer standing and balance times, and increased grip strength. 49 309005815v2 Attorney Docket No.: 243735.000414 [00221] 4-HB is administered as a 5 mg/mL solution in water, administered once daily orally. It is not administered with food. 4-HMA would be administered as a 10 mM solution in a similar manner. [00222] Ideally 4-HB would be administered as a suspension at a concentration of >10 mg/m, or as a pill, a lozenge, or a capsule. Consideration would need to be made for administration of this compound to neonates and infants who present with the more severe form of HPDL encephalopathy. [00223] Chemistry and Manufacturing Product Name 4-Hydroxybenzoic acid, 99% el wn in FIGS.7-9. [00225] General Method of Preparation and packaging [00226] 4-HB will be prepared as a monophasic solution in water for oral use.4-HB will be added to distilled water to a concentration of 5 mg/mL with gentle stirring followed by sonication. The solution will be vacuum filtered through a 0.2 µm PES membrane into a sterile bottle. The solution has a sour taste and is palatable. Storage will be at 4 ^C. Formulated compound should be consumed within 24 hours of preparation or frozen at -20 ^C immediately after formulation. [00227] The purity and concentration of 4-HB will be measured by liquid chromatography-mass spectrometry. The LC-MS method will use an Atlantis BEH Z-HILIC column mounted on a Dionex Ultimate 3000 UPLC coupled to a Thermo Q Exactive HF Orbitrap MS for detection.4- 50 309005815v2 Attorney Docket No.: 243735.000414 HB will be identified by retention time in comparison to unlabeled standards and a 13C6-4-HB internal standard, MS1 accurate mass, and MS2 fragmentation. Concentration will be determined by comparison to a standard curve with a 13C6-4-HB internal standard. Purity will be determined by measurement of the area under the 4-HB peak in comparison to the TIC. We will accept concentrations within 15% of the target concentration and purity of >80%, to account for high amounts of 13C6-4-HB internal standard. [00228] The final product will be packaged in a polypropylene bottle with tamper-evident packaging to be delivered to the patient. [00229] Solutions can be made and frozen at -20 ^C for at least a month without loss of efficacy in treating mice.4-HB is stable after storage at -20 ^C in distilled water for 3 months (FIG.11B). Once the solution has been thawed, it must be brought to room temperature to ensure that all 4- HB has dissolved prior to use, and used within 24 hours. [00230] Drug Components and Drug Product 51 309005815v2 Attorney Docket No.: 243735.000414 thawed, it will be mixed well to ensure that the 4-HB is dissolved and used with 24 hours. N ce 0 Pharmacokinetics: T1/2 (10 mg/kg. single dose, oral administration in water): 0.35 hr (n=3 C57 BL/6 mice) T1/2 (500 mg/kg, single dose, oral administration in water): 1.8 hr (n=3 C57 BL/6 mice) T1/2 (IV, 1 mg/kg, water): 0.09 hr (n=3 C57 BL/6 mice) [00232] Toxicology [00233] MTD > 500 mg/mL (mouse; n=20 C57 BL/6 mice; 10 M, 10 F). No toxicity observed. No gross pathology observed on necropsy at 8 days post administration. [00234] LD50 Mouse oral 2200 mg/kg (Lewis, R.J. Sax's Dangerous Properties of Industrial Materials.9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p.2897) [00235] LD50 Mouse ip 210 mg/kg (Lewis, R.J. Sax's Dangerous Properties of Industrial Materials.9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p.2897) [00236] LD50 Mouse sc 1050 mg/kg (Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2897) (https://pubchem.ncbi.nlm.nih.gov/compound/4-Hydroxybenzoic- acid#datasheet=LCSS&section=Non-Human-Toxicity-Values) [00237] Parabens (para-hydroxybenzoic acid esters) are simple ester precursors of 4- hydroxybenzoic acid (also known as para-hydroxybenzoic acid). Parabens are stable in air and resist hydrolysis in acidic medium and under conditions of sterilization. They have been used as preservatives in foods, cosmetics, and pharmaceutical additives for over five decades. FDA has approved the following uses for parabens: ^ Methyl and propyl paraben have been affirmed as Generally Recognized as Safe (GRAS) for direct addition to food at concentrations up to 0.1% and by prior sanction for indirect addition via packaging materials. 