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WO2024213932A1 - Commande de régénération d'axones par de nouveaux inhibiteurs d'enpp1 - Google Patents

Commande de régénération d'axones par de nouveaux inhibiteurs d'enpp1 Download PDF

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Publication number
WO2024213932A1
WO2024213932A1 PCT/IB2024/000162 IB2024000162W WO2024213932A1 WO 2024213932 A1 WO2024213932 A1 WO 2024213932A1 IB 2024000162 W IB2024000162 W IB 2024000162W WO 2024213932 A1 WO2024213932 A1 WO 2024213932A1
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WIPO (PCT)
Prior art keywords
enpp1
agents
injury
solution
nerve
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PCT/IB2024/000162
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English (en)
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Kai Liu
Yong Huang
Leung Ting CHAN
Chao Yang
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The Hong Kong University Of Science And Technology
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Publication of WO2024213932A1 publication Critical patent/WO2024213932A1/fr

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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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00

Definitions

  • Methods of promoting axon regeneration have focused on reducing extrinsic inhibitory substrates, such as CSPG, myelin-mediated inhibitory molecules, or depletion of glial scar, which have showed only modest effects.
  • Alternative approaches have targeted intrinsic signaling pathways to promote robust axon regeneration. Examples of such intrinsic factors include PTEN, SOCS3, KLF, GSK3b and Lin28, However, these intrinsic targets do not have highly potent smallmolecule agonists or antagonists, which means manipulation requires gene therapy. The safety of gene therapy is still concerning for clinical practices. Additionally, some suppressors of axon regeneration also function as tumor suppressors. Deletion or inhibition of these genes may hyperactivate intrinsic pathways, causing damaged intracellular homeostasis, impaired neuronal functions or tumorigenesis.
  • CSPGs chondroitin sulfate proteoglycans
  • MAIs Myelin associated inhibitors
  • Nogo and MAG exposed during nerve injury also block axon regeneration in the CNS. Targeting these extrinsic inhibitory molecules and their receptors are commonly used to promote axon regeneration according to prior arts.
  • the identified therapeutic target for the treatment of CNS injuries is druggable and show significant axon regeneration effect through CRISPR/Cas9-mediated depletion.
  • Enppl knockout mouse is viable, encouraging clinical use of the ectonucleotide pyrophosphatase/phosphodiesterase I (ENPP1) inhibitors for treatment.
  • ENPP1 inhibition and stimulator of interferon genes (STING) activation do not have tumorigenic effects.
  • This signaling pathway is the immunotherapy drug target for cancer. Systemic delivery of ENPP1 inhibitors and local delivery of STING agonist have been tested in clinical trials, indicating their safety for clinical translation.
  • Embodiments are directed to small molecule ENPP1 inhibitors and their use to target intrinsic pathways that promote axon regeneration.
  • intravitreal injection of these ENPP1 inhibitors for retinal ganglion cells (RGCs) manipulation can be restricted to the projecting neurons if there are fears of adverse side effects to other organs caused by systemic delivery.
  • the small molecule ENPP1 inhibitors can be used to suppress ENPP1 activity, allowing the avoidance of gene therapy.
  • ENPP1 inhibition and STING activation is achieved by ENPP1 inhibitor (compound) administration, such as, but not limited to, injection.
  • the ENPP1 inhibitors are optimized derivatives and analogues of known ENPP1 inhibitors that demonstrate axon regeneration after CNS injury.
  • the small molecule inhibitor allows identification of a neurite growth stimulator including an ENPP1 inhibitor such as 2-(3H-imidazo[4,5-b]pyridin-2-ylthio)-7V-(3,4- dimethoxyphenyl)acetamide (ENP001); and P-[2-[l-(6,7-dimethoxy-4-quinazolinyl)-4- piperidinyl]ethyl]-phosphonic acid (ENP002).
  • ENPP1 inhibitor such as 2-(3H-imidazo[4,5-b]pyridin-2-ylthio)-7V-(3,4- dimethoxyphenyl)acetamide (ENP001); and P-[2-[l-(6,7-dimethoxy-4-quinazolinyl)-4- piperidinyl]ethyl]-phosphonic acid (ENP002).
