Methods for treating dhdds-related disorders

Abstract

The present disclosure relates generally to compounds and pharmaceutical compositions for treating or preventing a condition or disorder mediated by DHDDS.

Description

Attorney Docket No.: 228 J-419245- WOMETHODS FOR TREATING DHDDS-RELATED DISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application No. 63 / 701,223, filed September 30, 2024, which is hereby incorporated by reference in its entirety.FIELD

[0002] Provided herein are compounds, pharmaceutical compositions, and methods for treating or preventing DHDDS-related disorders.BACKGROUND

[0003] The mammalian DHDDS gene encodes dehydrodolichyl diphosphate synthase subunit (DHDDS). This catalytic subunit, along with NgBR (also known as Nogo-B receptor), encoded by the NUS1 gene, forms the cis-prenyltransferase (c / .s-PTase) complex. This complex catalyzes the rate-limiting step in dolichol biosynthesis, by condensing farnesyl diphosphate (FPP) with multiple isopentenyl pyrophosphate (IPP) units to generate polyprenol diphosphate (polyprenol- PP). Dolichol kinase (DOLK) catalyzes the phosphorylation of dolichol using cytidine triphosphate (CTP) to generate dolichyl-phosphate (Dol-P). Dol-P is known as an essential lipid that serves as a lipid carrier for protein N-glycosylation and as monosaccharide donor (Dol-P- glucose and Dol-P mannose) in N-glycosylation, O-mannosylation, C-mannosylation and glycophosphatidylinositol (GPI) anchor biosynthesis.

[0004] Mutations in DHDDS gene are reported to be linked to several disorders, including an autosomal recessive form of retinitis pigmentosa (also known as retinitis pigmentosa 59), a fatal congenital disorder of glycosylation (also known as CDG type Ibb or DHDDS-CDG) and a neurodevelopmental and neurodegenerative disorder caused by de novo pathogenic variants (also known as DHDDS disorder or developmental delay and seizures with or without movement abnormalities (DEDSM)). Over 70 patients with DEDSM have been reported worldwide, with clinical presentations characterized by neurodevelopmental delay, epilepsy, movement disorders, cognitive decline, and psychiatric symptoms.Attorney Docket No.: 228 J-419245- WO

[0005] Recurrent de novo pathogenic variants, Arg37His (R37H), Arg211Gln (R211Q), and Arg205Gln (R205Q) have been identified in DEDSM patients. Clinically, DEDSM presents progressively, often manifesting in infancy or childhood with symptoms such as neurodevelopmental disorders, generalized epilepsy, action myoclonus or cortical tremor, and ataxia. As the disease advances, clinical symptoms evolve to include a gradual neurological decline, marked by the onset of hyperkinetic or hypokinetic movement disorders, cognitive deterioration, and psychiatric disturbances.

[0006] Congenital disorders of glycosylation (CDGs) are a group of more than 200 inherited metabolic diseases affecting protein and lipid-linked glycosylation. CDGs may be broadly classified according to the type(s) of glycosylation pathways affected, with DHDDS-CDG belonging to the subgroup of disorders of dolichol metabolism. Unlike other CDG types involving disorders of dolichol metabolism, hypoglycosylation of serum glycoproteins or an abnormal urinary Dol-18 / Dol-19 ratio has not been reported in DEDSM. It has been reported that there is evidence of lipid and cholesterol-like material accumulation and lysosomal dysfunction in Schwann cells, myelinated fibers, and fibroblasts in DEDSM.

[0007] Lysosomal storage diseases (LSDs) are a group of rare inherited metabolic disorders characterized by the accumulation of toxic substances within lysosomes, which leads to a diverse range of clinical presentations including developmental delays, enlarged organs and neurological symptoms. Nicotinamide adenine dinucleotide (NAD+) is a metabolite involved in energy production and cellular metabolism, and its depletion has been observed in cellular models of lysosomal storage diseases. It has been reported that DEDSM shares characteristics of both CDG and lysosomal storage diseases.

[0008] Currently, there is no cure for DEDSM or other DHDDS related diseases, and treatment is primarily supportive and symptomatic, focusing on managing individual symptoms as they arise. Development of improved treatment of DEDSM or other DHDDS related diseases is desired.Attorney Docket No.: 228 J-419245- WOSUMMARY

[0009] According to one embodiment, a method of treating a condition or disorder mediated, at least in part, by DHDDS in a patient in need thereof, is provided. The method comprises administering a therapeutically effective amount of one or more compounds selected from NADP-coenzyme, NAD+ precursor, cytidine / uridine or derivative thereof, one-carbon metabolism linked compound, flavonoid, terpenoid, steroid, neurotransmitter derivative or analog, amino acid precursor of noradrenaline, nonsteroidal anti-inflammatory drug (NSAID), alkylphospholipid, and cholesterol modulating agent, or a pharmaceutically acceptable salt or solvate thereof. “Cytidine / uridine or derivative thereof’ refers to a class of compounds including cytidine, uridine, and derivatives of cytidine and uridine.

[0010] In some embodiments, the administering may comprise administering two or more compounds selected from NADP-coenzyme, NAD+ precursor, cytidine / uridine or derivative thereof, one-carbon metabolism linked compound, flavonoid, terpenoid, steroid, neurotransmitter derivative or analog, amino acid precursor of noradrenaline, NSAID, and cholesterol modulating agent, or a pharmaceutically acceptable salt or solvate thereof. The NADP-coenzyme may be NADPH, NADP+, or a pharmaceutically acceptable salt or solvate thereof. The NAD+ precursor may be nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, NAD+, NADH, niacinamide (NAM), nicotinamide riboside (NR), nicotinic acid riboside (NAR), L-tryptophan, dihydronicotinamide riboside (NRH), or a pharmaceutically acceptable salt or solvate thereof. The cytidine / uridine derivative may be CDP-choline, UTP, CTP, uridine monophosphate (UMP), cytidine monophosphate (CMP), NU2058, or a pharmaceutically acceptable salt or solvate thereof. The one-carbon metabolism linked compound may be folic acid, S-(5'-adenosyl)-L methionine tosylate, methotrexate, or a pharmaceutically acceptable salt or solvate thereof. The flavonoid may be hesperetin 7-O-glucoside, flavomarein, quercetagetin, quercetin, 8-prenylnaringenin, or a pharmaceutically acceptable salt or solvate thereof. The terpenoid may be loganic acid, nardosinone, or a pharmaceutically acceptable salt or solvate thereof. The steroid may be clobetasol, medroxyprogesterone acetate, corticosterone, fluprednisolone, or a pharmaceutically acceptable salt or solvate thereof. The neurotransmitter derivative or analog may be 3-aminobutanoic acid, 3-guanidinopropionic acid, 4- guanidinobutyric acid, 3 -aminopropionitrile, N-acetyl-5-hydroxytryptamine, noradrenaline, or aAttorney Docket No.: 228 J-419245- WO pharmaceutically acceptable salt or solvate thereof. The amino acid precursor of noradrenaline may be noradrenaline bitartrate, L-tyrosine, L-phenylalanine, or a pharmaceutically acceptable salt or solvate thereof. The NSAID may be carprofen or a pharmaceutically acceptable salt or solvate thereof. The alkylphospholipid may be perifosine, miltefosine, or a pharmaceutically acceptable salt or solvate thereof. The cholesterol modulating agent may be dextrothyroxine, 2- hydroxypropyl-P-cyclodextrin, lapaquistat, lapaquistat acetate, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound may be selected from the group consisting of: NADP+, NU2058, uridine triphosphate (UTP), cytidine triphosphate (CTP), S-(5'- adenosyl)-L-methionine tosylate, methotrexate, triciribine, 8-prenylnaringenin, hesperetin 7-0- glucoside, quercetagetin, flavomarein, corticosterone, medroxyprogesterone acetate, fluprednisolone, clobetasol, loganic acid, nardosinone, 3-aminobutanoic acid, 3- guanidinopropionic acid, 4-guanidinobutyric acid, 3 -aminopropionitrile, N-Acetyl-5- hydroxytryptamine, cyclopenthiazide, isepamicin, rosavin, rubusoside, euquinine, TLR4-IN- C34, diclazuril, avoralstat, dextrothyroxine, chlortetracycline, salifungin, pidotimod, NSC59984, plinabulin, ciproxifan, cotinine, huperzine A, vicriviroc, netarsudil, TWS119, PF0147324, UNC2881, CHEMBL241987, perifosine, miltefosine, atracurium, denatonium, oteseconazole, DMXAA, methyl rosmarinate, p-Hydroxy-cinnamic acid, methyl 4-anthranilate, daphnetin, 1,5- isoquinolinediol, CIL62, methyl-4-anisate, nicotinic acid riboside (NAR), niacin, niacinamide, NAD+, NADH, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), nicotinamide riboside (NR), dihydronicotinamide riboside (NRH), quercetin, cytidine, CMP, CDP-Choline, Uridine, UMP, L-tyrosine, L-phenylalanine, L-tryptophan, 2- Hydroxypropyl-P-cyclodextrin, folic acid, lapaquistat, lapaquistat acetate, and a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound may be selected from cytidine triphosphate (CTP), NADPH, carprofen, methotrexate, noradrenaline bitartrate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, and a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the patient may have (a) reduced NAD+ level, (b) reduced CTP level, (c) increased lipid accumulation in Schwann cells, myelinated fibers, or fibroblasts, and / or (d) decreased glycosylation of glycoproteins, lysosomal enzymes, or serum proteins. In some embodiments, said condition or disorder is Developmental Delay and Seizures with or without Movement Abnormalities (DEDSM), DHDDS-CDG, or retinitis pigmentosa 59.Attorney Docket No.: 228 J-419245- WO