52 309005815v2 Attorney Docket No.: 243735.000414 ^ Methyl-, propyl- and butyl-paraben have been approved as synthetic flavoring substances and adjuvants for addition to beverages at minimum quantity, in amounts not to exceed 20 ppm. ^ Methyl-, propyl- and butyl-paraben can also be used as direct food additives for use as preservatives in synthetic flavoring substances and adjuvants. As indirect food additives, methyl and propyl paraben are permitted by prior sanction as antimycotics in packaging materials with no limit or restrictions. [00238] Acute oral toxicity studies in mice, rat, rabbit, and dog models showed that parabens are practically non-toxic by various routes of administration. Toxicities for these compounds are >1 g/L in large animal models. A summary of acute toxicity data is provided in the Table 2. Table 2. Acute oral toxicity of parabens in mice, rats, rabbits, and dogs. lethal assay, and host-mediated assay indicated that parabens are not genotoxic. The chemical structure of paraben is not indicative of carcinogenic potential, as they are rapidly metabolized and excreted from the body via several metabolic routes without accumulation of the paraben or its metabolites (Figure 12; (18)). [00240] The widespread use of parabens in cosmetic products in the US without a significant number of complaints reported provides additional support for their safety and effectiveness (13). [00241] We have tested 4-hydroxybenzoate in mice at doses of up to 500 mg/kg without observable toxicity. Toxicity would most likely be esophagitis or gastritis following administration of 4-hydroxybenzoic acid, as it has a pH of 4 in water (comparable to orange juice, which has a pH of 3.5). We will treat the patient with aluminum hydroxide/magnesium hydroxide (Maalox/Mylanta), or with sucrose/calcium carbonate if he develops any GI adverse events from treatment. [00242] Hazards Summary 53 309005815v2 Attorney Docket No.: 243735.000414 [00243] A mild skin irritant and sensitizer; A moderate eye irritant; In animal experiments, causes somnolence, ataxia and changes to liver and kidneys; Oral LD50 (mouse) = 2200 mg/kg; Safe when used as a flavoring agent; An irritant; Effects in high-dose animal studies include acute tubular necrosis); (https://pubchem.ncbi.nlm.nih.gov/compound/4-Hydroxybenzoic- acid#datasheet=LCSS&section=Non-Human-Toxicity-Values) [00244] Hair Growth Induced by 4-HMA Treatment [00245] 90-Week-old mice were pre-treated with vehicle (non-treated control; NTC) or 100 mg/kg 4-HMA in the drinking water for two weeks. Then, they were shaved, and the growth of hair was monitored. At 5 weeks, the mice were treated with topical 100 mg/kg 4-HMA in water. 4-HMA was applied directly to the skin using Q-tip every other day (week 5-week 12). Regrowth of hair in shaved 90-week-old-mice following treatment was observed (FIG.14). [00246] 90-Week-old mice (JAX C57/BL6 mice) were shaved and the shaved area was treated topically with 4-HMA (no systemic 4-HMA was provided). Shaved area was swabbed with 4HMA (100mg/mL) every other day.4-HMA-Treated animals appear to be closing the shaved area faster (FIG.15). [00247] References (1)-(18): 1. Wiessner M, Maroofian R, Ni M-Y, Pedroni A, Müller JS, Stucka R, et al. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia. Brain.2021 Jun 22;144(5):1422–34. PMCID: PMC8219359 2. Ghosh SG, Lee S, Fabunan R, Chai G, Zaki MS, Abdel-Salam G, et al. Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition. Genet Med.2021 Mar;23(3):524–33. 3. Husain RA, Grimmel M, Wagner M, Hennings JC, Marx C, Feichtinger RG, et al. Bi- allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia. Am J Hum Genet.2020 Aug 6;107(2):364–73. PMCID: PMC7413886 4. Morgan NV, Yngvadottir B, O'Driscoll M, Clark GR, Walsh D, Martin E, et al. Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL. Brain Commun.2021;3(1):fcab002. PMCID: PMC7892364 5. Guerra RM, Pagliarini DJ. Coenzyme Q biochemistry and biosynthesis. Trends Biochem Sci.2023 May;48(5):463–76. PMCID: PMC10106368 54 309005815v2 Attorney Docket No.: 243735.000414 6. Wang Y, Hekimi S. The efficacy of coenzyme Q10 treatment in alleviating the symptoms of primary coenzyme Q10 deficiency: A systematic review. J. Cell. Mol. Med. John Wiley & Sons, Ltd; 2022 Sep;26(17):4635–44. PMCID: PMC9443948 7. Holmgren D, Wahlander H, Eriksson BO, Oldfors A, Holme E, Tulinius M. Cardiomyopathy in children with mitochondrial disease; clinical course and cardiological findings. Eur Heart J.2003 Feb;24(3):280–8. 8. Barshop BA. Metabolomic approaches to mitochondrial disease: correlation of urine organic acids. Mitochondrion.2004 Sep;4(5-6):521–7. 9. Schüle R, Holland-Letz T, Klimpe S, Kassubek J, Klopstock T, Mall V, et al. The Spastic Paraplegia Rating Scale (SPRS): a reliable and valid measure of disease severity. Neurology. 2006 Aug 8;67(3):430–4. 10. Krosschell KJ, Townsend EL, Kiefer M, Simeone SD, Zumpf K, Welty L, et al. Natural history of 10-meter walk/run test performance in spinal muscular atrophy: A longitudinal analysis. Neuromuscular Disorders. Elsevier B.V; 2022 Feb 1;32(2):125–34. 11. Wang Y-C, Bohannon RW, Kapellusch J, Garg A, Gershon RC. Dexterity as measured with the 9-Hole Peg Test (9-HPT) across the age span. J Hand Ther.2015;28(1):53–9–quiz60. 12. Meseguer-Henarejos A-B, Sánchez-Meca J, López-Pina J-A, Carles-Hernández R. Inter- and intra-rater reliability of the Modified Ashworth Scale: a systematic review and meta- analysis. Eur J Phys Rehabil Med.2018 Aug;54(4):576–90. 13. Soni MG, Carabin IG, Burdock GA. Safety assessment of esters of p-hydroxybenzoic acid (parabens). Food and Chemical Toxicology.2005 Jul;43(7):985–1015. 14. Dey G, Chakraborty M, Mitra A. Profiling C6-C3 and C6-C1 phenolic metabolites in Cocos nucifera. J Plant Physiol.2005 Apr;162(4):375–81. 15. Goulas V, Stylos E, Chatziathanasiadou MV, Mavromoustakos T, Tzakos AG. Functional Components of Carob Fruit: Linking the Chemical and Biological Space. Int J Mol Sci. Multidisciplinary Digital Publishing Institute; 2016 Nov 10;17(11):1875. PMCID: PMC5133875 16. Tian R-R, Pan Q-H, Zhan J-C, Li J-M, Wan S-B, Zhang Q-H, et al. Comparison of phenolic acids and flavan-3-ols during wine fermentation of grapes with different harvest times. Molecules. Molecular Diversity Preservation International; 2009 Feb 18;14(2):827–38. PMCID: PMC6253884 55 309005815v2 Attorney Docket No.: 243735.000414 17. Banh RS, Kim ES, Spillier Q, Biancur DE, Yamamoto K, Sohn ASW, et al. The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway. Nature.2021 Sep;597(7876):420–5. 18. Abbas S, Greige-Gerges H, Karam N, Piet M-H, Netter P, Magdalou J. Metabolism of parabens (4-hydroxybenzoic acid esters) by hepatic esterases and UDP-glucuronosyltransferases in man. Drug Metab Pharmacokinet.2010;25(6):568–77. * * * [00248] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. [00249] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification. 56 309005815v2

Claims

Attorney Docket No.: 243735.000414 WHAT IS CLAIMED IS: 1. A method of treating a disease or disorder selected from the group consisting of heart disease, neurodegenerative disease, migraine headache, neurodevelopmental disease, infertility, pulmonary disease, muscle disease, liver disease, pancreatic disease, oral disease, ophthalmic disease, hearing disease, diseases of pregnancy, diseases of prematurity, aging disorders, movement disorders, infectious disease, and any disease in which Coenzyme Q declines, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), or a compound of Formula (I): R3 O O , wherein: R1 is selected from the group ; R2 is selected from the group R3 is selected from the group consisting of H and C1-C3 alkyl; and R4 is selected from the group consisting of H , or a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein the heart disease is selected from the group consisting of heart failure, high blood pressure, recovery post cardiac surgery, and statin-induced myopathy. 