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WO2024258929A1 - Méthodes de traitement de maladies associées à une perte de fonction taf1 - Google Patents

Méthodes de traitement de maladies associées à une perte de fonction taf1 Download PDF

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WO2024258929A1
WO2024258929A1 PCT/US2024/033552 US2024033552W WO2024258929A1 WO 2024258929 A1 WO2024258929 A1 WO 2024258929A1 US 2024033552 W US2024033552 W US 2024033552W WO 2024258929 A1 WO2024258929 A1 WO 2024258929A1
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taf1
lof
tadpoles
lamotrigine
subject
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Richard Novak
Frederic VIGNEAULT
Erica GARDNER
Rahul Nihalani
Sevgi REAGH
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Unravel Biosciences Inc
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Unravel Biosciences Inc
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    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • X-linked Dystonia Parkinsonism is a severe neurodegenerative disease endemic to the Philippines [1] linked to a DNA repeat expansion within an intronic SINE-VNTR-Alu (SVA)-type retrotransposon insertion in the TAF1 gene [2,3], The insertion disrupts TAF1 splicing and reduces levels of the full-length transcript [4],
  • SVAs are large segments of repetitive DNA, and the TAF1 intron in which this element is inserted is not conserved in lower animals.
  • TAF1 loss of function (LOF) tadpoles that have robust phenotypes including developmental delay, swimming deficit, shorter lifespan, and a range of abnormal behavior reminiscent of XDP symptoms in humans.
  • these symptoms include forced and uncontrolled mandibular movements, tail spams ranging from mild to severe, and loss of spatial orientation.
  • TAF1 expression is reduced in XDP cells compared to matched controls [3-9] supporting that a partial loss of TAF1 function may contribute to XDP pathogenesis and that small molecules that mitigate the effects of this loss could provide therapeutic benefit.
  • This disclosure provides compounds, compositions and methods of treatment of diseases and/or disorders associated with TAF1 LOF.
  • diseases and/or disorders include X-linked Dystonia Parkinsonism (XDP) X-linked syndromic intellectual developmental disorder-33.
  • Non-limiting examples of compounds useful in the treatment of diseases and/or disorders associated with TAF1 LOF include, and are not limited to, SAK3, Pridopidine, succinanilic acid (4-anilino-4-oxo-butanoic acid) and/or Lamotrigine.
  • This disclosure provides compounds, compositions and methods of treatment of diseases and/or disorders associated with TAF1 LOF.
  • diseases and/or disorders include X-linked Dystonia Parkinsonism (XDP) X-linked syndromic intellectual developmental disorder-33.
  • compounds useful in the treatment of diseases and/or disorders associated with TAF1 LOF include, and are not limited to, SAK3, Pridopidine, succinanilic acid (4-anilino-4-oxo-butanoic acid), and/or Lamotrigine.
  • FIGs. 2A-2E Succinanilic acid (4-anilino-4-oxo-butanoic acid) shows distinct and complementary benefits in TAF1 LOF tadpoles. Viability: TAF1 LOF tadpoles (KD) have decreased viability which is apparent starting at 15 days post fertilization (dpf). Fig. 2A. Succinanilic acid (4-anilino-4-oxo-butanoic acid; RVL2 or RVL002 in the figures) showed viability improvements compared with controls and did not cause significant toxicity.
  • Figs. 2B-2E Succinanilic acid (4-anilino-4-oxo-butanoic acid) mildly improves viability (Fig. 2A), swimming behavior (Fig. 2B), swimming mobility (Figs. 2C and 2E) and body orientation (Fig. 2D). The compound did not impact the behavior of WT animals.
  • FIGs. 3A-3D Overexpression of HCN2 mRNA aggravates the phenotypes TAF1 Loss- of-Function in tadpoles.
  • FIG. 3A HCN2 overexpression does not result in a decrease in viability when injected into wild-type (WT) tadpoles. However, it further exacerbates the decrease the viability when injected concomitantly in TAF1 LOF tadpoles. Combined with lamotrigine (RVL27), HCN2 overexpression further decreases their viability.
  • FIG. 3B Upright orientation is a measure of spatial awareness and general motor function. WT tadpoles normally adopt a dorso-ventral, i.e. upright position.
  • FIG. 3C The overall time spent in the middle of the dish is a measure of swimming behavior related to both neuro-motor function and cognitive function. WT tadpoles normally spent more time swimming around the edge of the petri dish spending minimal time in the middle, only to cross it briefly without stopping. HCN2 overexpression does not change the normal swimming behavior in WT tadpoles.