[0011] According to one embodiment, a method of treating DEDSM in a patient in need thereof is provided. The method comprises administering a therapeutically effective amount of one or more compounds selected from a NADP-coenzyme, NAD+ precursor, cytidine / uridine or derivative thereof; NADP+, NU2058, uridine triphosphate (UTP), cytidine triphosphate (CTP), S-(5'-adenosyl)-L-methionine tosylate, methotrexate, triciribine, 8-prenylnaringenin, hesperetin 7-O-glucoside, quercetagetin, flavomarein, corticosterone, medroxyprogesterone acetate, fluprednisolone, clobetasol, loganic acid, nardosinone, 3-aminobutanoic acid, 3- guanidinopropionic acid, 4-guanidinobutyric acid, 3 -aminopropionitrile, N-acetyl-5- hydroxytryptamine, cyclopenthiazide, isepamicin, rosavin, rubusoside, euquinine, TLR4-IN- C34, diclazuril, avoralstat, dextrothyroxine, chlortetracycline, salifungin, pidotimod, NSC59984, plinabulin, ciproxifan, cotinine, huperzine A, vicriviroc, netarsudil, TWS119, PF0147324, UNC2881, CHEMBL241987, perifosine, miltefosine, atracurium, denatonium, oteseconazole, DMXAA, methyl rosmarinate, p-Hydroxy-cinnamic acid, methyl 4-anthranilate, daphnetin, 1,5- isoquinolinediol, CIL62, methyl-4-anisate, nicotinic acid riboside (NAR), niacin, niacinamide, NAD+, NADH, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), nicotinamide riboside (NR), dihydronicotinamide riboside (NRH), quercetin, cytidine, CMP, CDP-Choline, Uridine, UMP, L-tyrosine, L-phenylalanine, L-tryptophan, 2- Hydroxypropyl-P-cyclodextrin, folic acid, lapaquistat, lapaquistat acetate, and a pharmaceutically acceptable salt or solvate thereof.

[0012] In some embodiments, the compound may be selected from cytidine triphosphate (CTP), NADPH, carprofen, methotrexate, noradrenaline bitartrate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, and a pharmaceutically acceptable salt or solvate thereof. In some embodiment, the patient may have Arg37His (R37H), Arg21 IGln (R21 IQ) and / or Arg205Gln (R205Q) mutation in DHDDS.

[0013] According to one embodiment, a method of treating DEDSM in a patient in need thereof is provided. The method comprises administering a therapeutically effective amount of one or more compounds selected from methotrexate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, carprofen, and a pharmaceutically acceptable salt or solvate thereof.Attorney Docket No.: 228 J-419245- WO

[0014] According to one embodiment, a method of treating DHDDS-CDG in a patient in need thereof is provided. The method comprises administering a therapeutically effective amount of one or more compounds selected from methotrexate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, carprofen, and a pharmaceutically acceptable salt or solvate thereof.

[0015] According to one embodiment, a method of treating retinitis pigmentosa 59 in a patient in need thereof is provided. The method comprises administering a therapeutically effective amount of one or more compounds selected from methotrexate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, carprofen, and a pharmaceutically acceptable salt or solvate thereof.

[0016] According to one embodiment, provided herein is a method of treating DHDDS-CDG in a patient in need thereof, comprising administering a therapeutically effective amount of nicotinamide mononucleotide (NMN), or a pharmaceutically acceptable salt or solvate thereof.

[0017] According to one embodiment, provided herein is a method of increasing energy metabolism in a patient with DEDSM, comprising administering a therapeutically effective amount of nicotinamide mononucleotide (NMN), or a pharmaceutically acceptable salt or solvate thereof.

[0018] According to one embodiment, provided herein is a method of treating DEDSM in a patient in need thereof, comprising administering a therapeutically effective amount of nicotinamide mononucleotide (NMN), or a pharmaceutically acceptable salt or solvate thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 illustrates the growth defect of human DHDDS patient alleles expressed in a yeast model in a 24-hour luminescent-based growth assays.

[0020] FIG. 2 illustrates the distribution of luminescence values of DHDDS mutant cells treated with 20mM of compounds compared to DMSO controls. Mean luminescence for each group is shown.Attorney Docket No.: 228 J-419245- WO

[0021] FIGS. 3A-C illustrate the dose response of Compounds 1-10 in DHDDS-R205Q mutant yeast compared to DMSO control in a 24-hour luminescent-based growth assay.

[0022] FIGS. 4A-B illustrate Oxygen Consumption Rate of DHDDS and healthy control organoids with or without treatment of 0.5 pM nicotinamide mononucleotide (NMN).

[0023] FIGS. 5A-B illustrate Oxygen Consumption Rate of DHDDS and healthy control organoids with or without treatment of 1 pM NMN.

[0024] FIGS. 6A-C illustrate high-density microelectrode array measurement of healthy control organoids and DHDDS organoids with or without treatment of 0.5 pM NMN.

[0025] FIG. 7 illustrates International Cooperative Ataxia Rating Scale (ICARS) of DEDSM patients before and after 6 month treatment with 250 mg / day NMN.DETAILED DESCRIPTIONDefinitions

[0026] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0027] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0028] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. In certain other embodiments, the term “about” includes the indicated amount ± 0.05%. Also, to the term “about X” includes description of “X.”Attorney Docket No.: 228 J-419245- WO

[0029] Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0030] Provided are also pharmaceutically acceptable salts, stereoisomers, mixture of stereoisomers, hydrates, solvates, solid forms, and tautomeric forms of the compounds described herein.

[0031] In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0032] “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0033] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise,Attorney Docket No.: 228 J-419245- WO pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso- propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0034] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0035] The term “solvate” refers to a complex formed by a combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. As used herein, the term “solvate” includes a “hydrate” (i.e. a complex formed by combination of water molecules with molecules or ions of the solute), hemihydrate, channel hydrate, etc. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure.

[0036] The term “solid form” refers to a type of solid-state material that includes amorphous as well as crystalline forms. The term “crystalline form” refers to polymorphs as well as solvates, hydrates, etc. The term “polymorph” refers to a particular crystal structure having particular physical properties such as X-ray diffraction, melting point, and the like.

[0037] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds areAttorney Docket No.: 228 J-419245- WO understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0038] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0039] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g. , stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival).

[0040] “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0041] “Subject” or “patient” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject or patient is a mammal. In some embodiments, the subject or patient is a human.Attorney Docket No.: 228 J-419245- WO

[0042] The term “therapeutically effective amount” or “effective amount” of a compound described herein means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a condition or disorder described herein, including but not limited to a condition or disorder mediated, at least in part, by DHDDS, such as retinitis pigmentosa 59, DHDDS-CDG and DEDSM. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.

[0043] The methods described herein may be applied to cell populations in vivo or ex vivo. "In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and / or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.Attorney Docket No.: 228J-419245-WOCompounds, Pharmaceutical Compositions, and Modes of Administration

[0044] It is contemplated that the compounds provided herein are useful for treating a condition or disorder mediated, at least in part, by DHDDS, such as retinitis pigmentosa 59, DHDDS-CDG and DEDSM.

[0045] In some embodiments, the compound has the following structure:Compound 1.

[0046] In some embodiments, the compound is a pharmaceutically acceptable salt or solvate of Compound 1. Compound 1, also known as cytidine triphosphate (CTP), is commercially available and also may be synthesized according to methods known in the art.

[0047] In some embodiments, the compound has the following structure:Compound 2.Attorney Docket No.: 228J-419245-WO

[0048] Compound 2, also known as nicotinamide adenine dinucleotide phosphate (NADPH) tetracyclohexamine, is commercially available and also may be synthesized according to methods known in the art. In some embodiments, the compound is NADPH or other pharmaceutically acceptable salt or solvate of NADPH.