3. The method of claim 1, wherein the method comprises one or more of reducing LDL cholesterol, improving insulin sensitivity, and decreasing diabetic or other neuropathy. 57 309005815v2 Attorney Docket No.: 243735.000414 4. The method of claim 1, wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS), and demyelinating and white matter disease. 5. The method of claim 1, wherein the neurodevelopmental disease is cerebral palsy. 6. The method of claim 1, wherein the method comprises augmenting egg or sperm quality. 7. The method of claim 1, wherein the pulmonary disease is chronic obstructive pulmonary disease (COPD) or asthma. 8. The method of claim 1, wherein the muscle disease is muscular dystrophy. 9. The method of claim 1, wherein the liver disease is characterized by toxicity due to statins or liver injury. 10. The method of claim 1, wherein the pancreatic disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, and exocrine insufficiency. 11. The method of claim 1, wherein the oral disease is selected from the group consisting of tooth decay, periodontitis, and gum decay. 12. The method of claim 1, wherein the ophthalmic disease is selected from the group consisting of macular degeneration, cataract formation, retinal detachment, and retinitis pigmentosa. 13. The method of claim 1, wherein the hearing disease is hearing loss. 14. The method of claim 1, wherein the disease of pregnancy is placental insufficiency or pre- eclampsia. 58 309005815v2 Attorney Docket No.: 243735.000414 15. The method of claim 1, wherein the disease of prematurity is selected from the group consisting of prematurity, retinopathy of prematurity, and cerebral palsy. 16. A method of improving wound healing in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I): R3 O R1 O , wherein: R1 is selected from the group ; R2 is selected from the group R3 is selected from the group consisting of H and C1-C3 alkyl; and R4 is selected from the group consisting of H , or a pharmaceutically acceptable salt thereof. 17. A method of treating a neurodevelopmental disorder with spastic paresis and brain white matter abnormalities in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), or a compound of Formula (I): R3 O , wherein: R1 is selected from the group ; 59 309005815v2 Attorney Docket No.: 243735.000414 R2 is selected from the group consisting of H and C1-C3 alkyl; R3 is selected from the group consisting of H and C1-C3 alkyl; and R4 is selected from the group consisting of H , or a pharmaceutically acceptable salt thereof. 18. A method of treating a subject having a white matter abnormality, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I): R3 O O , wherein: R1 is selected from the group ; R2 is selected from the group R3 is selected from the group consisting of H and C1-C3 alkyl; and R4 is selected from the group consisting of H , or a pharmaceutically acceptable salt thereof. 19. The method of claim 17 or 18, wherein the subject has 4-hydroxyphenylpyruvate dioxygenase- like (HPDL) deficiency. 20. The method of any one of claims 17-19, wherein the subject has a variant in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway. 21. The method of claim 20, wherein the mutation is homozygous. 60 309005815v2 Attorney Docket No.: 243735.000414 22. A method of treating a subject having a variant in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway, comprising administering to the subject a therapeutically effective amount of 4- hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), or a compound of Formula (I): R3 O R1 O , wherein: R1 is selected from the group ; R2 is selected from the group R3 is selected from the group R4 is selected from the group consisting of H and , or a pharmaceutically acceptable salt thereof. 