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• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
  • A61K31/10—Sulfides; Sulfoxides; Sulfones
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• • 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
  • A61K31/4965—Non-condensed pyrazines
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• This application claims priority of US Provisional application number 63/374,981 filed September 8, 2022, the entire contents being incorporated herein by reference as though set forth in full.
• Field of the Invention The present invention relates the fields of the amelioration of symptoms associated with CLEC16A dysfunction or loss. More specifically, the invention provides agents useful for the treatment of autoimmune disorders, lipodystrophic disorders, and neurodegenerative disorders in patients in need thereof. Background of the Invention Several publications and patent documents are cited through the specification in order to describe the state of the art to which this invention pertains.
• the CLEC16A-associated disorder is selected from an autoimmune disorder, a lipodystrophic disorder, and a neurodegenerative disorder.
• the at least one mitophagy enhancer enhances the clearance of mitochondria.
• Exemplary mitophagy enhancers are probucol, quercetin, or acipimox.
• the methods further comprise administering one or more agents selected from a JAK-STAT inhibitor, an ER stress modulator, and a SOCS1 inhibitor.
• JAK-STAT inhibitors are selected from tofacitinib, ruxolitinib, baricitinib, peficitinib, decernotiniba, filgotinib, solcitinibb, itacitinib, SHR0302, upadacitinib, and PF-04965842.
• Exemplary ER stress modulators are selected from Rapamycin, 4-phenylbutyric acid (4-PBA), trimethylamine N-oxide dehydrate (TMAO), dimethyl sulfoxide (DMSO), tauroursodeoxycholic acid (TUDCA), AMPK-activated protein kinase, 5′-aminoimidazole-4-carboxymide-1- ⁇ -d- ribofuranoside (AICAR), Glucagon-Like Peptide-1 (GLP-1), DPP4 inhibitors, and n- acetylcysteine (NAC).
• the methods further comprise administration of a PPAR ⁇ inhibitor.
• the methods described herein rescue spleen atrophy and/or improves the organ weight ratio of Thymus, inguinal white adipose tissue (iWAT), and/or gonal white adipose tissue (gWAT) when compared to an untreated control.
• the treatment delays CLEC16A-associated symptom progression when compared to an untreated control.
• methods for treating CLEC16A-associated degeneration of the thymus comprising administration of a mitophagy enhancer, thereby altering the weight ratio in thymus and ameliorating symptoms associated with degeneration of the thymus.
• Methods for treating CLEC16A-associated degeneration of spleen comprising administration of a mitophagy enhancer, thereby altering the weight ratio in spleen, providing therapeutic benefit, and ameliorating symptoms associated with degeneration of the spleen, are also provided herein.
• methods for treating CLEC16A-associated degeneration of iWAT comprising administration of a mitophagy enhancer, thereby altering the weight ratio in iWAT and ameliorating symptoms associated with degeneration of the iWAT are provided.
• FIG. 3A Immunoblot analysis of spleen lysates depicting disrupted mitophagy and rescue by probucol.
• FIG. 3B Quantitation graph depicts expression levels of CLEC16A, P62, LC3I/II, PINK1, and Parkin from control ⁇ probucol and KO ⁇ probucol treated mice.
• FIG. 3C Schematic depicts probucol action in clearing defective mitochondria in Mitophagy.
• Probucol delays the phenotype progression in KO mice.
• Probucol partially rescues the lipodystrophic phenotype and improve the survival of CLEC16A KO mice.
• Representative dorsal and ventral dissection image depicting gross morphology and distribution of fat in control, KO and KO + probucol treated mice.
• Bottom panel shows amount of iWAT, BAT, and gWAT harvested from control, KO and KO + probucol (score 1, 2, and 3.5) mice.
• FIG. 6A-6B Quercetin attenuates the CLEC16a KO phenotype.
• Figure 7A -7C Organ weight/body weight ratios for control ⁇ quercetin and KO ⁇ quercetin groups and control ⁇ acipimox and KO ⁇ acipimox groups.