  • FIG. 3D The swimming velocity is a measure of swimming behavior and activity related to neuro-motor function and spatial orientation while swimming. Compared with WT tadpoles HCN2 overexpression does not change the normal swimming behavior in WT. However, it shows a significant decrease in a TAF1 LOF background.
  • One-way analysis of variance are indicated for statistical p-value ⁇ 0.05.
  • WT wild-type tadpoles
  • HCN2 overexpression of HCN2 with mRNA injection
  • RVL27 Lamotrigine at 25 pM
  • Dpf Days post fertilization.
  • FIGs. 4A-4B Treatment with the Notch agonist Ynhu-3792 or the voltage-dependent calcium channel blocker gabapentin aggravated the phenotypes of TAF1 Loss-of-Function tadpoles.
  • FIG. 4A Treatment with 50 pM gabapentin (RVL66) non-significantly decreased the viability of TAF1 LOF tadpoles, while 1 pM of Ynhu-3792 (RVL67) significantly decreased the viability of TAF1 LOF tadpoles at 10 dpf. Gabapentin or Ynhu-3792 did not affect the viability of the WT.
  • Upright orientation is a measure of spatial awareness and general motor function. Nearly 100% of WT tadpoles adopt a dor so- ventral, i.e. upright position, by 8 dpf. Both gabapentin and Ynhu-3792 decreased the adoption of an upright position in WT, and even more so in TAF1 LOF tadpoles. Legend: Two-way analysis of variance (Two-way ANOVA) are indicated for statistical p-value ⁇ 0.05 compared to WT.
  • WT wild-type tadpoles
  • TAFL mosaic model of TAF1 loss-of-function using CRISPR RVL66: gabapentin at 50pM
  • RVL67 Ynhu-3792 at 10 pM (viability assay) or at 1 pM (spatial orientation)
  • Dpf Days post fertilization.
  • FIG. 5 Distribution of Lamotrigine candidate hits based on Thermal Proteome Profiling. TPP values were used to calculate a log2 fold-change and the log2 Z-score. The top proteins with Log2 fold-change and Z-score > 0. were considered hits (boxed area). Hit proteins (PSEN2, U2AF1, PSME3, and HBZ) involved in Notch signaling are indicated in the boxed area.
  • the present disclosure relates to compounds and compositions for the treatment of diseases and/or disorders associated with a loss-of-function (LOF) mutation of a gene encoding TATA-box binding protein associated factor 1 (TAF1).
  • LEF loss-of-function
  • TAF1 TATA-box binding protein associated factor 1
  • diseases or disorders include, and are not limited to, XPD and/or X-linked syndromic intellectual developmental disorder-33.
  • the terms “treat”, “treating”, “inhibiting”, “inhibit”, “suppressing”, “suppress”, “decrease” and “decreasing” are used, in the context of this disclosure, to refer to the reduction, improvement, stabilization and/or elimination of a symptom of disease, or slowing the progression of disease.
  • the disease or diseases to be treated include X-linked dystonia parkinsonism (XDP; phenotype MIM number 314250, omim.org/entry/314250) and/or X-linked syndromic intellectual developmental disorder-33 (phenotype MIM number 300966, omim.org/entry/300966). Each of these OMIM entries is hereby incorporated by reference in their entireties.
  • the disclosed methods of treatment may result in decreased torsion dystonia and/or reduced spasmodic eye blinking, and/or decreased Parkinsonia symptoms that accompany or precede dystonia.
  • the clinical course of XPD is highly variable with parkinsonism as the initial presenting sign and, mor significantly, dystonia as the disease progresses.
  • Parkinsonian symptoms include, and are not limited to resting tremor, chorea, bradykinesia, rigidity, postural instability, and severe shuffling gait.
  • Dystonia may develop focally, most commonly in the jaw, neck, trunk, and eyes, and less commonly in the limbs, tongue, pharynx, and larynx, the most characteristic being jaw dystonia often progressing to neck dystonia.
  • Some individuals have parkinsonism and non-disabling symptoms that are only slowly progressive.
  • Other individuals develop a combination of parkinsonism and dystonia and can develop multifocal or generalized symptoms within a few years.
  • Most XPD patients are male, although females may also develop XPD.
  • certain embodiments of this disclosure envision the treatment of male patients only and other embodiments envision the treatment of female patients only.
