WO2015191931A1 - Composition and method for the treatment of neurological diseases and cerebral injury - Google Patents
Composition and method for the treatment of neurological diseases and cerebral injury Download PDFInfo
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Definitions
- This application relates to compositions and methods for treating neurological and systemic diseases, proteostatic / lysosomal disorders, and the like.
- the application relates to compositions and methods suitable for histone deacetlylation inhibition therapy in treating Niemann- Pick Type C disease.
- Histone deacetylase inhibitors are an important class of emerging therapeutics, approved for three rare cancers. HDACi 's elicit complex cellular responses by blocking HDAC enzymes to promote acetylation of both histones and non-histone proteins. In genetic disorders, HDACi-induced histone modification can result in increased or decreased transcriptional expression of mutated gene(s) of interest but also confer indirect benefits through non-histone proteins (such as transcription factors and heat shock proteins) that modulate chaperone and proteostatic networks. Because of their broad effects on transcription, maximizing HDACi efficacy while limiting the dose is a major challenge in HDACi therapy.
- NPC Niemann-Pick Type C disease
- NPC Niemann-Pick Type C disease
- NPC is an autosomal recessive neurodegenerative disease caused by defect in either Npcl or Npc2 genes. 95% of NPC cases are due to defect in Npcl.
- the physiological function of both Npcl and Npc2 are in the transport of cellular cholesterol. Cells with defects in these genes accumulate cholesterol primarily in late endosomal lysosomal system because of a block in cholesterol transport from the lysosome to the ER . Insertion of a point mutation in Npcl gene that blocks cholesterol transport in cells confers neurodegenerative disease in a mouse model, providing definitive molecular evidence that NPCl protein function is critical for disease.
- NPC neurodegeneration
- Disease progression can be heterogeneous, and neurodegenerative decline may span one to two decades, but once initiated, leads to fatal outcomes.
- splenomegaly and hepatomegaly are common presenting symptoms followed by neurocognitive and neuromuscular degeneration.
- ZavescaTM an iminosugar marketed under the trade name, ZavescaTM. It was developed to treat type 1 Gaucher' s disease, another lysosomal disorder that arises from accumulation of glycosphingo lipids. Miglustat acts as a substrate reduction therapy to decrease sphingo lipids. ZavescaTM is approved for NPC treatment in Europe, Canada and Japan but was denied FDA approval because of insufficient data. ZavescaTM is therefore prescribed off- label in the U.S. It confers mild improvement in clinical neurological symptoms but fails to prevent disease progression.
- HPBCD 2-Hydroxypropyl-P-cyclodextrin
- systemic drug delivery primarily benefits the liver and other organ systems of the body cavity, while direct drug delivery into the central nervous system (CNS) is needed for substantial neurological improvement.
- CNS central nervous system
- Direct CNS delivery inheres several disadvantages, however. It increases the procedural risk in lifelong therapies, is associated with hearing loss, and provides little or no benefit for systemic disease.
- the present inventors have found that there is a need for a simplified therapeutic approach to integrate the treatment of both cerebral and systemic defects in challenging genetic diseases such as NPC.
- a therapeutic strategy based on, inter alia, the development and validation of a murine model of a fatal cerebellar disorder Niemann-Pick Type C (NPC) disease with both cerebral and systemic defects, which closely mimics human disease.
- NPC Niemann-Pick Type C
- a method for treating or preventing a disease or injury comprising administering to a subject a composition, comprising:
- hydrophobic drug prodrug thereof, salt thereof, isoform thereof, or a combination thereof
- cyclodextrin, prodrug thereof, salt thereof, or a combination thereof polyethylene glycol, propylene glycol, or combination thereof;
- a pharmaceutically acceptable carrier optionally, a pharmaceutically acceptable carrier.
- composition comprising:
- hydrophobic drug prodrug thereof, salt thereof, isoform thereof, or a combination thereof
- cyclodextrin, prodrug thereof, salt thereof, or a combination thereof polyethylene glycol, propylene glycol, or combination thereof;
- a pharmaceutically acceptable carrier optionally, a pharmaceutically acceptable carrier.
- composition comprising:
- hydrophobic drug prodrug thereof, salt thereof, isoform thereof, or a combination thereof
- cyclodextrin, prodrug thereof, salt thereof, or a combination thereof polyethylene glycol, propylene glycol, or combination thereof;
- a pharmaceutically acceptable carrier optionally, a pharmaceutically acceptable carrier
- hydrophobic drug is present in an administration amount of 0.1 - 500 mg/kg; and wherein cyclodextrin is present in an administration amount of 1000 - 40,000 mg/kg.
- HDACi Although HDACi's are of significant interest as drugs, the major drawback to their use is the intrinsic toxicity associated with blocking nuclear targets that influence a large number of cellular pathways such as apoptosis, cell-cycle arrest, necrosis, autophagy and differentiation (to name just a few), and the like.
- HDAC3 is needed for Purkinje cell function, which is compromised in a wide range of cerebellar disorders. This has raised the issue about whether HDACi can be used to treat neurodegenerative disease, especially long-term treatments that are often required to substantially improve survival and neurobehavioral symptoms.