[0049] In some embodiments, the compound has the following structure:Compound 3.

[0050] In some embodiments, the compound is a pharmaceutically acceptable salt or solvate of Compound 3. Compound 3, also known as 2-(6-chloro-9H-carbazol-2-yl)propanoic acid or carprofen, is commercially available and also may be synthesized according to methods known in the art.

[0051] In some embodiments, the compound has the following structure:Compound 4.

[0052] In some embodiments, the compound is a pharmaceutically acceptable salt or solvate of Compound 4. Compound 4, also known as (S)-2-(4-(((2,4-diaminopteridin-6- yl)methyl)(methyl)amino)benzamido)pentanedioic acid, or methotrexate, is commercially available and also may be synthesized according to methods known in the art.

[0053] In some embodiments, the compound has the following structure:Attorney Docket No.: 228J-419245-WOCompound 5.

[0054] Compound 5, also known as noradrenaline bitartrate monohydrate, is commercially available and also may be synthesized according to methods known in the art. In some embodiments, the compound is noradrenaline or other pharmaceutically acceptable salt or solvate of noradrenaline.

[0055] In some embodiments, the compound has the following structure:Compound 6.

[0056] In some embodiments, the compound is a pharmaceutically acceptable salt or solvate of Compound 6. Compound 6, also known as nicotinamide mononucleotide or NMN, is commercially available and also may be synthesized according to methods known in the art. In some embodiments, the compound is a free base, pharmaceutically acceptable salt or solvate of Compound 6.Attorney Docket No.: 228J-419245-WO

[0057] In some embodiments, the compound has the following structure:Compound 7.

[0058] In some embodiments, the compound is a pharmaceutically acceptable salt or solvate of Compound 7. Compound 7, also known as reduced nicotinamide mononucleotide or NMNH, is commercially available and also may be synthesized according to methods known in the art.

[0059] In some embodiments, the compound has the following structure:Compound 8.

[0060] In some embodiments, the compound is a pharmaceutically acceptable salt or solvate of Compound 8. Compound 8, also known as niacin or vitamin B3, is commercially available and also may be synthesized according to methods known in the art.

[0061] In some embodiments, the compound has the following structure:Attorney Docket No.: 228 J-419245- WOCompound 9.

[0062] In some embodiments, the compound is a pharmaceutically acceptable salt or solvate of Compound 9. Compound 9, also known as niacinamide (NAM), is commercially available and also may be synthesized according to methods known in the art.

[0063] In some embodiments, the compound has the following structure:Compound 10.

[0064] In some embodiments, the compound is a pharmaceutically acceptable salt or solvate of Compound 10. Compound 10, also known as nicotinamide riboside (NR), is commercially available and also may be synthesized according to methods known in the art.

[0065] In some embodiments, the compound may be selected from certain classes of compounds. For example, the compound may be selected from: NADP-coenzyme, NAD+ precursor, cytidine / uridine or derivative thereof, one-carbon metabolism linked compound, flavonoid, terpenoid, steroid, neurotransmitter derivative or analog, amino acid precursor of noradrenaline, NS AID, alkylphospholipid, and cholesterol modulating agent, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, two or more compounds are selected from NADP-coenzyme, NAD+ precursor, cytidine / uridine or derivative thereof, one-carbon metabolism linked compound, flavonoid, terpenoid, steroid, neurotransmitter derivative or analog, amino acid precursor of noradrenaline, NSAID, and cholesterol modulating agent, or a pharmaceutically acceptable salt or solvate thereof.

[0066] In some embodiments, the NADP-coenzyme is NADPH, NADP+, or a pharmaceutically acceptable salt or solvate each thereof.Attorney Docket No.: 228 J-419245- WO

[0067] In some embodiments, the NAD+ precursor is nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, NAD+, NADH, niacinamide (NAM), nicotinamide riboside (NR), nicotinic acid riboside (NAR), L-tryptophan, dihydronicotinamide riboside (NRH), or a pharmaceutically acceptable salt or solvate each thereof.

[0068] In some embodiments, the cytidine / uridine derivative is CDP-choline, UTP, CTP, UMP, CMP, NU2058, or a pharmaceutically acceptable salt or solvate each thereof.

[0069] In some embodiments, the one-carbon metabolism linked compound is folic acid, S-(5'- adenosyl)-L methionine tosylate, methotrexate, or a pharmaceutically acceptable salt or solvate each thereof.

[0070] In some embodiments, the flavonoid is hesperetin 7-O-glucoside, flavomarein, quercetagetin, quercetin, 8-prenylnaringenin, or a pharmaceutically acceptable salt or solvate each thereof.

[0071] In some embodiments, the terpenoid is loganic acid, nardosinone, or a pharmaceutically acceptable salt or solvate each thereof.

[0072] In some embodiments, the steroid is clobetasol, medroxyprogesterone acetate, corticosterone, fluprednisolone, or a pharmaceutically acceptable salt or solvate each thereof.

[0073] In some embodiments, the neurotransmitter derivative or analog is 3 -aminobutanoic acid, 3-guanidinopropionic acid, 4-guanidinobutyric acid, 3-aminopropionitrile, N-acetyl-5- hydroxytryptamine, noradrenaline, or a pharmaceutically acceptable salt or solvate each thereof.

[0074] In some embodiments, the amino acid precursor of noradrenaline is noradrenaline bitartrate (e.g., noradrenaline bitartrate monohydrate), L-tyrosine, L-phenylalanine, or a pharmaceutically acceptable salt or solvate each thereof.

[0075] In some embodiments, the NSAID is carprofen or a pharmaceutically acceptable salt or solvate each thereof.

[0076] In some embodiments, the alkylphospholipid is perifosine, miltefosine, or a pharmaceutically acceptable salt or solvate each thereof.Attorney Docket No.: 228 J-419245- WO

[0077] In some embodiments, the cholesterol modulating agent is dextro thyroxine, 2- hydroxypropyl-P-cyclodextrin, lapaquistat, lapaquistat acetate, or a pharmaceutically acceptable salt or solvate each thereof.

[0078] In some embodiments, the compound may be selected from NADP+, NADPH, carprofen, NU2058, UTP, CTP, S-(5'-adenosyl)-L-methionine tosylate, methotrexate, triciribine, 8-prenylnaringenin, hesperetin 7-O-glucoside, quercetagetin, flavomarein, corticosterone, medroxyprogesterone acetate, fluprednisolone, clobetasol, loganic acid, nardosinone, 3- aminobutanoic acid, 3-guanidinopropionic acid, 4-guanidinobutyric acid, 3-aminopropionitrile, N-acetyl-5-hydroxytryptamine, noradrenaline, noradrenaline bitartrate, noradrenaline bitartrate monohydrate, cyclopenthiazide, isepamicin, rosavin, rubusoside, euquinine, TLR4-IN-C34, diclazuril, avoralstat, dextrothyroxine, chlortetracycline, salifungin, pidotimod, NSC59984, plinabulin, ciproxifan, cotinine, huperzine A, vicriviroc, netarsudil, TWS119, PF0147324, UNC2881, CHEMBL241987, perifosine, miltefosine, atracurium, denatonium, oteseconazole, DMXAA, methyl rosmarinate, p-Hydroxy-cinnamic acid, methyl 4-anthranilate, Daphnetin, 1,5- isoquinolinediol, CIL62, methyl-4-anisate, and a pharmaceutically acceptable salt or solvate of each thereof. In some embodiments, the compound may be selected from nicotinic acid riboside (NAR), niacin, niacinamide (NAM), NAD+, NADH, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), nicotinamide riboside (NR), dihydronicotinamide riboside (NRH), quercetin, cytidine, CMP, CDP-Choline, Uridine, UMP, L- tyrosine, L-phenylalanine, L-tryptophan, 2-Hydroxypropyl-P-cyclodextrin, folic acid, lapaquistat, lapaquistat acetate, and a pharmaceutically acceptable salt or solvate of each thereof.

[0079] Also provided herein, in some embodiments, are pharmaceutical compositions that comprise one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).Attorney Docket No.: 228 J-419245- WO

[0080] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0081] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0082] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0083] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.Attorney Docket No.: 228 J-419245- WO

[0084] The compositions that include at least one compound described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0085] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0086] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0087] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. TheAttorney Docket No.: 228 J-419245- WO liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, such as orally or nasally, from devices that deliver the formulation in an appropriate manner.Kits

[0088] Provided herein are also kits that include a compound of the disclosure and suitable packaging. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of the disclosure and a label and / or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.