  • ENPP1 inhibitor such as 2-(3H-imidazo[4,5-b]pyridin-2-ylthio)-7V-(
  • the pharmaceutically active carrier can be selected from: solvents; diluents; buffers, neutral buffered saline, phosphate buffered saline, Tris-HCl, acetate buffers, and phosphate buffers; oil-in-water emulsions; water-in-oil emulsions; aqueous compositions without cosolvents; aqueous compositions with organic co-solvents; solubilizers, Polysorbate 65, Polysorbate 80; colloids; dispersion media; fillers; chelating agents, EDTA, glutathione; amino acids; proteins; disintegrants; binders; lubricants; wetting agents; emulsifiers; sweeteners; colorants; flavorings; aromatizers; thickeners, carbomer, gelatin, or sodium alginate; coatings; preservatives, thimerosal, benzyl alcohol, and polyquaterium; antioxidants, ascorbic acid, and sodium metabisulfit
  • the nerve treatment medication can be employed for treatment of a neurological injury to regenerate axons by administrating the nerve treatment medication to an injured nerve and their cell bodies.
  • the neurological injury can be a spinal cord injury, a traumatic brain injury, an optic neuropathy, a stroke, or glaucoma.
  • Administering can be in the form of an aerosol or spray that is formulated in the form of a powder, particle, solution, suspension, or emulsion.
  • Such formulations can include: saline; polyethylene glycol or glycols; DPPC; methylcellulose; powdered dispersing agents; fluorocarbons; propellants, dichlorodifluoromethane, propane, nitrogen, fluorocarbons; and any combination thereof.
  • the formulation may include a solution or suspension, which may employ: mannitol; 1,3- butanediol; water; Ringer's solution; isotonic sodium chloride solution; synthetic mono- or diglycerides; fatty acids; oleic acid; 10% USP ethanol; 40% USP propylene glycol; polyethylene glycol 600; triethanolamine; dipalmitoyl diphosphatidylcholine; squalene; or parenteral vegetable oil-in-water emulsion; dextrose; glycerol; phosphate buffered saline (PBS); triethanolamine; or any combination thereof.
  • mannitol 1,3- butanediol
  • water Ringer's solution
  • isotonic sodium chloride solution synthetic mono- or diglycerides
  • fatty acids oleic acid
  • 10% USP ethanol 40% USP propylene glycol
  • polyethylene glycol 600 triethanolamine
  • Fig. 1A shows sections of optic nerves from WT mice at 2 weeks post injury (WPI), where the vitreous body was injected with either PBS or lOmM of a commercial ENPP1 inhibitor (ENPP1 inhibitor C, Cayman chem 29809) immediately after optic nerve injury with a Scale bar of 200 pm.
  • WEP1 inhibitor C a commercial ENPP1 inhibitor
  • Fig. 1C shows sections of optic nerves from WT mice at 2 WPI, where the vitreous body was injected with either vehicle (DMSO) or lOmM of ENP002 with a Scale bar of 200 pm.
  • Fig. ID is a bar graph giving the number of regenerating axons at indicated distances from the lesion site, where **p ⁇ 0.01, *p ⁇ 0.05.
  • Fig. 2A shows sections of optic nerves from Rosa26-Cas9 mice at 2 WPI injected with either AAV-control-sgRNA or AAV-Enppl-sgRNA with a Scale bar of 200 pm.
  • Fig. 3A shows a representative image of replated DRG neurons treated by the indicated concentration of ENP001 and ENP002 with a Scale bar: 400pm.
  • Fig. 3B shows a quantification of the longest neuron length in Fig 3 A.
  • Embodiments are directed to ectonucleotide pyrophosphatase/phosphodiesterase I (ENPP1) inhibitors having superior bioactivity towards axonal growth, demonstrated by primary neuronal culture. These ENPP1 inhibitors promote CNS axon regeneration after injury. The therapeutic strategy is promoting axon regeneration after CNS injury through modulating the intrinsic neuronal mechanism.