  • the disclosed methods can be used to improve delayed psychomotor development, intellectual disability, delayed speech, spastic diplegia, tremor, and/or dystonic movements.
  • the disclosed methods improve symptoms associated with spastic diplegia, tremor, and/or dystonic movement.
  • the disclosed methods reduce the severity or frequency of spastic diplegia, tremor, and/or dystonic movement in the treated subjects.
  • terapéuticaally effective amount is intended to constitute an amount of a compound disclosed herein that treats or suppresses symptoms associated with diseases and/or disorders associated with a loss-of-function (LOF) mutation of a gene encoding TATA-box binding protein associated factor 1 (TAF1).
  • diseases or disorders include, and are not limited to, XPD and/or X-linked syndromic intellectual developmental disorder-33.
  • compounds are administered in an amount sufficient to constitute a treatment of the disease and cause a reduction, improvement, stabilization and/or elimination of a symptom of a disease or slowing the progression of a disease associated with the loss of function of TAF1.
  • Such amounts could range from about 0.01 to about 1,000 mg/kg of a subject to be treated.
  • compositions containing amounts of ingredients where the terms “about” or “approximately” are used these compositions contain the stated amount of the ingredient with a variation (error range) of 0-10% around the value (X ⁇ 10%).
  • error range 0-10% around the value (X ⁇ 10%).
  • the term is intended to include a period of ⁇ 6 hours for days, ⁇ 1 day for weeks, and ⁇ 7 days for months.
  • a, b, and/or c be construed as a alone, b alone, c alone, a combination of a and b, a combination of a and c, a combination of b and c, or a combination of a, b, and c.
  • ranges are stated in shorthand, so as to avoid having to set out at length and describe each and every value within the range. Any appropriate value within the range can be selected, where appropriate, as the upper value, lower value, or the terminus of the range.
  • a range of 0.1-1.0 represents the terminal values of 0.1 and 1.0, as well as the intermediate values of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and all intermediate ranges encompassed within 0.1-1.0, such as 0.2-0.5, 0.2-0.8, 0.7-1.0, etc.
  • “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.
  • compositions comprise one or more of the disclosed active agents in combination with a pharmaceutically acceptable carrier such as a phosphate buffered saline, a bicarbonate solution, or formulated with a carrier such as starch into a pill to produce a pharmaceutical composition.
  • a pharmaceutically acceptable carrier such as a phosphate buffered saline, a bicarbonate solution, or formulated with a carrier such as starch into a pill to produce a pharmaceutical composition.
  • the carrier must be “acceptable” in the sense that it is compatible with the active ingredient (agent) of the composition, and preferably capable of stabilizing the active agent and not deleterious to the subject to be treated.
  • the carrier is selected on the basis of the mode and route of administration and standard pharmaceutical practice. Suitable pharmaceutical carriers and diluents, as well as pharmaceutical necessities for their use, are described in Remington’s Pharmaceutical Sciences.
  • subject refers to any member of the phylum Chordata, more preferably any member of the subphylum vertebrata, or most preferably, any member of the class Mammalia, including, without limitation, humans and other primates, including non-human primates such as rhesus macaques, chimpanzees and other monkey and ape species; farm animals, such as cattle, sheep, pigs, goats and horses; domestic mammals, such as dogs and cats; laboratory animals, including amphibians (e.g., frogs, tadpoles, salamanders, caecilians), rabbits, mice, rats and guinea pigs; birds, including domestic, wild, and game birds, such as chickens, turkeys, ducks, and geese.
  • amphibians e.g., frogs, tadpoles, salamanders, caecilians
  • rabbits mice, rats and guinea pigs
  • birds including domestic, wild, and game birds, such as chickens,
  • a host cell is derived from a subject (e.g., tissue specific cells, such as hepatocytes).
  • reduces is meant a negative alteration of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%.
  • a “pharmaceutical” refers to a compound manufactured for use as a medicinal and/or therapeutic drug.
  • the compounds to be used for the treatment of XPD include SAK3 ((ethyl-8-methyl-2,4-dioxo-2-(piperidin-l-yl)-2H- spiro[cyclopentane-l,3-imidazo[l,2-a]pyridin]-2-ene-3-carboxylate), pridopidine, succinanilic acid (4-anilino-4-oxo-butanoic acid), and lamotrigine.