23. A method for improving physical performance and energy production in a subject having an HPDL deficiency comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), or a compound of Formula (I): R3 O , wherein: R1 is selected from the group ; R2 is selected from the group R3 is selected from the group consisting of H and C1-C3 alkyl; and 61 309005815v2 Attorney Docket No.: 243735.000414 R4 is selected from the group consisting of H and , or a pharmaceutically acceptable salt thereof. 24. The method of claim 23, wherein the method comprises one or more of decreasing fatigue, increasing strength and stamina, increasing functional performance, and improving balance. 25. A method of treating a 4-hydroxyphenylpyruvate dioxygenase-like (HPDL)-related disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), or a compound of Formula (I): , wherein: R1 is selected from the group ; R2 is selected from the group R3 is selected from the group consisting of H and C1-C3 alkyl; and R4 is selected from the group consisting of H , or a pharmaceutically acceptable salt thereof in an antacid. 26. The method of claim 25, wherein the antacid is selected from the group consisting of aluminum, calcium, magnesium, and sodium salts. 27. A method of accelerating, promoting, or restoring hair growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4- hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), or a compound of Formula (I): 62 309005815v2 Attorney Docket No.: 243735.000414 R3 O R1 O N , wherein: R1 is selected from the group ; R2 is selected from the group R3 is selected from the group R4 is selected from the group consisting of H , or a pharmaceutically acceptable salt thereof. 28. A method of treating hair loss in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I): R3 O , wherein: R1 is selected from the group ; R2 is selected from the group R3 is selected from the group consisting of H and C1-C3 alkyl; and R4 is selected from the group consisting of H , or a pharmaceutically acceptable salt thereof. 63 309005815v2 Attorney Docket No.: 243735.000414 29. A method of treating a condition or disorder affecting hair growth in a subject, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4- HMA), 4-hydroxybenzoate (4-HB), or a compound of Formula (I): R3 O R1 O , wherein: R1 is selected from the group ; R2 is selected from the group R3 is selected from the group R4 is selected from the group consisting of H , or a pharmaceutically acceptable salt thereof. 30. The method of claim 29, wherein the condition or disorder affecting hair growth is baldness or alopecia. 31. The method of any one of claims 1-30, wherein 4-hydroxymandelic acid (4-HMA) or pharmaceutically acceptable salt thereof is administered to the subject. 32. The method of any one of claims 1-31, wherein the 4-HMA is enantioentriched (R)-4-HMA. 33. The method of claim 32, wherein the enantioentriched (R)-4-HMA has enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%. 34. The method of any one of claims 1-33, wherein the 4-HMA is enantiopure (R)-4-HMA. 64 309005815v2 Attorney Docket No.: 243735.000414 35. The method of any one of claims 1-30, wherein 4-hydroxybenzoate (4-HB) or pharmaceutically acceptable salt thereof is administered to the subject. 36. The method of any one of claims 1-30, wherein a compound of Formula (I) or pharmaceutically acceptable salt thereof is administered to the subject. 37. The method of any one of claims 1-30 or 36, wherein R1 is H. 38. The method of any one of claims 1-30 or 36, . 39. The method of any one of claims 1-30 or 36-38, wherein R2 is methyl. 40. The method of any one of claims 1-30 or 36-38, wherein R2 is H. 41. The method of any one of claims 1-30 or 36-40, wherein R3 is H. 42. The method of any one of claims 1-30 or 36-40, wherein R3 is methyl. 43. The method of any one of claims 1-30 or 36-42, wherein R4 is H. 44. The method of any one of claims 1-30 or 36-42, wherein R4 . 45. The method of any one of claims 1-30 or 36, wherein the compound of Formula (I) has the structure according to Formula (II): wherein: 65 309005815v2 Attorney Docket No.: 243735.000414 R1 is selected from the group R4 is selected from the group . 