  • ENPP1 ectonucleotide pyrophosphatase/phosphodiesterase I
  • Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a second messenger participating in the cGAMP synthase (STINGs) stimulator of interferon genes (STINGs) signaling, promotes CNS axon regeneration.
  • the cGAS-STING pathway is identified as a key mediator of innate immunity to combat pathogens.
  • cGAS belongs to a class of DNA sensors known as pattern recognition receptors (PRRs). When cGAS detects cytosolic DNA, it is activated and produces 2', 3 '-cGAMP as a second messenger, which activates STING. Activated STING translocated from the endoplasmic reticulum to the Golgi induces autophagy.
  • Activated STING also recruits tank-binding kinase 1 (TBK1), leading to autophosphorylation of TBK1 and phosphorylation of interferon regulatory factor 3 (IRF3), and other transcription factors, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), in turn, driving the transcription of multiple downstream target genes, such as type I interferon.
  • TBK1 tank-binding kinase 1
  • IRF3 interferon regulatory factor 3
  • NFkB nuclear factor kappa-light-chain-enhancer of activated B cells
  • the cGAS-STING pathway has been shown to play critical roles in neuronal functions, such as neurodevelopment and nociception.
  • the first trial is: First-in-human experience using RBS2418, an oral ENPP1 inhibitor within an expanded access protocol in combination with pembrolizumab in a patient with metastatic adrenal cancer.
  • Source https://ascopubs.org/doi/abs/10.1200/JCQ.2022.40.16 suppl. e!4550).
  • the Phase 1 trial has been completed, and the results showed that RBS2418 led to complete enzyme inhibition throughout the trial.
  • SR-8541A ENPP1 Inhibitor
  • Source https://clinicaltrials.gov/ct2/show/NCT06063681.
  • SR8541 A is a potent inhibitor of ENPP1 and exhibits dendritic cell mediated antitumor activity.
  • ENPP1 is a type II transmembrane glycoprotein with nucleotide pyrophosphatase and phosphodiesterase activities.
  • ENPP1 has been identified as the dominant 2'3'-cGAMP hydrolase, and that a hydrolysis resistant form of 2'3'-cGAMP showed strong human STING (hSTING) agonist activities. Therefore, inhibition of ENPP1 allows activating the cGAS- STING signaling axis to promote axon regeneration.
  • Two types of ENPP1 inhibitors have been developed. The first type is nucleotide based ENPP1 inhibitors, which consist of substrate analogs that act by competition with natural substrates of ENPP1. However, poor oral availability and high off-target potentials preclude their use in therapeutic application.
  • ENPP1 inhibitors Another type is non-nucleotide based ENPP1 inhibitors, which inhibit ENPP1 in both competitive and non-competitive mode of action, with kinase inhibition (Ki) at concentrations ranging from 0.00146 to 1400 pM. While some of these inhibitors potently inhibit ENPP1, many are nonspecific and affect multiple biological processes. For example, heparin is also a well-known anticoagulant. Suramin, which shows high potency to ENPP1, also inhibits multiple receptors such as epidermal growth factor receptor (EGFR) and follicle-stimulating hormone receptor (FSHR).
  • EGFR epidermal growth factor receptor
  • FSHR follicle-stimulating hormone receptor
  • a panel of three ENPP1 inhibitors are identified as effective towards neurite growth stimulators.
  • the delivery of the ENPP1 inhibitors in a vehicle such as, but not limited to, a solvent or solution, can be included at a concentration of lOpM or more. Delivery can be conducted via one or a series of administrations. For example, but not limited to intracranial injection and intravitreal injection.
  • the ENPP1 inhibitors are:
  • the subject compositions are formulated as an orally-consumable product, such as, for example a food item, capsule, pill, or drinkable liquid.
  • An orally deliverable pharmaceutical is any physiologically active substance delivered via initial absorption in the gastrointestinal tract or into the mucus membranes of the mouth.
  • the topic compositions can also be formulated as a solution that can be administered via, for example, injection, which includes intravenously, intraperitoneally, intramuscularly, intrathecally, or subcutaneously.