• Figure 8A-8C CLEC16A KO phenotype (FIG. 8A). Probucol mediated rescue in clearing late stage dysregulated mitophagy (FIG. 8B). Experimental design and Probucol dosage and administration over the course of the study (FIG. 8C) Figure 9. Late-stage mitophagy enhancer delays phenotype progression in a dose dependent manner.
• Probucol was purchased from Cayman Chemical (cat# 15043) and was formulated in saline (0.9%NaCl) with 2% DMSO, 2.5% PEG 300 and 2.5% Tween 80. The solution was administered intraperitoneally (IP) daily for 16 days at three doses of 3.5mg/kg, 10mg/kg, and 50mg/kg (Fig. 8C). Vehicle treated mice received 2% DMSO, 2.5% PEG 300 and 2.5% Tween 80 in saline. A fresh solution was made daily prior to the injections. All animals were sacrificed according to humane endpoint according to the approved IACUC protocol. Probucol (late-stage mitophagy enhancer) delays phenotype progression in a dose dependent manner.
• IP intraperitoneally
• Probucol (late stage mitophagy enhancer) exerts its multifaceted effect by modulating PINK1/Parkin mediated disrupted mitophagy, improves survival, and delays the lipodystrophy and sensory neurodegeneration resembling spinocerebellar ataxia phenotype in Clec16a ⁇ UBC (KO) mice in a dose dependent manner.
• drugs with modulatory effects on mitophagy/ER Stress/SOCS1-JAK-STAT signaling compensate for the attenuated CLEC16A activity and can be used in targeted interventions.
• Example VII Test and Treat Method for Ameliorating Symptoms Associated with CLEC16A Deficiency
• the information herein above can be applied clinically to patients for therapeutic intervention, particularly for the treatment of symptoms associated with CLEC16A deficiency.
• a preferred embodiment of the invention comprises clinical application of the information described herein to a patient.
• Important clinical assessments for CLEC16A-associated diseases or symptoms include amelioration or delayed progression of one or more of robust autoimmune inflammatory responses, severe weight loss, severe neurological symptoms, neuroinflammation, progressive neurodegeneration resembling spinocerebellar ataxia, and fat loss.
• Other clinical assessments include, enhanced clearance of mitochondria, the rescue spleen atrophy and/or improvements in the organ weight ratio of Thymus, inguinal white adipose tissue (iWAT), and/or gonal white adipose tissue (gWAT) when compared to an untreated control.
• the derived therapeutic dose of mitophagy enhancer for human could be by those skilled in the art based on response rate.
• JAK-STAT inhibitors include, without limitation, tofacitinib, ruxolitinib, baricitinib, peficitinib, decernotiniba, filgotinib, solcitinibb, itacitinib, SHR0302, upadacitinib, and PF- 04965842.
• Exemplary ER stress modulators include, without limitation, Rapamycin, 4- phenylbutyric acid (4-PBA), trimethylamine N-oxide dehydrate (TMAO), dimethyl sulfoxide (DMSO), tauroursodeoxycholic acid (TUDCA), AMPK-activated protein kinase, 5′- aminoimidazole-4-carboxymide-1- ⁇ -d-ribofuranoside (AICAR), Glucagon-Like Peptide-1 (GLP-1), DPP4 inhibitors, and N-acetylcysteine (NAC). Treatment can occur after a patient arrives in the clinic and presents with CLEC16A- associated diseases or symptoms.
• 4-PBA 4- phenylbutyric acid
• TMAO trimethylamine N-oxide dehydrate
• DMSO dimethyl sulfoxide
• TDCA tauroursodeoxycholic acid
• AICAR 5′- aminoimidazole-4-carboxymide-1- ⁇ -d
• Mitophagy enhancers such as probucol, quercetin, and acipimox, have been shown to be well tolerated and the symptoms were assessed using clinical scores criteria. While certain of the preferred embodiments of the present invention have been described and specifically exemplified above, it is not intended that the invention be limited to such embodiments. Various modifications may be made thereto without departing from the scope and spirit of the present invention, as set forth in the following claims.

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• 2023
  • 2023-09-07 WO PCT/US2023/032170 patent/WO2024054558A2/en not_active Ceased
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