[0089] Provided herein are also articles of manufacture that include a compound described herein in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.Treatment Methods and Uses

[0090] Mutations in DHDDS are associated with several disorders, such as retinitis pigmentosa 59, DHDDS-CDG and Developmental Delay and Seizures with or without Movement abnormalities (DEDSM). DEDSM is caused by de novo mutations in the DHDDS gene, which encodes the enzyme dehydrodolichyl diphosphate synthase.

[0091] Provided herein are methods for increasing NAD+ levels, increasing CTP levels, reducing lipid accumulation, restoring glycosylation, restoring mitochondrial function and / or restoring lysosomal function in a patient in need thereof, comprising administering a therapeutically effective amount of a compound as described herein, or a combination of the compounds described herein, or a composition as described herein.Attorney Docket No.: 228 J-419245- WO

[0092] Also provided herein are methods for treating a condition or disorder mediated, at least in part, by DHDDS in a patient in need thereof comprising administering a therapeutically effective amount of a compound as described herein, or a combination of the compounds described herein, or a composition as described herein.

[0093] In some embodiments, the condition or disorder mediated, at least in part, by DHDDS, is a neurodevelopmental disorder known as DHDDS disorder, or Developmental Delay and Seizures with or without Movement Abnormalities (DEDSM).

[0094] In some embodiments, the condition or disorder mediated, at least in part, by de novo mutation of DHDDS.

[0095] In some embodiments, the condition or disorder mediated, at least in part, by DHDDS, is an autosomal recessive disorder of retinitis pigmentosa, also known as retinitis pigmentosa 59.

[0096] In some embodiments, the condition or disorder mediated, at least in part, by DHDDS, is a congenital disorder of glycosylation. In some embodiments, the congenital disorder of glycosylation is a Type I disorder (e.g., la, lb, Ic, Id, le, If, Ih, li, Ij, Ik, IL, Im, In, Io, Ip, Iq, Ir, DPM2-CDG, TUSC3-CDG, MAGT1-CDG, and I / IIx). In some embodiments, the congenital disorder of glycosylation is a Type II disorder (e.g., Ila, lib, lie, lid, He, Ilf, Ilg, Hh, Hi, Ilj, III, ATP6V0A2-CDG, MAN1B1-CDG, and ST3GAL3-CDG).

[0097] In some embodiments, the congenital disorder of glycosylation is not classified as Type I or Type II. Other CDGs include N-linked type I forms of CDG (such as PMM2-CDG, MPL CDG, GMPPA-CDG, and PGM1-CDG); N-linked type II forms of CDG (such as MAN1GB1- CDG and MGAT2-CDG); O-linked forms of CDG (such as EXT1 / EXT2-CDG, B4GALT7- CDG and B3GALTL-CDG); CDG due to defects in multiple glycosylation pathways (such as DPM1-CDG and DOLK-CDG); CDG due to GPI-anchor synthesis defects (such as PIGN-CDG or PIGV-CDG); and CDG due to glycosphingolipid synthesis defects (such as ST3GAL5-CDG or B4GALNT1-CDG).

[0098] In some embodiments the congenital disorder of glycosylation is disorder of dolichol metabolism.Attorney Docket No.: 228 J-419245- WO

[0099] In some embodiments, the congenital disorder of glycosylation is DHDDS-CDG. In certain instances, DEDSM can be considered a type of DHDDS-CDG, and DEDSM and DHDDS-CDG may be used interchangeably.

[0100] It is contemplated herein that, in some embodiments, a compound described herein may be useful for treating congenital disorders of deglycosylation (CDDG).

[0101] In some embodiments, the condition or disorder mediated, at least in part, by DHDDS, is a lysosomal storage disease (LSD). In some embodiments, the lysosomal storage disease is a mucopolysaccharidosis (MPS), such as MPS I (Hurler syndrome), MPS II (Hunter syndrome), or MPS III (Sanfilippo syndrome). In some embodiments, the lysosomal storage disease is a sphingolipidosis, including Gaucher disease, Fabry disease, or Tay-Sachs disease. In some embodiments, the lysosomal storage disease is a glycoproteinosis, such as Pompe disease or Niemann-Pick disease. In some embodiments, the lysosomal storage disease is a mucolipidosis, such as Mucolipidosis II (Lcell disease) or Mucolipidosis III (Pseudo-Hurler Poly dystrophy). In some embodiments, the lysosomal storage disease is not classified into the aforementioned categories but is nonetheless related to lysosomal dysfunction.

[0102] In some embodiments, restoring glycosylation provides restoring levels of glycosylated glycoproteins, lysosomal enzymes, or serum proteins as compared to levels of glycoproteins, lysosomal enzymes, or serum proteins prior to administration. Measurement of glycosylated glycoproteins, lysosomal enzymes, or serum proteins are methods known in the art. See, e.g., Carchon et al, Clinical Chemistry, 50: 1, 101-111 (2004).

[0103] In some embodiments, the patient of the condition or disorder mediated, at least in part, by DHDDS, including DHDDS-CDG or DEDSM, has (a) reduced NAD+ level, (b) reduced CTP level, (c) increased lipid accumulation in Schwann cells, myelinated fibers, or fibroblasts, and / or (d) decreased glycosylation of glycoproteins, lysosomal enzymes, or serum proteins. These properties can be measured by methods known in the art.

[0104] In some embodiments, provided herein is a method of increasing energy metabolism in a patient with a DHDDS mediated disorder, such as DEDSM, comprising administering a therapeutically effective amount of a compound as described herein, or a combination of theAttorney Docket No.: 228 J-419245- WO compounds described herein, or a composition as described herein. For example, provided herein is a method of increasing energy metabolism in a patient with DEDSM comprising administering a therapeutically effective amount of nicotinamide mononucleotide (NMN), or a pharmaceutically acceptable salt or solvate thereof. “Energy metabolism” as used herein may refer to the process of converting nutrients into usable energy (ATP), and the mitochondria being the primary site for this process through aerobic respiration. The energy metabolism may be measured by methods known in the art, such as the Seahorse (or XF) instrument which quantifies the cell’s oxygen consumption rate (OCR).

[0105] In any of the embodiments described herein, a patient is administered one or more of the compounds described herein. The one or more compounds can be administered simultaneously or sequentially. In some embodiments, a patient is administered two or more of the compounds described herein.

[0106] In any of the embodiments described herein, a patient is administered a pharmaceutical composition that comprises one or more of the compounds described herein. In some embodiments, a patient is administered a pharmaceutical composition that comprises two or more of the compounds described herein.

[0107] In any of the embodiments described herein, the patient is further administered a therapeutically effective amount of another therapeutic agent useful for restoring or increasing glycosylation (e.g., tunicamycin). Said another therapeutic agent may be administered simultaneously or sequentially with a compound, or compounds, described herein or a composition described herein.Dosing

[0108] The specific dose level of a compound of the present disclosure for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg / kg).Attorney Docket No.: 228 J-419245- WODosages of between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg / kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.

[0109] The daily dosage may also be described as a total amount of a compound described herein administered per dose or per day. Daily dosage of a compound described herein may be between about 1 mg / day and 4,000 mg / day, between about 2,000 to 4,000 mg / day, between about 1 to 2,000 mg / day, between about 1 to 1,000 mg / day, between about 10 to 500 mg / day, between about 20 to 500 mg / day, between about 50 to 300 mg / day, between about 75 to 200 mg / day, or between about 15 to 150 mg / day.

[0110] When administered orally, the total daily dosage for a human subject may be between 1 mg / day and 1,000 mg / day, between about 1,000-2,000 mg / day, between about 10-500 mg / day, between about 50-300 mg / day, between about 75-200 mg / day, or between about 100-150 mg / day.

[0111] The compounds of the present disclosure or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.

[0112] In some embodiments, the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.Attorney Docket No.: 228 J-419245- WOOther Embodiments

[0113] Embodiment 1. A method of treating a condition or disorder mediated, at least in part, by DHDDS in a patient in need thereof, comprising administering a therapeutically effective amount of one or more compounds selected from NADP-coenzyme, NAD+ precursor, cytidine / uridine or derivative thereof, one-carbon metabolism linked compound, flavonoid, terpenoid, steroid, neurotransmitter derivative or analog, amino acid precursor of noradrenaline, NSAID, alkylphospholipid, and cholesterol modulating agent, or a pharmaceutically acceptable salt or solvate thereof.

[0114] Embodiment 2. The method of Embodiment 1 , wherein the administering comprises administering two or more compounds selected from NADP-coenzyme, NAD+ precursor, cytidine / uridine or derivative thereof, one-carbon metabolism linked compound, flavonoid, terpenoid, steroid, neurotransmitter derivative or analog, amino acid precursor of noradrenaline, NSAID, and cholesterol modulating agent, or a pharmaceutically acceptable salt or solvate thereof.

[0115] Embodiment 3. The method of any preceding Embodiment, wherein the NADP- coenzyme is NADPH, NADP+, or a pharmaceutically acceptable salt or solvate thereof.