  • the subject compositions are formulated to be administered via the skin through a patch or directly onto the skin for local or systemic effects.
  • the compositions can be administered sublingually, buccally, rectally, or vaginally.
  • the compositions can be sprayed into the nose for absorption through the nasal membrane, nebulized, inhaled via the mouth or nose, or administered in the eye or ear.
  • Orally consumable products according to the invention are any preparations or compositions suitable for consumption, for nutrition, for oral hygiene, or for pleasure, and are products intended to be introduced into the human or animal oral cavity, to remain there for a certain period of time, and then either be swallowed (e.g., food ready for consumption or pills) or to be removed from the oral cavity again (e.g., chewing gums or products of oral hygiene or medical mouth washes). While an orally-deliverable pharmaceutical can be formulated into an orally consumable product, and an orally consumable product can comprise an orally deliverable pharmaceutical, the two terms are not meant to be used interchangeably herein.
  • Orally consumable products include all substances or products intended to be ingested by humans or animals in a processed, semi-processed, or unprocessed state. This also includes substances that are added to orally consumable products (particularly food and pharmaceutical products) during their production, treatment, or processing and intended to be introduced into the human or animal oral cavity.
  • Orally consumable products can also include substances intended to be swallowed by humans or animals and then digested in an unmodified, prepared, or processed state; the orally consumable products according to the invention therefore also include casings, coatings, or other encapsulations that are intended to be swallowed together with the product or for which swallowing is to be anticipated.
  • the orally consumable product is a capsule, pill, syrup, emulsion, or liquid suspension containing a desired orally deliverable substance.
  • the orally consumable product can comprise an orally deliverable substance in powder form, which can be mixed with water or another liquid to produce a drinkable orally-consumable product.
  • the orally-consumable product according to the invention can comprise one or more formulations intended for nutrition or pleasure.
  • these particularly include baking products (e.g., bread, dry biscuits, cake, and other pastries), sweets (e.g., chocolates, chocolate bar products, other bar products, fruit gum, coated tablets, hard caramels, toffees and caramels, and chewing gum), alcoholic or non-alcoholic beverages (e.g., cocoa, coffee, green tea, black tea, black or green tea beverages enriched with extracts of green or black tea, Rooibos tea, other herbal teas, fruit-containing lemonades, isotonic beverages, soft drinks, nectars, fruit and vegetable juices, and fruit or vegetable juice preparations), instant beverages (e.g., instant cocoa beverages, instant tea beverages, and instant coffee beverages), meat products (e.g., ham, fresh or raw sausage preparations, and seasoned or marinated fresh meat or salted meat products), eggs or egg products (e.g., dried whole egg, egg white, and
  • the subject composition can further comprise one or more pharmaceutically acceptable carriers, and/or excipients, and can be formulated into preparations, for example, solid, semisolid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, and aerosols.
  • pharmaceutically acceptable carriers for example, solid, semisolid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, and aerosols.
  • pharmaceutically acceptable means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof.
  • 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, colorants, flavorings, aromatizers, thickeners (e.g.
  • solubilizers e.g.
  • 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.
  • compositions of the subject invention can be made into aerosol formulations so that, for example, it can be nebulized or inhaled.
  • Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, powders, particles, solutions, suspensions, or emulsions.
  • Formulations for oral or nasal aerosol or inhalation administration may also be formulated with carriers, including, for example, saline, polyethylene glycol or glycols, DPPC, methylcellulose, or in mixture with powdered dispersing agents or fluorocarbons.
  • Aerosol formulations can be placed into pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • delivery may be by use of a single-use delivery device, a mist nebulizer, a breath-activated powder inhaler, an aerosol metered-dose inhaler (MDI), or any other of the numerous nebulizer delivery devices available in the art.
  • MDI aerosol metered-dose inhaler
  • mist tents or direct administration through endotracheal tubes may also be used.
  • compositions 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 subject invention can be formulated for administration via topical application onto the skin, for example, as topical compositions, which include rinse, spray, or drop, lotion, gel, ointment, cream, foam, powder, solid, sponge, tape, vapor, paste, tincture, or using a transdermal patch.