  • SAK3 (ethyl-8-methyl-2,4-dioxo-2-(piperidin-l-yl)-2H- spiro[cyclopentane-l,3-imidazo[l,2-a]pyridin]-2-ene-3-carboxylate), pridopidine, succinanilic acid (4-anilino-4-oxo-but
  • the compounds and compositions disclosed herein can be administered by any acceptable route for the treatment of XPD or a subject with a mutation of a gene encoding TAF1 that confers a loss-of-function.
  • Non-limiting examples include administering the compounds and/or compositions disclosed herein orally, by injection, by subcutaneous injection, by intraperitoneal injection, by intravenous infusion, topically, or by inhalation.
  • compositions of the subject invention can be formulated according to known methods for preparing pharmaceutically useful compositions.
  • the compositions of the subject invention will be formulated such that an effective amount of the subject compounds is combined with a suitable carrier in order to facilitate effective administration of the composition.
  • suitable carrier in order to facilitate effective administration of the composition.
  • the compositions used in the present methods can also be in a variety of forms. These include, for example, solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspension, suppositories, injectable and infusible solutions, and sprays. The preferred form depends on the intended mode of administration and therapeutic application.
  • compositions also preferably include conventional pharmaceutically acceptable carriers and diluents which are known to those skilled in the art.
  • carriers or diluents for use with the subject compounds include, but are not limited to, water, saline, oils including mineral oil, ethanol, dimethyl sulfoxide, gelatin, cyclodextrins, magnesium stearate, sodium croscarmellose, dextrose, cellulose, sugars, calcium carbonate, glycerol, alumina, starch, and equivalent carriers and diluents, or mixtures of any of these.
  • the subject composition can further comprise one or more pharmaceutically acceptable carriers and/or excipients.
  • Carriers and/or excipients according the subject invention can include any and all solvents, diluents, buffers (such as, e.g., neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate or phosphate buffers), oil-in-water or water-in-oil emulsions, aqueous compositions with or without inclusion of organic co-solvents suitable for, e.g., IV use, solubilizers (e.g., Polysorbate 65, Polysorbate 80), colloids, dispersion media, vehicles, fillers, chelating agents (e.g., EDTA or glutathione), amino acids (e.g., glycine), proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners
  • buffers such as, e.g., neutral buffered saline, phosphate buffered saline,
  • compositions carbomer, gelatin, or sodium alginate
  • coatings preservatives (e.g., Thimerosal, benzyl alcohol, polyquaterium), antioxidants (e.g., ascorbic acid, sodium metabisulfite), tonicity controlling agents, absorption delaying agents, adjuvants, bulking agents (e.g., lactose, mannitol) and the like.
  • preservatives e.g., Thimerosal, benzyl alcohol, polyquaterium
  • antioxidants e.g., ascorbic acid, sodium metabisulfite
  • tonicity controlling agents e.g., absorption delaying agents, adjuvants, bulking agents (e.g., lactose, mannitol) and the like.
  • carrier or excipient use in the subject compositions may be contemplated.
  • the compounds of the subject invention can be formulated for administration via injection, for example, as a solution or suspension.
  • the solution or suspension can comprise suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3 -butanediol, water, Ringer's solution, or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, non-irritant, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • a carrier for intravenous use includes a mixture of 10% USP ethanol, 40% USP propylene glycol or polyethylene glycol 600 and the balance USP Water for Injection (WFI).
  • Other illustrative carriers for intravenous use include 10% USP ethanol and USP WFI; 0.01- 0.1% triethanolamine in USP WFI; or 0.01-0.2% dipalmitoyl diphosphatidylcholine in USP WFI; and 1-10% squalene or parenteral vegetable oil-in-water emulsion.
  • Water or saline solutions and aqueous dextrose and glycerol solutions may be preferably employed as carriers, particularly for injectable solutions.
  • Illustrative examples of carriers for subcutaneous or intramuscular use include phosphate buffered saline (PBS) solution, 5% dextrose in WFI and 0.01-0.1% triethanolamine in 5% dextrose or 0.9% sodium chloride in USP WFI, or a 1 to 2 or 1 to 4 mixture of 10% USP ethanol, 40% propylene glycol and the balance an acceptable isotonic solution such as 5% dextrose or 0.9% sodium chloride; or 0.01-0.2% dipalmitoyl diphosphatidylcholine in USP WFI and 1 to 10% squalene or parenteral vegetable oil-in-water emulsions.
  • PBS phosphate buffered saline
  • compositions of the invention will advantageously comprise between about 0.1% and 99%, and especially, 1% and 15% by weight of the total of the subject compounds based on the weight of the total composition including carrier or diluent.