[0116] Embodiment 4. The method of any preceding Embodiment, wherein the NAD+ precursor is nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, NAD+, NADH, niacinamide (NAM), nicotinamide riboside (NR), nicotinic acid riboside (NAR), L-tryptophan, dihydronicotinamide riboside (NRH), or a pharmaceutically acceptable salt or solvate thereof.

[0117] Embodiment 5. The method of any preceding Embodiment, wherein the cytidine / uridine derivative is CDP-choline, UTP, CTP, UMP, CMP, NU2058, or a pharmaceutically acceptable salt or solvate thereof.

[0118] Embodiment 6. The method of any preceding Embodiment, wherein the one- carbon metabolism linked compound is folic acid, S-(5'-adenosyl)-L methionine tosylate, methotrexate, or a pharmaceutically acceptable salt or solvate thereof.Attorney Docket No.: 228 J-419245- WO

[0119] Embodiment 7. The method of any preceding Embodiment, wherein the flavonoid is hesperetin 7-O-glucoside, flavomarein, quercetagetin, quercetin, 8-prenylnaringenin, or a pharmaceutically acceptable salt or solvate thereof.

[0120] Embodiment 8. The method of any preceding Embodiment, wherein the terpenoid is loganic acid, nardosinone, or a pharmaceutically acceptable salt or solvate thereof.

[0121] Embodiment 9. The method of any preceding Embodiment, wherein the steroid is clobetasol, medroxyprogesterone acetate, corticosterone, fluprednisolone, or a pharmaceutically acceptable salt or solvate thereof.

[0122] Embodiment 10. The method of any preceding Embodiment, wherein the neurotransmitter derivative or analog is 3 -aminobutanoic acid, 3-guanidinopropionic acid, 4- guanidinobutyric acid, 3 -aminopropionitrile, N-acetyl-5-hydroxytryptamine, noradrenaline, or a pharmaceutically acceptable salt or solvate thereof.

[0123] Embodiment 11. The method of any preceding Embodiment, wherein the amino acid precursor of noradrenaline is noradrenaline bitartrate, L-tyrosine, L-phenylalanine, or a pharmaceutically acceptable salt or solvate thereof.

[0124] Embodiment 12. The method of any preceding Embodiment, wherein the NSAID is carprofen or a pharmaceutically acceptable salt or solvate thereof.

[0125] Embodiment 13. The method of any preceding Embodiment, wherein the alkylphospholipid is perifosine, miltefosine, or a pharmaceutically acceptable salt or solvate thereof.

[0126] Embodiment 14. The method of any preceding Embodiment, wherein the cholesterol modulating agent is dextrothyroxine, 2-hydroxypropyl-P-cyclodextrin, lapaquistat, lapaquistat acetate, or a pharmaceutically acceptable salt or solvate thereof.

[0127] Embodiment 15. The method of Embodiment 1, wherein the compound is selected from the group consisting of: NADP+, NU2058, uridine triphosphate (UTP), cytidine triphosphate (CTP), S-(5'-adenosyl)-L-methionine tosylate, methotrexate, triciribine, 8- prenylnaringenin, hesperetin 7-O-glucoside, quercetagetin, flavomarein, corticosterone,Attorney Docket No.: 228 J-419245- WO medroxyprogesterone acetate, fluprednisolone, clobetasol, loganic acid, nardosinone, 3- aminobutanoic acid, 3-guanidinopropionic acid, 4-guanidinobutyric acid, 3-aminopropionitrile, N-acetyl-5-hydroxytryptamine, cyclopenthiazide, isepamicin, rosavin, rubusoside, euquinine, TLR4-IN-C34, diclazuril, avoralstat, dextrothyroxine, chlortetracycline, salifungin, pidotimod, NSC59984, plinabulin, ciproxifan, cotinine, huperzine A, vicriviroc, netarsudil, TWS119, PF0147324, UNC2881, CHEMBL241987, perifosine, miltefosine, atracurium, denatonium, oteseconazole, DMXAA, methyl rosmarinate, p-Hydroxy-cinnamic acid, methyl 4-anthranilate, daphnetin, 1,5-isoquinolinediol, CIL62, methyl-4-anisate, nicotinic acid riboside (NAR), niacin, niacinamide, NAD+, NADH, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), nicotinamide riboside (NR), dihydronicotinamide riboside (NRH), quercetin, cytidine, CMP, CDP-Choline, Uridine, UMP, L-tyrosine, L-phenylalanine, L- tryptophan, 2-Hydroxypropyl-P-cyclodextrin, folic acid, lapaquistat, lapaquistat acetate, and a pharmaceutically acceptable salt or solvate thereof.

[0128] Embodiment 16. The method of Embodiment 1 or 14, wherein the compound is selected from cytidine triphosphate (CTP), NADPH, carprofen, methotrexate, noradrenaline bitartrate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, and a pharmaceutically acceptable salt or solvate thereof.

[0129] Embodiment 17. The method of any preceding Embodiment, wherein the patient has (a) reduced NAD+ level, (b) reduced CTP level, (c) increased lipid accumulation in Schwann cells, myelinated fibers, or fibroblasts, and / or (d) decreased glycosylation of glycoproteins, lysosomal enzymes, or serum proteins.

[0130] Embodiment 18. The method of any preceding Embodiment, wherein said condition or disorder is Developmental Delay and Seizures with or without Movement Abnormalities (DEDSM), DHDDS-CDG, or retinitis pigmentosa 59.

[0131] Embodiment 19. A method of treating Developmental Delay and Seizures with or without Movement Abnormalities (DEDSM) in a patient in need thereof, comprising administering a therapeutically effective amount of one or more compounds selected from a NADP-coenzyme, NAD+ precursor, cytidine / uridine or derivative thereof; NADP+, NU2058, uridine triphosphate (UTP), cytidine triphosphate (CTP), S-(5'-adenosyl)-L-methionine tosylate,Attorney Docket No.: 228 J-419245- WO methotrexate, triciribine, 8-prenylnaringenin, hesperetin 7-O-glucoside, quercetagetin, flavomarein, corticosterone, medroxyprogesterone acetate, fluprednisolone, clobetasol, loganic acid, nardosinone, 3 -aminobutanoic acid, 3-guanidinopropionic acid, 4-guanidinobutyric acid, 3- aminopropionitrile, N-acetyl-5-hydroxytryptamine, cyclopenthiazide, isepamicin, rosavin, rubusoside, euquinine, TLR4-IN-C34, diclazuril, avoralstat, dextrothyroxine, chlortetracycline, salifungin, pidotimod, NSC59984, plinabulin, ciproxifan, cotinine, huperzine A, vicriviroc, netarsudil, TWS119, PF0147324, UNC2881, CHEMBL241987, perifosine, miltefosine, atracurium, denatonium, oteseconazole, DMXAA, methyl rosmarinate, p-Hydroxy-cinnamic acid, methyl 4-anthranilate, daphnetin, 1,5-isoquinolinediol, CIL62, methyl-4-anisate, nicotinic acid riboside (NAR), niacin, niacinamide, NAD+, NADH, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), nicotinamide riboside (NR), dihydronicotinamide riboside (NRH), quercetin, cytidine, CMP, CDP-Choline, uridine, UMP, L- tyrosine, L-phenylalanine, L-tryptophan, 2-hydroxypropyl-P-cyclodextrin, folic acid, lapaquistat, lapaquistat acetate, and a pharmaceutically acceptable salt or solvate thereof.

[0132] Embodiment 20. The method of Embodiment 19, wherein the compound is selected from cytidine triphosphate (CTP), NADPH, carprofen, methotrexate, noradrenaline bitartrate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, and a pharmaceutically acceptable salt or solvate thereof.

[0133] Embodiment 21. The method of Embodiment 19 or 20, wherein the patient has Arg37His (R37H), Arg21 IGln (R21 IQ) and / or Arg205Gln (R205Q) mutation in DHDDS.

[0134] Embodiment 22. A method of treating DEDSM in a patient in need thereof, comprising administering a therapeutically effective amount of one or more compounds selected from methotrexate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, carprofen, and a pharmaceutically acceptable salt or solvate thereof.

[0135] Embodiment 23. A method of treating DHDDS-CDG in a patient in need thereof, comprising administering a therapeutically effective amount of one or more compounds selected from methotrexate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, carprofen, and a pharmaceutically acceptable salt or solvate thereof.Attorney Docket No.: 228 J-419245- WO

[0136] Embodiment 24. A method of treating retinitis pigmentosa 59 in a patient in need thereof, comprising administering a therapeutically effective amount of one or more compounds selected from methotrexate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, carprofen, and a pharmaceutically acceptable salt or solvate thereof.