  • topical compositions which include rinse, spray, or drop, lotion, gel, ointment, cream, foam, powder, solid, sponge, tape, vapor, paste, tincture, or using a transdermal patch.
  • Suitable formulations of topical applications can comprise in addition to any of the pharmaceutically active carriers, for example, emollients such as carnauba wax, cetyl alcohol, cetyl ester wax, emulsifying wax, hydrous lanolin, lanolin, lanolin alcohols, microcrystalline wax, paraffin, petrolatum, polyethylene glycol, stearic acid, stearyl alcohol, white beeswax, or yellow beeswax.
  • emollients such as carnauba wax, cetyl alcohol, cetyl ester wax, emulsifying wax, hydrous lanolin, lanolin, lanolin alcohols, microcrystalline wax, paraffin, petrolatum, polyethylene glycol, stearic acid, stearyl alcohol, white beeswax, or yellow beeswax.
  • compositions may contain humectants such as glycerin, propylene glycol, polyethylene glycol, sorbitol solution, and 1,2,6 hexanetri ol or permeation enhancers such as ethanol, isopropyl alcohol, or oleic acid.
  • humectants such as glycerin, propylene glycol, polyethylene glycol, sorbitol solution, and 1,2,6 hexanetri ol or permeation enhancers such as ethanol, isopropyl alcohol, or oleic acid.
  • compositions containing amounts of ingredients where the term “about” is used, these compositions contain the stated amount of the ingredient with a variation (error range) of 0-10% around the value (X ⁇ 10%). In other contexts, the term “about” is used provides a variation (error range) of 0-10% around a given value (X ⁇ 10%).
  • this variation represents a range that is up to 10% above or below a given value, for example, X ⁇ 1%, X ⁇ 2%, X ⁇ 3%, X ⁇ 4%, X ⁇ 5%, X ⁇ 6%, X ⁇ 7%, X ⁇ 8%, X ⁇ 9%, or X ⁇ 10%.
  • ranges are stated in shorthand 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. Values having at least two significant digits within a range are envisioned, for example, a range of 5-10 indicates all the values between 5.0 and 10.0 as well as between 5.00 and 10.00 including the terminal values. When ranges are used herein, combinations and subcombinations of ranges (e.g., subranges within the disclosed range) and specific embodiments therein are explicitly included.
  • Treatment “Treatment”, “treating”, “palliating” and “ameliorating” (and grammatical variants of these terms), as used herein, are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit. A therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease or symptom thereof such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the disease or symptom thereof.
  • the term “subject” refers to an animal, needing or desiring delivery of the benefits provided by a therapeutic composition.
  • the animal may be a primate or rodent.
  • the animal may be, for example, humans, pigs, horses, goats, cats, mice, rats, dogs, apes, fish, chimpanzees, orangutans, guinea pigs, hamsters, cows, sheep, birds, chickens, as well as any other vertebrate or invertebrate.
  • These benefits can include, but are not limited to, the treatment of a health condition, disease, or disorder; prevention of a health condition, disease, or disorder; immune health; enhancement of the function of an organ, tissue (e.g., solid tissue), or system in the body.
  • the subject can be of any age or stage of development, including infant, toddler, adolescent, teenager, adult, or senior.
  • the terms “subject” and “patient” can be used interchangeably.
  • reduces is meant a negative alteration of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%.
  • ENPP1 depletion promotes axon regeneration.
  • ENPP1 inhibitor C stimulated significant axon regeneration, in a dosedependent manner, as indicated in Fig. 1 A and Fig. IB.
  • the structure of ENPP1 Inhibitor C is:
  • the CRISPR technique was used to knock out Enppl in RGCs and assessed the effect on axon regeneration.
  • Adeno-associated virus (AAV)-expressing sgRNAs targeting Enppl (sgEnppl) with mCherry tag was injected into the eyes of mice constitutively expressing the Cas9 enzyme.
  • AAV-sgEnppl but not AAV-expressing sgRNA targeting LacZ (sgCtrl) promoted axon regeneration after injection into Cas9 mice, as indicated in Fig. 2A and Fig. 2B).