46. The method of any one of claims 1-30 or 36, wherein the compound of Formula (I) has the structure according to Formula (III): wherein: R1 is selected from the group R4 is selected from the group consisting of H and . 47. The method of any one of claims 1-30 or 36, wherein the compound having the structure of Formula (I) is selected from the group consisting of: 66 309005815v2 Attorney Docket No.: 243735.000414 , 48. The method of any one of claims 1-30 or 36, wherein the compound having the structure of Formula (I) is selected from the group consisting of: a 49. The method of any one of claims 1-48, wherein the subject is a mammal. 50. The method of claim 49, wherein the subject is a human. 51. The method of claim 50, wherein the subject is a male. 52. The method of claim 50, wherein the subject is a pediatric subject 0 to 18 month of age. 67 309005815v2 Attorney Docket No.: 243735.000414 53. The method of claim 50, wherein the subject is a pediatric subject 0 to 2 years of age. 54. The method of claim 50, wherein the subject is a pediatric subject 0 to 10 years of age. 55. The method of claim 50, wherein the subject is a pediatric subject 0 to 18 years of age. 56. The method of claim 50, wherein the subject is a pediatric subject 0 to 21 years of age. 57. The method of claim 50, wherein the subject is an adult. 58. The method of claim 50, wherein the subject is an elderly adult. 59. The method of claim 50, wherein the subject is 65 years or older. 60. The method of claim 50, wherein the subject is a male 35 years or older. 61. The method of claim 50, wherein the subject is a male 45 years or older. 62. The method of any one of claims 1-61, wherein 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional therapeutic agents. 63. The method of any one of claims 1-62, wherein the method further comprises detecting in a biological sample obtained from the subject the presence of the one or more variants in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway prior to said administration. 64. The method of any one of claims 1-62, wherein the method further comprises detecting plasma 4-HMA concentration in a biological sample obtained from the subject prior to said administration. 68 309005815v2 Attorney Docket No.: 243735.000414 65. The method of claim 63 or claim 64, wherein the biological sample comprises peripheral blood mononuclear cells, or a biopsy specimen. 66. The method of claim 63 or claim 64, wherein when the subject is a pregnant female, the biological sample is a fetal DNA sample. 67. The method of claim 66, wherein the fetal DNA sample is obtained by circulating fetal DNA isolation, chorionic villus sampling, or amnioscentesis. 68. The method of any one of claims 63 or 65-67, wherein the detection of one or more variants in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway is conducted by sequencing of said gene(s) or immunohistochemistry (IHC) of the protein(s) produced by said gene(s). 69. A method of treating a 4-hydroxyphenylpyruvate dioxygenase-like (HPDL)-related disease or disorder in a subject in need thereof, comprising: a. detecting in a biological sample obtained from the subject the plasma 4-HMA concentration; and b. administering to the subject having a reduced plasma 4-HMA concentration (<20 nM) a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I): R3 O , wherein: R1 is selected from the group ; R2 is selected from the group R3 is selected from the group consisting of H and C1-C3 alkyl; and 69 309005815v2 Attorney Docket No.: 243735.000414 R4 is selected from the group consisting of H and , or a pharmaceutically acceptable salt thereof. 70. A method of increasing CoQ10 biosynthesis in a subject in need thereof, comprising: a. detecting in a biological sample obtained from the subject the plasma 4-HMA concentration; and b. administering to the subject having a reduced plasma 4-HMA concentration a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I): R3 O O , wherein: R1 is selected from the group ; R2 is selected from the group R3 is selected from the group consisting of H and C1-C3 alkyl; and R4 is selected from the group consisting of H , or a pharmaceutically acceptable salt thereof. 