[0137] Embodiment 25. A method of treating DHDDS-CDG in a patient in need thereof, comprising administering a therapeutically effective amount of nicotinamide mononucleotide (NMN), or a pharmaceutically acceptable salt or solvate thereof.

[0138] Embodiment 26. A method of increasing energy metabolism in a patient with DEDSM, comprising administering a therapeutically effective amount of nicotinamide mononucleotide (NMN), or a pharmaceutically acceptable salt or solvate thereof.

[0139] Embodiment 27. A method of treating DEDSM in a patient in need thereof, comprising administering a therapeutically effective amount of nicotinamide mononucleotide (NMN), or a pharmaceutically acceptable salt or solvate thereof.EXAMPLES

[0140] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.General MethodsStrains and plasmids

[0141] All strains used herein were in the S288C (BY4742) background. The S. cerevisiae strains KG405 (nuslA rer2A srtlA), carrying the GIcis-PT gene on a URA3 marked plasmid was used as previously described (Park et al. 2016). Strain KG405 was transformed withAttorney Docket No.: 228 J-419245- WO multi-copy vectors pKG-GWl encoding human DHDDS variants R37H, R205Q or R211Q (leucine selection), or wild-type DHDDS under leucine selection. pKG-GW2 vectors expression either expressing either wild-type NgBR or lacking NbBR (empty), as a negative control, under methionine selection were co-transformed. Transformed strains were grown in Synthetic Complete (“SC”) medium lacking uracil, methionine and leucine or at 30°C unless otherwise noted. Standard procedures were followed for yeast transformation and strain generation. The following four strains were assessed:1. BY4742:MATa; his3Al; leu2A0; lys2A0 ura3A0; nuslA rer2A srtl A:kanMX+pKG- GWl-R205Q-LEU+pKG-GW2-NgBR-MET+pGlcis-PTase-URA2. BY4742:MATa; his3Al; leu2A0; lys2A0 ura3A0; nuslA rer2A srtl A:kanMX+pKG- GW 1 -R211 Q-LEU+pKG-GW2-NgBR-MET+pGlcis-PTase-URA3. BY4742:MATa; his3Al; leu2A0; lys2A0 ura3A0; nuslA rer2A srtl A:kanMX+pKG- GWl-R37H-LEU+pKG-GW2-NgBR-MET+pGlcis-PTase-URA4. BY4742:MATa; his3Al; leu2A0; lys2A0 ura3A0; nuslA rer2A srtl A:kanMX+pKG- GW 1 -hCIT-LEU+pKG-GW2-NgBR-MET+pGlcis-PTase-URAGrowth assay

[0142] Cells were cultured overnight in SD-leu-ura-met. Cells from overnight cultures were resuspended in SD-leu-met + FOA media to GD600 = 0.4, then serial diluted into 100 pL YPD media in 96-well plates at 10-1, 10-2, 10-3, 10-4 and 10 -5. Plates were incubated at 30°C for 24 hours. 50 pL of yeast cell suspension was transferred to a 96-well plate into with 50 pL of BacTiter-Glo (Promega), briefly vortexed and incubated for 5 minutes. Luminescence readings were measured by a plate reader (ThermoFisher Varioskan Lux Multimode Microplate Reader).Drug screens

[0143] A drug screen was performed using the 8, 387 -compound L400 Bioactive Compound library (TargetMol). 200 nL of compounds from the L4000 Bioactive Compound library, or DMSO, were dispensed into 384-well plates using the Echo acoustic dispenser (Beckman Coulter Labcyte Echo 650) to achieve a final concentration of 20 pM. Cells from overnight cultures were resuspended in SD-leu-met + FOA media to OD600 = 0.0025 and 25 pL of yeast cell suspensions were dispensed into the 384-well plates containing compounds or DMSO with a EL406 automated dispenser (Biotek). Plates were covered and incubated at 30°C for 24 hours. 25Attorney Docket No.: 228 J-419245- WO pL of BacTiter-Glo was dispensed into the plates. Plates were briefly vortexed and then incubated for 20 minutes prior to reading (Envision Plate reader).EXAMPLE 1 - Yeast Mutant Models of DEDSM

[0144] In Saccharomyces cerevisiae, the cis-PTase complex subunits are encoded by RER2 and SRT1 (DHDDS orthologs) and NUS1 (NgBR ortholog). A triple deletion yeast strain (“KG405”) lacking its three endogenous c / .s-PTase components (rer2A / srt 1 A / nus 1 A) is lethal and is complemented by co-expression of wild-type human DHDDS and NgBR (“WT-DHDDS / WT- NgBR”) but not individual genes. To facilitate high-throughput screening for compounds that may treat DEDSM, previously generated yeast models co-expressing a human DEDSM- associated patient allele and wild-type NgBR (Galosi et al. 2022) were used. In the triple deletion yeast strain, human DEDSM-associated patient alleles R37H, R21 IQ and R205Q under the native RER2 promoter were co-expressed with NgBR to generate yeast models of DHDDS disorder.

[0145] The growth defect of each DHDDS “patient avatar” was measured by a luminescencebased growth assay and compared to a positive control, KG405 yeast co-expressing wild-type DHDDS and NUS1 (“WT-DHDDS / WT-NgBR”) and a negative control, KG405 yeast coexpressing empty DHDDS and NUS 1 (“DHDDS vector / NgBR vector”). All DHDDS patient alleles exhibited reduced growth compared to wild-type, as shown in FIG. 1.EXAMPLE 2 - Drug Screen in a Yeast Model Expressing the DHDDS-R205Q Patient Allele

[0146] The DHDDS-R205Q mutant was advanced to a high-throughput drug screen. The 8,387-compound L4000 Bioactive TargetMol library collection comprising FDA-approved drugs, drugs in various stages of clinical development, bioactive tool compounds, and natural products was used for screening at 20 pM. The DHDDS-R205Q mutant was screened in singlicate and in 384-well plates, with each plate containing 32 wells of R205Q mutant cells (negative control) and 32 wells of wild-type cells (positive control), each in 0.72% DMSO.Attorney Docket No.: 228 J-419245- WO

[0147] The positive and negative controls exhibited a distinct separation of luminescence values, enabling the identification of compounds which rescued growth of the mutant strain, as shown in FIG. 2. 61 compounds, excluding pan-assay interference compounds, were identified that rescued the growth of the mutant strain. It is contemplated that these compounds can exert their therapeutic effects in human DEDSM, having corresponding mutations in DHDDS, by boosting NAD+ levels and / or CTP levels, reducing lipid accumulation, restoring glycosylation and / or lysosomal function.

[0148] For example, Compound 1 is the pyrimidine nucleoside triphosphate, cytidine triphosphate (CTP). CTP is high-energy molecule used in the biosynthesis of RNA and lipids, and in protein glycosylation. In glycosylation, the phosphorylation of dolichol to generate the lipid carrier Dol-P is a CTP-dependent reaction. Uridine triphosphate (UTP), another pyrimidine nucleotide, also rescued DHDDS mutant yeast. UTP is involved in the synthesis of RNA and acts as a precursor in the biosynthesis of CTP.

[0149] Compound 2 is the reduced form of nicotinamide adenine dinucleotide phosphate (NADP+), NADPH tetracyclohexamine. NADPH is a coenzyme used in anabolic reactions, such as lipid and nucleic acid synthesis, and plays a vital role in maintaining cellular redox balance by providing reducing power for antioxidant defense. NADP+ or a pharmaceutically acceptable salt thereof (e.g., sodium salt), the oxidized form of NADPH, was also a rescuer of DHDDS mutant yeast. NADP+ is also involved in metabolic processes and serves as a substrate in the NADPH production cycle, maintaining the balance between its reduced and oxidized states.

[0150] Compounds linked to one-carbon metabolism were identified as rescuers of DHDDS mutant yeast. This includes methotrexate (Compound 4) and S-(5'-adenosyl)-L-methionine (SAM) tosylate. Methotrexate is an antifolate drug that inhibits dihydrofolate reductase, thereby interfering with DNA synthesis and cell division by limiting the availability of tetrahydrofolate, a critical component in one-carbon metabolism. SAM is a methyl donor involved in numerous methylation reactions and has been reported to regulate cholesterol metabolism. Triciribine, an AKT inhibitor, was also a rescuer and shares structural similarity with SAM and methotrexate through its nitrogen-containing ring systems.Attorney Docket No.: 228 J-419245- WO

[0151] Compound 3 is carprofen, a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase enzymes involved in prostaglandin synthesis.

[0152] Compound 5 is noradrenaline bitartrate monohydrate, a synthetic form of the neurotransmitter norepinephrine. Other compounds identified as rescuers of DHDDS mutant yeast include various neurotransmitter derivatives and analogs. These compounds, such as 3- aminobutanoic acid, 3-guanidinopropionic acid, 4-guanidinobutyric acid, 3-aminopropionitrile, and N-acetyl-5-hydroxytryptamine, are structurally related to neurotransmitters.