  • ENPP1 inhibitors identified to promote neurite growth in DRG replating assay.
  • a neurite growth stimulator comprising an ENPP1 inhibitor selected from:
  • a nerve treatment medication comprising; the neurite growth stimulator according to Embodiment 1; and a pharmaceutically active carrier.
  • Embodiment 3 The nerve treatment medication according to Embodiment 2, wherein the pharmaceutically active carrier is selected from: solvents; diluents; buffers, neutral buffered saline, phosphate buffered saline, Tris-HCl, acetate buffers, and phosphate buffers; oil-in-water emulsions; water-in-oil emulsions; aqueous compositions without cosolvents; aqueous compositions with organic co-solvents; solubilizers, Polysorbate 65, Polysorbate 80; colloids; dispersion media; fillers; chelating agents, EDTA, glutathione; amino acids; proteins; disintegrants; binders; lubricants; wetting agents; emulsifiers; sweeteners; colorants; flavorings; aromatizers; thickeners, carbomer, gelatin, or sodium alginate; coatings; preservatives, thimerosal, benzyl alcohol, and polyqua
  • Embodiment 5 The method according to Embodiment 4, wherein the neurological injury is a spinal cord injury, a traumatic brain injury, an optic neuropathy, a stroke, or glaucoma.
  • the neurological injury is a spinal cord injury, a traumatic brain injury, an optic neuropathy, a stroke, or glaucoma.
  • Embodiment 6 The method according to Embodiment 4, wherein administering is in the form of an aerosol or spray.
  • Embodiment 7 The method according to Embodiment 7, wherein a formulation of the aerosol or spray is in the form of a powder, particle, solution, suspension, or emulsion.
  • Embodiment 8 The method according to Embodiment 7, wherein the formulation comprises: saline; polyethylene glycol or glycols; DPPC; methylcellulose; powdered dispersing agents; fluorocarbons; propellants, dichlorodifluoromethane, propane, nitrogen, fluorocarbons; or any combination thereof.
  • Embodiment 10 The method according to Embodiment 9, wherein a formulation for injecting the nerve treatment medication comprises a solution or suspension.
  • Embodiment 11 The method according to Embodiment 10, wherein the solution or suspension comprises: mannitol; 1,3 -butanediol; water; Ringer's solution; isotonic sodium chloride solution; synthetic mono- or diglycerides; fatty acids; oleic acid; 10% USP ethanol; 40% USP propylene glycol; polyethylene glycol 600; triethanolamine; dipalmitoyl diphosphatidylcholine; squalene; or parenteral vegetable oil-in-water emulsion; dextrose; glycerol; phosphate buffered saline (PBS); triethanolamine; or any combination thereof.
  • REFERENCES REFERENCES
  • Donnelly C. R. et al. STING controls nociception via type I interferon signaling in sensory neurons. Nature. 2021 Mar;591(7849):275-280. doi: 10.1038/s41586-020-03151-1. Epub 2021 Jan 13. PMID: 33442058; PMCID: PMC7977781.
  • thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury.
  • KLF family members regulate intrinsic axon regeneration ability Science, vol. 326, no. 5950, pp. 298-301, Oct. 2009, doi: 10.1126/science.1175737.
  • GSK3P regulates AKT-induced central nervous system axon regeneration via an eIF2B£-dependent, mTORCl -independent pathway,” eLife, vol. 5, doi: 10.7554/eLife.l 1903.

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Abstract

Un stimulateur de croissance de neurites est un inhibiteur d'ENPP1 à petites molécules. L'inhibiteur d'ENPP1 à petites molécules permet le traitement d'une lésion du système nerveux central (SNC) avec la promotion de la régénération d'axones. L'inhibiteur d'ENPP1 dans un véhicule peut être administré à une lésion neurologique pour favoriser la régénération d'axones.
PCT/IB2024/000162 2023-04-11 2024-04-09 Commande de régénération d'axones par de nouveaux inhibiteurs d'enpp1 WO2024213932A1 (fr)

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