71. The method of any one of claims 1-70, wherein 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered orally. 72. The method of claim 71, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4- HB), or a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered as a liquid dosage form. 70 309005815v2 Attorney Docket No.: 243735.000414 73. The method of claim 72, wherein the liquid dosage form is selected from the group consisting of dispersion, solution, gel, syrup, elixir, slurry, and suspension. 74. The method of any one of claims 1-72, wherein 4-hydroxybenzoate (4-HB) or a pharmaceutically acceptable salt thereof is administered as a suspension. 75. The method of any one of claims 71, wherein 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered as a solid dosage form. 76. The method of claim 74, wherein the solid oral dosage form is selected from the group consisting of tablet, powder, pill, dragee, capsule, effervescent formulation, and lyophilized formulation. 77. The method of any one of claims 1-70, wherein 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered topically. 78. The method of any one of claims 1-77, wherein 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered at an amount from about 1mg to about 20g. 79. The method of any one of claims 1-78, wherein 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered at an amount from about 100mg to about 10g. 80. The method of any one of claims 1-79, wherein 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered at an amount from about 1g to about 5g. 71 309005815v2 Attorney Docket No.: 243735.000414 81. The method of any one of claims 1-80, wherein 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered at an amount of about 3g. 82. The method of claim 26, wherein the antacid is selected from the group consisting of aluminum hydroxide, magnesium hydroxide, sucrose/calcium carbonate, sodium citrate, citric acid, sodium bicarbonate, tartaric acid, and alginic acid. 83. The method of any one of claims 1-82, wherein 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), or a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered at a concentration of about 10 mg/mL. 84. The method of any one of claims 1-82, wherein 4-hydroxybenzoate (4-HB) or a pharmaceutically acceptable salt thereof is administered at a concentration of about 10 mg/mL. 72 309005815v2
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110212913A1 (en) * 2008-10-31 2011-09-01 Provexis Natural Products Limited Therapeutic compositions comprising phenolic acids for treating conditions related to inappropriate platelet aggregation
US20110229554A1 (en) * 2010-03-12 2011-09-22 Niven Rajin Narain INTRAVENOUS FORMULATIONS OF COENZYME Q10 (CoQ10) AND METHODS OF USE THEREOF
CN110982771A (en) * 2019-12-26 2020-04-10 江南大学 Method for synthesizing p-hydroxymandelic acid
WO2022159473A1 (en) * 2021-01-20 2022-07-28 New York University Methods and compositions for treating 4-hydroxyphenylpyruvate dioxygenase-like (hpdl)-related diseases or disorders
WO2023168053A2 (en) * 2022-03-03 2023-09-07 New York University Hpdl inhibitors and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110212913A1 (en) * 2008-10-31 2011-09-01 Provexis Natural Products Limited Therapeutic compositions comprising phenolic acids for treating conditions related to inappropriate platelet aggregation
US20110229554A1 (en) * 2010-03-12 2011-09-22 Niven Rajin Narain INTRAVENOUS FORMULATIONS OF COENZYME Q10 (CoQ10) AND METHODS OF USE THEREOF
CN110982771A (en) * 2019-12-26 2020-04-10 江南大学 Method for synthesizing p-hydroxymandelic acid
WO2022159473A1 (en) * 2021-01-20 2022-07-28 New York University Methods and compositions for treating 4-hydroxyphenylpyruvate dioxygenase-like (hpdl)-related diseases or disorders
WO2023168053A2 (en) * 2022-03-03 2023-09-07 New York University Hpdl inhibitors and uses thereof

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