[0153] Other prominent classes of rescue compounds identified in the DHDDS yeast screen included flavonoids, terpenes, steroids, and alkylphospholipids.EXAMPLE 3 - Dose-dependent Rescue of DHDDS-R205Q Mutant Growth

[0154] Dose response assays were performed to evaluate the effect of Compound 1 , Compound 2, Compound 3, Compound 4, and Compound 5 on DHDDS-R205Q mutant yeast growth.Given that NADP+ and NADPH significantly rescued DHDDS mutant yeast growth, the NAD+ precursor molecules NMN (Compound 6), NMNH (Compound 7), niacin (Compound 8), niacinamide (Compound 9) and nicotinamide riboside (Compound 10) were also evaluated by dose response assays. Compounds 1-8 exhibited a dose-dependent rescue effect of DHDDS- R205Q mutant yeast compared to the negative control. It is contemplated that the compounds may individually or collectively boost NAD+ levels, increase CTP levels, reduce lipid accumulation, and restore glycosylation and / or lysosomal function in DEDSM and related diseases. FIG. 3 illustrates the dose response of Compounds 1-10 in DHDDS-R205Q mutant yeast compared to DMSO control in a 24-hour luminescent-based growth assay. Compounds 1-8 demonstrated dose-dependent rescue of DHDDS mutant yeast growth compared to the negative control, as shown in FIG. 3.EXAMPLE 4 - Energy Metabolism of DHDDS Patient Derived Organoids with NMN Treatment

[0155] The genetic, laboratory, and clinical data of 3 patients with heterozygous DHDDS variants, having DHDDS associated disorder developmental delay and seizures with or without movement abnormalities (DEDSM), enrolled in the Frontier in CDG Consortium (FCDGC)Attorney Docket No.: 228 J-419245- WO natural history study (NCT04199000) were collected. All patients’ skin biopsies were obtained for establishing fibroblasts as part of the standard clinical care. Residual samples from patients were deidentified and used for further studies. Additional healthy fibroblasts were obtained from Coriell Institute for Medical Research.

[0156] The induced pluripotent stem cells (iPSCs) from patients and controls were reprogrammed and cultured as previously described. Patient-derived iPSC’s were assessed for pluripotency markers and ability to differentiate into all 3 germ layers. All controls iPSCs have also been previously validated for pluripotency. The DHDDS and control iPSCs were cultured in a 10 cm plate and the organoids were developed using the Aggrewell method.

[0157] DHDDS and control organoids were collected for Seahorse measurements between Day 65 and Day 100, in parallel with controls. Mitochondrial respiration was assessed using the Agilent Seahorse XF Cell Mito Stress Test to measure oxygen consumption rate (OCR) in DHDDS-deficient and control cortical organoids. Each organoid was sectioned into four equal pieces (approximately 1 mm3), with one piece placed per well in the XF assay plate. Prior to measurement, the culture medium was replaced with Seahorse XF DMEM (Agilent, 102353- 100) supplemented with 10 mM glucose, 1 mM pyruvate, and 2 mM E-glutamine. OCR was normalized to citrate synthase (CS) activity to account for differences in mitochondrial content. Each condition was assayed in 8 technical replicates, with five repeated measurements per sample.

[0158] Seahorse measurement to evaluate energy metabolism in 4 patient cell (“DHDDS”) derived brain organoid between day of 120-150 days of culture showed abnormal basal (Basal OCR) and maximal respiration (Max OCR) compared to 4 healthy control (“HC”) derived brain organoids. Organoids were treated with 0.5 mM (FIGS. 4A-B) and ImM (FIGS. 5A-B) nicotinamide mononucleotide (NMN) for two weeks. As shown in FIGS. 4B and 5B, both Basal OCR and Max OCR improved significantly on treatment with NMN for DHDDS patient organoids, either with 0.5 pM and 1 pM NMN, and the degree with improvement in basal / max OCR were greater than healthy control derived brain organoids.Attorney Docket No.: 228 J-419245- WOEXAMPLE 5 - Energy Current of DEDSM Organoids with NMN Treatment

[0159] Electrophysiological recordings were conducted using the 6-well high-density microelectrode array (MEA) MaxTwo system (HD-MEA) from MaxWell Biosystems. Wells were prepared following the MaxWell “Brain Organoid Plating Protocol, V2.0,” with minor modifications. Briefly, 6-well MEA plates were incubated in 1% Tergazyme solution for 2 hours at room temperature (RT), washed three times with distilled water, sterilized in ethanol for 30 minutes, and washed again three times with distilled water. Each well received 1 mL of Neurobasal-A (NBA) medium and was incubated for 48 hours for pre-conditioning.

[0160] After incubation, 50 pL of 0.07% poly(ethyleneimine) (PEI) was added to each well and incubated for 1 hour. Wells were then washed three times with distilled water and air-dried for 1 hour at RT. Next, 50 pL of 0.04 mg / mL laminin in NBA was added and incubated overnight. Laminin was aspirated, and health control and DEDSM patient cortical brain organoids were placed directly on the electrodes without media for 2-5 minutes. Subsequently, 50 pL of 0.04 mg / mL laminin in NBA was slowly added to each well, and the plates were incubated for 2 hours. For each organoid line, four MEA wells were prepared. After the 2-hour incubation, 1 mL of NBA was gently added to each well. The following day, half of the media was replaced with fresh NBA.

[0161] Organoids were maintained by changing the media every 3-4 days, and for the measurements, Neurobasal-A media was changed to BrainPhys media at least 24 hours before MEA recording. Recordings were performed using MaxLab software. The built-in “Activity Scan” protocol was used to identify active areas and assess firing rates. All parameters were kept at default except the recording duration, which was extended to 60 seconds to better detect slower activity. This was followed by the “Network Assay” protocol to evaluate neuronal network firing, using the neuronal units parameter. Lastly, the “Axon Tracking Assay” was performed using block parameters to detect axonal signal propagation.

[0162] Results were averaged across the six wells plated for each individual, and the results are shown in FIGS. 6A-C (FIG. 6A: healthy control; FIG. 6B: DEDSM patient (“DHDDS”); FIG. 6C: DHDDS patient with 0.5 pM nicotinamide mononucleotide (NMN) treatment). Burst threshold was >2 Hz (root mean square of the firing rate). Only wells with a firing rate >0.2 HzAttorney Docket No.: 228 J-419245- WO were included for activity and network analysis. As shown in FIG. 6, 0.5 pM NMN modified energy current pattern, showing burst similar to healthy control organoids.EXAMPLE 6 - Clinical Effect of NMN Treatment for DEDSM Patients

[0163] Clinical efficacy of nicotinamide mononucleotide (NMN) (250 mg / day) was evaluated in four patients with DEDSM using the International Cooperative Ataxia Rating Scale (ICARS). ICARS is a standardized scale (range: 0 = normal to 100 = most severe impairment) that measures four domains of neurological dysfunction: limb ataxia, dysarthria, posture and gait disturbances, and oculomotor disorders (Trouillas P, et al 1997; Martinez-Monseny et al. 2019). Assessments were conducted prior to initiation of NMN treatment and after 6 months of continuous therapy. The results are shown in FIG. 7. As shown in FIG. 7, all four patients showed decrease in ICARS in 6 months.* * *

[0164] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0165] The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including,” “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed.

[0166] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.Attorney Docket No.: 228 J-419245- WO

[0167] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

Attorney Docket No.: 228 J-419245- WOWHAT IS CLAIMED IS:

1. A method of treating a condition or disorder mediated, at least in part, by DHDDS in a patient in need thereof, comprising administering a therapeutically effective amount of one or more compounds selected from NADP-coenzyme, NAD+ precursor, cytidine / uridine or derivative thereof, one-carbon metabolism linked compound, flavonoid, terpenoid, steroid, neurotransmitter derivative or analog, amino acid precursor of noradrenaline, NSAID, alkylphospholipid, and cholesterol modulating agent, or a pharmaceutically acceptable salt or solvate thereof.

2. The method of claim 1 , wherein the administering comprises administering two or more compounds selected from NADP-coenzyme, NAD+ precursor, cytidine / uridine or derivative thereof, one-carbon metabolism linked compound, flavonoid, terpenoid, steroid, neurotransmitter derivative or analog, amino acid precursor of noradrenaline, NSAID, and cholesterol modulating agent, or a pharmaceutically acceptable salt or solvate thereof.

3. The method of any preceding claim, wherein the NADP-coenzyme is NADPH, NADP+, or a pharmaceutically acceptable salt or solvate thereof.