  • the subject compounds can also be administered utilizing liposome technology, slow release capsules, implantable pumps, and biodegradable containers. These delivery methods can, advantageously, provide a uniform dosage over an extended period of time.
  • the subject invention also concerns a packaged dosage formulation comprising in one or more packages, packets, or containers the subject compounds and/or a composition of the subject invention formulated in a pharmaceutically acceptable dosage.
  • the package can contain discrete quantities of the dosage formulation, such as tablet, capsules, lozenge, and powders.
  • the quantity of the subject compounds in a dosage formulation and that can be administered to a patient can vary from about 1 mg to about 1000 mg. In some embodiments, the amount is in the range of 5 mg to 500 mg, to be administered 1, 2, 3, or 4 times per day, for about 2, about 3, about 4, about 5, about 6, about 7, about 10 , about 14, about 21, about 28, about 35, about 40, about 45, about 50, about 55, about 60, about 120, about 180, about 365 days or more days.
  • the subject compounds or compositions can be administered a certain number of times per week or month (for example, 1, 2, 3, 4, 5, 6, or 7 times per week or between 1 day and x days per month, where x is 28, 29, 30, or 31 days depending on the month or year (if a leap year)).
  • “A week” refers to a period of time of about 5, about 6 or about 7 days.
  • “A month” refers to a period of time of about 28, about 29, about 30, or about 31 days.
  • the subject compounds can be administered in an amount that ranges from about 0.01 mg/kg to about 150 mg/kg of a subject to be treated; about 1 mg/kg to about 75 mg/kg of a subject to be treated; about 1 mg/kg to about 50 mg/kg of a subject to be treated; about 10 mg/kg to about 100 mg/kg of a subject to be treated; about 10 mg/kg to about 75 mg/kg of a subject to be treated; about 10 mg/kg to about 50 mg/kg of a subject to be treated; about 1 mg/kg to about 75 mg/kg of a subject to be treated; about 10 mg/kg to about 30 mg/kg of a subj ect to be treated; about 15 mg/kg to about 30 mg/kg of a subj ect to be treated; about 15 mg/kg to about 25 mg/kg of a sub
  • the subject compositions or compounds can be administered before symptoms of XPD have developed, including, for example, dystonia and/or parkinsonian symptoms such as resting tremor, bradykinesia, rigidity, postural instability, and/or severe shuffling gait. Additionally or alternatively, the subject compositions can be administered after symptoms of XPD have developed or after a subject has been diagnosed XPS. In certain embodiments, diagnosing XPD comprises identifying at least one mutation in the gene encoding TAF I (OMIM entry 313650, the disclosure of which is hereby incorporated by reference in its entirety).
  • TAFI LOF tadpoles Phenotypic rescue in TAFI LOF tadpoles by SAK3, Pridopidine and Lamotrigine.
  • TAFI LOF tadpoles presents robust phenotypes including developmental delays resulting in a delayed start of swimming at 8 days post fertilization (8 dpf) compared with 6 dpf for wildtype tadpoles. They also present abnormal swimming behavior, -50% lower viability, and a range of abnormal behaviors, including forced and uncontrolled mandibular movements, mild to severe tail spasms, loss of spatial orientation, the frequency of observing any of those last three phenotypes, which we liken to dystonia-like symptoms as far as tadpole goes, being approximately 0.1 event per minute. Highlights are presented below and Figure 1.
  • Figs. 1A-1G. SAK3, Pridopidine, Lamotrigine show distinct and complementary benefits in TAFI LOF tadpoles. Viability: TAFI LOF tadpoles (KD) have decreased viability which is apparent starting at 6-8 days post fertilization (dpf). Fig. 1A. Sak3 showed mild viability improvements compared with controls and did not cause significant toxicity. Fig. IB. Pridopidine showed more dramatic improvement in viability, albeit with some toxicity at the dose tested. Fig. 1C. Lamotrigine proved to be toxic at the concentration tested, however it did delay the initial drop in viability typically by 2 dpf.
  • TAF1 LOF tadpoles are developmentally delayed which also delays the dpf at which they start swimming and perdure as a 10 dpf TAF1 LOF tadpoles will tend to rest more often than swim, like a 6 dpf WT tadpoles would do.
  • Fig. ID. Sak3 mildly rescued developmental delay (not shown) which resulted in a partial rescue of swimming activity by 10 dpf. Fig. IE.
  • both pridopidine and lamotrigine partially rescued the developmental delay, more so with Lamotrigine at 10 dpf. Fig. IF.