4. The method of any preceding claim, wherein the NAD+ precursor is nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, NAD+, NADH, niacinamide (NAM), nicotinamide riboside (NR), nicotinic acid riboside (NAR), L- tryptophan, dihydronicotinamide riboside (NRH), or a pharmaceutically acceptable salt or solvate thereof.

5. The method of any preceding claim, wherein the cytidine / uridine derivative is CDP- choline, UTP, CTP, UMP, CMP, NU2058, or a pharmaceutically acceptable salt or solvate thereof.

6. The method of any preceding claim, wherein the one-carbon metabolism linked compound is folic acid, S-(5'-adenosyl)-L methionine tosylate, methotrexate, or a pharmaceutically acceptable salt or solvate thereof.Attorney Docket No.: 228 J-419245- WO7. The method of any preceding claim, wherein the flavonoid is hesperetin 7-O-glucoside, flavomarein, quercetagetin, quercetin, 8-prenylnaringenin, or a pharmaceutically acceptable salt or solvate thereof.

8. The method of any preceding claim, wherein the terpenoid is loganic acid, nardosinone, or a pharmaceutically acceptable salt or solvate thereof.

9. The method of any preceding claim, wherein the steroid is clobetasol, medroxyprogesterone acetate, corticosterone, fluprednisolone, or a pharmaceutically acceptable salt or solvate thereof.

10. The method of any preceding claim, wherein the neurotransmitter derivative or analog is 3-aminobutanoic acid, 3-guanidinopropionic acid, 4-guanidinobutyric acid, 3 -aminopropionitrile, N-acetyl-5-hydroxytryptamine, noradrenaline, or a pharmaceutically acceptable salt or solvate thereof.

11. The method of any preceding claim, wherein the amino acid precursor of noradrenaline is noradrenaline bitartrate, L-tyrosine, L-phenylalanine, or a pharmaceutically acceptable salt or solvate thereof.

12. The method of any preceding claim, wherein the NS AID is carprof en or a pharmaceutically acceptable salt or solvate thereof.

13. The method of any preceding claim, wherein the alkylphospholipid is perifosine, miltefosine, or a pharmaceutically acceptable salt or solvate thereof.

14. The method of any preceding claim, wherein the cholesterol modulating agent is dextrothyroxine, 2-hydroxypropyl-P-cyclodextrin, lapaquistat, lapaquistat acetate, or a pharmaceutically acceptable salt or solvate thereof.Attorney Docket No.: 228 J-419245- WO15. The method of claim 1, wherein the compound is selected from the group consisting of: NADP+, NU2058, uridine triphosphate (UTP), cytidine triphosphate (CTP), S-(5'-adenosyl)-L- methionine tosylate, methotrexate, triciribine, 8-prenylnaringenin, hesperetin 7-O-glucoside, quercetagetin, flavomarein, corticosterone, medroxyprogesterone acetate, fluprednisolone, clobetasol, loganic acid, nardosinone, 3 -aminobutanoic acid, 3-guanidinopropionic acid, 4- guanidinobutyric acid, 3 -aminopropionitrile, N-acetyl-5-hydroxytryptamine, cyclopenthiazide, isepamicin, rosavin, rubusoside, euquinine, TLR4-IN-C34, diclazuril, avoralstat, dextrothyroxine, chlortetracycline, salifungin, pidotimod, NSC59984, plinabulin, ciproxifan, cotinine, huperzine A, vicriviroc, netarsudil, TWS119, PF0147324, UNC2881, CHEMBL241987, perifosine, miltefosine, atracurium, denatonium, oteseconazole, DMXAA, methyl rosmarinate, p-Hydroxy-cinnamic acid, methyl 4-anthranilate, daphnetin, 1,5- isoquinolinediol, CIL62, methyl-4-anisate, nicotinic acid riboside (NAR), niacin, niacinamide, NAD+, NADH, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), nicotinamide riboside (NR), dihydronicotinamide riboside (NRH), quercetin, cytidine, CMP, CDP-Choline, Uridine, UMP, L-tyrosine, L-phenylalanine, L-tryptophan, 2- Hydroxypropyl-P-cyclodextrin, folic acid, lapaquistat, lapaquistat acetate, and a pharmaceutically acceptable salt or solvate thereof.

16. The method of claim 1 or 14, wherein the compound is selected from cytidine triphosphate (CTP), NADPH, carprofen, methotrexate, noradrenaline bitartrate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, and a pharmaceutically acceptable salt or solvate thereof.

17. The method of any preceding claim, wherein the patient has (a) reduced NAD+ level, (b) reduced CTP level, (c) increased lipid accumulation in Schwann cells, myelinated fibers, or fibroblasts, and / or (d) decreased glycosylation of glycoproteins, lysosomal enzymes, or serum proteins.

18. The method of any preceding claims, wherein said condition or disorder is Developmental Delay and Seizures with or without Movement Abnormalities (DEDSM), DHDDS-CDG, or retinitis pigmentosa 59.Attorney Docket No.: 228 J-419245- WO19. A method of treating Developmental Delay and Seizures with or without Movement Abnormalities (DEDSM) in a patient in need thereof, comprising administering a therapeutically effective amount of one or more compounds selected from a NADP-coenzyme, NAD+ precursor, cytidine / uridine or derivative thereof; NADP+, NU2058, uridine triphosphate (UTP), cytidine triphosphate (CTP), S-(5'-adenosyl)-L-methionine tosylate, methotrexate, triciribine, 8- prenylnaringenin, hesperetin 7-O-glucoside, quercetagetin, flavomarein, corticosterone, medroxyprogesterone acetate, fluprednisolone, clobetasol, loganic acid, nardosinone, 3- aminobutanoic acid, 3-guanidinopropionic acid, 4-guanidinobutyric acid, 3-aminopropionitrile, N-acetyl-5-hydroxytryptamine, cyclopenthiazide, isepamicin, rosavin, rubusoside, euquinine, TLR4-IN-C34, diclazuril, avoralstat, dextrothyroxine, chlortetracycline, salifungin, pidotimod, NSC59984, plinabulin, ciproxifan, cotinine, huperzine A, vicriviroc, netarsudil, TWS119, PF0147324, UNC2881, CHEMBL241987, perifosine, miltefosine, atracurium, denatonium, oteseconazole, DMXAA, methyl rosmarinate, p-Hydroxy-cinnamic acid, methyl 4-anthranilate, daphnetin, 1,5-isoquinolinediol, CIL62, methyl-4-anisate, nicotinic acid riboside (NAR), niacin, niacinamide, NAD+, NADH, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), nicotinamide riboside (NR), dihydronicotinamide riboside (NRH), quercetin, cytidine, CMP, CDP-Choline, uridine, UMP, L-tyrosine, L-phenylalanine, L- tryptophan, 2-hydroxypropyl-P-cyclodextrin, folic acid, lapaquistat, lapaquistat acetate, and a pharmaceutically acceptable salt or solvate thereof.

20. The method of claim 19, wherein the compound is selected from cytidine triphosphate (CTP), NADPH, carprofen, methotrexate, noradrenaline bitartrate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, and a pharmaceutically acceptable salt or solvate thereof.

21. The method of claim 19 or 20, wherein the patient has Arg37His (R37H), Arg21 IGln (R21 IQ) and / or Arg205Gln (R205Q) mutation in DHDDS.

22. A method of treating DEDSM in a patient in need thereof, comprising administering a therapeutically effective amount of one or more compounds selected from methotrexate,Attorney Docket No.: 228 J-419245- WO nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, carprofen, and a pharmaceutically acceptable salt or solvate thereof.

23. A method of treating DHDDS-CDG in a patient in need thereof, comprising administering a therapeutically effective amount of one or more compounds selected from methotrexate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, carprofen, and a pharmaceutically acceptable salt or solvate thereof.

24. A method of treating retinitis pigmentosa 59 in a patient in need thereof, comprising administering a therapeutically effective amount of one or more compounds selected from methotrexate, nicotinamide mononucleotide (NMN), dihydronicotinamide mononucleotide (NMNH), niacin, carprofen, and a pharmaceutically acceptable salt or solvate thereof.

25. A method of treating DHDDS-CDG in a patient in need thereof, comprising administering a therapeutically effective amount of nicotinamide mononucleotide (NMN), or a pharmaceutically acceptable salt or solvate thereof.

26. A method of increasing energy metabolism in a patient with DEDSM, comprising administering a therapeutically effective amount of nicotinamide mononucleotide (NMN), or a pharmaceutically acceptable salt or solvate thereof.

27. A method of treating DEDSM in a patient in need thereof, comprising administering a therapeutically effective amount of nicotinamide mononucleotide (NMN), or a pharmaceutically acceptable salt or solvate thereof.

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