  • Example of tadpoles at 6 dpf (bar 2 mm).
  • Fig. 1G Visual output from our tadpole tracker system showing the swimming behavior of each of the 5 tadpoles in a 60 mm dish represented as density map. WT are to very active and swim along the edge in circular motion. The compounds do not impact the behavior of WT animals. We can see that lamotrigine is able to rescue the behavior in the TAF1 LOF, while SAK3 offer a partial rescue. We are in the process of assessing combinations of these drugs to identify synergistic effects.
  • Figs. 2A-2E Succinanilic acid (4-anilino-4-oxo-butanoic acid) shows distinct and complementary benefits in TAF1 LOF tadpoles. Viability: TAF1 LOF tadpoles (KD) have decreased viability which is apparent starting at 15 days post fertilization (dpf). Fig. 2A. Succinanilic acid (4-anilino-4-oxo-butanoic acid; RVL2) showed viability improvements compared with controls and did not cause significant toxicity.
  • Figs. 2B-2E Succinanilic acid (4-anilino-4-oxo-butanoic acid; RVL2) mildly improves viability (Fig. 2A), swimming behavior (Fig. 2B), swimming mobility (Figs. 2C and 2E) and body orientation (Fig. 2D). The compound did not impact the behavior of WT animals.
  • Notch signaling is triggered when a Notch ligand binds to a transmembrane NOTCH receptor. This binding initiates two successive proteolytic cleavages, through a- and y- secretases, releasing the Notch intracellular domain (NICD).
  • NBD Notch intracellular domain
  • NOTCH intracellular domain leads to dysregulation of the NOTCH signaling, resulting in impaired neuronal patterning and bioelectric signals, including in vertebrate animals such Xeopus laevis tadpoles (Pai VP, Lemire JM, Pare J-F, Lin G, Chen Y, Levin M. Endogenous gradients of resting potential instructively pattern embryonic neural tissue via Notch signaling and regulation of proliferation. J Neurosci. 2015 Mar 1 l;35(10):4366— 4385. PMCID: PMC4355204).
  • HCN2 in the form of an mRNA was able to rescue the phenotypes associated with NOTCH disruption, similar to lamotrigine (Pai VP, Levin M. HCN2 channel-induced rescue of brain, eye, heart and gut teratogenesis caused by nicotine, ethanol and aberrant notch signalling. Wound Repair Regen. 2022 Nov;30(6):681-706. PMID: 35662339).
  • HCN2 overexpression could rescue TAF1 loss-of-function (LOF) in the tadpole model, which would indicate a similar NOTCH signaling disruption.
  • LEF loss-of-function
  • HCN2 mRNA aggravated the phenotypes caused by TAF1 LOF.
  • EXAMPLE 3 Evaluating treatment with NOTCH agonist Ynhu-3792 or with voltagedependent calcium channel blocker gabapentin in tadpoles. Based on our HCN2 results we evaluated a NOTCH agonist.
  • Ynhu-3792 (5-(3- methoxyphenoxy)-A 72 -[4-(1-methylethyl)phenyl]-2,4-quinazolinediamine hydrochloride; CAS Registry No. 2624336-93-0) activates Notch signaling pathway and expression of Hes3 and Hes5.
  • mice It was shown to promotes neurogenesis in the hippocampal dentate gyrus, and to increases the spatial and episodic memory abilities of mice (Lu H, Cheng G, Hong F, Zhang L, Hu Y, Feng L. A Novel 2-Phenylamino-Quinazoline-Based Compound Expands the Neural Stem Cell Pool and Promotes the Hippocampal Neurogenesis and the Cognitive Ability of Adult Mice. Stem Cells. 2018 Aug;36(8): 1273-1285. PMID: 29726088).
  • Gabapentin is known to block the voltage-dependent calcium channels activation by binding to the a25 subunit (CACNA2-D1, -D2, -D3 and -D4). Voltage-dependent calcium channels are regulated by Notch signaling, such as when constitutively expressing Notch intracellular domains (NICD). It has been shown that Gabapentin would have similar benefit than lamotrigine in rescuing the effect of sustained NICD expression in tadpoles (Pai VP, Levin M. HCN2 channel-induced rescue of brain, eye, heart and gut teratogenesis caused by nicotine, ethanol and aberrant notch signalling. Wound Repair Regen. 2022 Nov;30(6):681-706. PMID: 35662339 ⁇ .
  • EXAMPLE 4 Identification of Notch signaling proteins targeted by lamotrigine using thermal proteome profiling.
  • Tadpoles at 15 dpf where dosed for 2 hours with 50 pM of lamotrigine then submitted to one-pot thermal proteome profiling (TPP).
  • Tadpoles samples were snap-frozen in dry ice/methanol (4 cycles of snap-freezing). Then samples were centrifuged, and 11.1 pl of each of the 9 temperature treatments of a single condition were pooled in a new tube (total 100 pL). The 16 pool samples were centrifuged for 75 minutes at a max speed and at 4°C, then 80 pL were transferred to new tubes. The protein content of each pool was determined and completed to 100 pL with 50 mM Tris pH 8.
  • Samples were then acidified with 2% formic acid, and the peptides were purified by reversed-phase SPE. Each sample was analyzed in SWATH mode on a 30-minute LC-MS/MS gradient (GPF mode).
  • the ion library is composed of a pool of the 16 samples.
  • the ion library was analyzed in IDA mode on a 30-minute LC-MS/MS gradient.
  • the acquisition was performed with a Sciex ZenoTOF 7600 (Sciex, Foster City, CA, USA) equipped with an OptiFlow Turbo V ion source using the micro probe and an electrode 1-10 pL/min. Sciex OS 3.0 software was used to control the instrument and for data processing and acquisition.
  • the acquisition was performed in Zeno Dependant Data Acquisition (Zeno- DDA or IDA) mode for the ion library.
  • the samples were analyzed in Zeno SWATH (Zeno- DIA) acquisition mode.
  • the source voltage was set to 4.5 kV and maintained at 200°C; curtain gas was set at 35 psi, gas one at 20 psi, and gas two at 60 psi.
  • a Waters ACQUITY UPLC M- class system was used (Waters, Milford, MA, USA) with a reversed-phase Kinetex XB C18 column 0.3 mm i.d., 2.6 pm particles, 150 mm (Phenomenex), which was maintained at 60°C. Samples were injected in direct-inject mode using a 5 pL loop (full loop mode with overfilling). For the 30 minutes LC gradient, the mobile phase consisted of the following solvent A (H2O 0.2% FA 3% DMSO) and solvent B (EtOH 0.2% FA 3% DMSO) at a flow rate of 5 pL/min.
  • solvent A H2O 0.2% FA 3% DMSO
  • solvent B EtOH 0.2% FA 3% DMSO
  • Peptides and proteins for the ion library were identified using Protein Pilot (Sciex). We used an ion library constructed with the IDA samples for SWATH peptide quantification. Peptides were quantified using DIA-NN (version 1.8.1). Peptide areas were then corrected using the RT -LOESS algorithm from the NormalyzerDE package and summed for each protein. TPP value were used to calculate a log2 fold-change and the log2 Z-score. The top proteins with Log2 fold-change and Z-score > 0.58 were considered a hit.
  • TPP revealed 4 proteins that are part of the NOTCH signaling pathways likely interact directly with Lamotrigine: The Hemoglobin subunit zeta (HBZ), Presenilin-2 (PSEN2), Proteasome activator complex subunit 3 (PSME3), and Splicing factor U2AF 35 kDa subunit (U2AF1).
  • HBZ Hemoglobin subunit zeta
  • PSEN2 Presenilin-2
  • PSME3 Proteasome activator complex subunit 3
  • U2AF1 Splicing factor 35 kDa subunit
  • HBZ interacts with several regulators of NOTCH expression, including Jun, ATF2, CREBP1, MAFB and MAFG (Sanalkumar R, Indulekha CL, Divya TS, Divya MS, Anto RJ, Vinod B, Vidyanand S, Jagatha B, Venugopal S, James J.
  • ATF2 maintains a subset of neural progenitors through CBFl/Notch independent Hes-1 expression and synergistically activates the expression of Hes-1 in Notch-dependent neural progenitors. J Neurochem. 2010 May;l 13(4):807-18. doi: 10.1111/j .1471-4159.2010.06574.X. Epub 2010 Jan 8. PMID: 20067572.
  • PSEN2 a subunit of the gamma-secretase complex along with PSEN1, is known to be involved in processing and cleaving of NOTCH.
  • Amber C Lovejoy C, Harris L, Willumsen N, Alatza A, Casey JM, Lines G, Kerins C, Mueller AK, Zetterberg H, Hardy J, Ryan NS, Fox NC, Lashley T, Wray S. Familial alzheimer’s disease mutations in PSEN1 lead to premature human stem cell neurogenesis. Cell Rep. 2021 Jan 12;34(2): 108615.
  • PMCID PMC7809623)(Kostyszyn B, Cowbum RF, Seiger A, Kjaeldgaard A, Sundstrbm E. Distribution of presenilin 1 and 2 and their relation to Notch receptors and ligands in human embryonic/foetal central nervous system. Brain Res Dev Brain Res. 2004 Jul 19; 151(1— 2):75— 86. PMID: 15246694).
  • PSME3 part of the 26S and 20S proteasome-ubiquitination systems, which are involved in ubiquitination of NOTCH (Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A, Chui I, Deshaies RJ, Kitajewski J. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Mol Cell Biol. 2001 Nov;21(21):7403-15. doi: 10.1128/MCB.21.21.7403-7415.2001. PMID: 11585921; PMCID: PMC99913.)(Oberg C, Li J, Pauley A, Wolf E, Gurney M, Lendahl U.
  • Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sei- 10 homolog. J Biol Chem. 2001 Sep 21;276(38):35847-53. doi: 10.1074/jbc.M103992200. Epub 2001 Jul 18. PMID: 11461910.).
  • U2AF1 (Splicing factor U2AF 35 kDa subunit) is involved in both the expression of NOTCH genes and CSL transcription factors who also regulates NOTCH genes. Notch and CSL form a Coactivator Complex, which includes CREBBP, p300, HATs, HDACs, NCORs. (Laaref AM, Manchon L, Bareche Y, Lapasset L, Tazi J. The core spliceosomal factor U2AF1 controls cell-fate determination via the modulation of transcriptional networks. RNA Biol. 2020 Jun;17(6):857-871. PMCID: PMC7549707)(Oswald F, Kovall RA. CSL-Associated Corepressor and Coactivator Complexes.

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Abstract

La présente divulgation concerne des composés, des compositions et des méthodes de traitement de maladies et/ou de troubles associés à une perte de fonction TAF1 (LOF). Des exemples non limitatifs de ces maladies et/ou troubles comprennent la dystonie parkinsonienne liée à l'X (XDP) et le trouble-33 syndromique du développement intellectuel lié à l'X. Des exemples non limitatifs de composés utiles dans le traitement de maladies et/ou de troubles associés à TAF1 LOF comprennent, et ne sont pas limités à, SAK3, pridopidine et/ou lamotrigine.
PCT/US2024/033552 2023-06-12 2024-06-12 Méthodes de traitement de maladies associées à une perte de fonction taf1 Pending WO2024258929A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040192690A1 (en) * 2002-07-29 2004-09-30 Buxton Ian Richard Novel formulations and method of treatment
WO2015112601A1 (fr) * 2014-01-22 2015-07-30 IVAX International GmbH Formulations à libération modifiée de pridopidine
US20190192496A1 (en) * 2016-08-24 2019-06-27 Prilenia Therapeutics Development Ltd. Use of pridopidine for treating dystonias
WO2021252950A2 (fr) * 2020-06-12 2021-12-16 Arizona Board Of Regents On Behalf Of The University Of Arizona Activateur de canal calcique de type t pour traiter des défauts neurologiques associés à taf1

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040192690A1 (en) * 2002-07-29 2004-09-30 Buxton Ian Richard Novel formulations and method of treatment
WO2015112601A1 (fr) * 2014-01-22 2015-07-30 IVAX International GmbH Formulations à libération modifiée de pridopidine
US20190192496A1 (en) * 2016-08-24 2019-06-27 Prilenia Therapeutics Development Ltd. Use of pridopidine for treating dystonias
WO2021252950A2 (fr) * 2020-06-12 2021-12-16 Arizona Board Of Regents On Behalf Of The University Of Arizona Activateur de canal calcique de type t pour traiter des défauts neurologiques associés à taf1

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ITO NAOTO, HENDRIKS WILLIAM T., DHAKAL JYOTSNA, VAINE CHRISTINE A., LIU CHRISTINA, SHIN DAVID, SHIN KYLE, WAKABAYASHI-ITO NORIKO, : "Decreased N-TAF1 expression in X-Linked Dystonia-Parkinsonism patient-specific neural stem cells", DISEASE MODELS & MECHANISMS, vol. 9, 1 January 2016 (2016-01-01), GB , pages 451 - 462, XP093259935, ISSN: 1754-8403, DOI: 10.1242/dmm.022590 *

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