- Vorinostat received FDA exemption for an exploratory Phase I study for NPC, which is currently accruing patients 18 years and older (https://clinicaltrials.gov/ct2/show/NCT02124083). This was in the absence of information on the efficacy of vorinostat (or other HDACi's) in animal models and their potential for treating neurological disease (in either models or patients), especially in balance with the caveats of the effects of HDACi on cerebellar function. Our data suggest vorinostat, if used alone, does not penetrate the mouse brain sufficiently to either directly stimulate NPCl transcription and therefore protein expression in the brain or indirectly enhance NPCl protein and Purkinje cell function in the cerebellum.
- HPBCD injected into the CNS is also being evaluated as a therapy for NPC. Notably CNS delivery is associated with higher risk.
- Ommaya reservoirs implanted in the brain to directly deliver drug were discontinued
- TCF triple combination formulation
- HDACi in the TCF may protect through increased NPC 1 level by a direct increase of transcript and protein. Indirect mechanisms (such as increased expression of heat shock proteins and chaperone that stabilize NPCl protein without increasing Npcl transcript) may also play a role. In this regard HDACi in TCF may have higher restorative efficacy in treating neurological disease than chaperone therapies alone.
- HPBCD is GRAS and no adverse effects have been reported so far about their use in limited number of NPC patients. PEG is also well tolerated.
- Our current dose, in some embodiments, of vorinostat of 150 mg/m is substantially below the daily adult dose and frequency (6-900 mg/m daily for 5 to 3 days for 21 days for hematological and solid tumors).
- our vorinostat dose in TCF is within the weekly pediatric dose but exceeds the daily pediatric dose of 99 mg/m (given iv daily for 28 days in cancer treatments). It is considered that dose modulations may be required for pediatric treatment. But in some embodiments, these are within 1.5 fold and may be accommodated by two consecutive days of half dose TCF administration followed by a suitable rest period. Different routes of treatment may also influence dose, but it is expected that the TCF will be applicable for treatment of both adult and pediatric disease.
- the formulation of the TCF was designed to be optimal for NPC treatment. However, it can be easily extended to other proteostatic/ lysosomal disorders with or without neurological deficit and accompanying lipid accumulation and protein aggregation in cells and organs. Intraperitoneal HPBCD alone has been shown to be beneficial in a murine model of Alzheimer's disease. Although the mechanistic basis by which intraperitoneal HPBCD improves neurological disease remains unknown, it is reasonable to expect that the TCF that stimulates functional HDACi activity in the brain could provide significant treatment value for Alzheimer's. Other neurological diseases like Parkinson's, where cerebellar functions are compromised may also benefit from the TCF.
- Figure 1 shows analyses of comparative composition and an exemplary embodiment in inmfl64lick ⁇
- Figure 2 shows analyses of comparative composition and an exemplary embodiment in neurodegeneration and animal survival.
- Figure 3 shows a murine neurobehavorial disease score for NPC and analyses of comparative composition and an exemplary embodiment Npcl nm ⁇ 64 mice.
- Figure 4 shows analyses of comparative composition and an exemplary embodiment in liver inflammation in Npcl nmfl 64 mice.
- Figure 5 shows analyses of comparative composition and an exemplary embodiment in plasma, liver, and brain in Npcl nmfl 64 mice.
- Figure 6 presents one embodiment of a proposed model for TCF in treating cerebral and systemic disease.
- Figure SI presents data showing the acetylation levels of histone H3 and H4 in the brain of NPC mice were similar to healthy mice.
- Figure S2 presents a qPCR analysis of various inflammatory markers as indicated in the brain of drug treated Npcl nmf764 mice at 100 days.
- Figure S3 presents neurobehavioral scoring of NPC and healthy mice and operator independence.
- compositions and methods are disclosed herein, which provide several advantages.
- One advantage relates to significantly improved brain protein acetylation and preservation of neurites and Purkinje cells, broadly delayed symptoms of neurodegeneration and extended mouse life span from four to almost nine months.
- Another advantage relates to increased plasma concentration of an HDAC inhibitor.
- Another advantage relates to increased plasma concentration of Npcl transcript levels in both the liver, which is an index of systemic expression, and the brain.
- Another advantage relates to increased levels of NPC 1 protein in preserved cerebellar Purkinje cells.
- Another advantage relates to improved HDACi access across the blood brain barrier and significant attendant benefit against cerebral disease as well as cerebellar Purkinje cells and neurites.
- Another advantage relates to improved dose efficacy, which is a major challenge in HDACi therapy.
- Another advantage relates to improved therapeutic treatments for both cerebral and systemic disease in Niemann Pick Type C and other challenging disorders.
- the hydrophobic drug is not particularly limiting, and it may be in any form.
- Non-limiting examples of the drug form include the free compound, salt thereof, prodrug thereof, isoform thereof, or any combination thereof.
- the hydrophobic drug is an HDAC inhibitor, or a combination of two or more HDAC inhibitors.
- the HDACi is a Class I, Class Ila, Class lib, or Class IV HDAC inhibitor, or a combination thereof. In some embodiments, the HDACi is a Class I HDAC inhibitor of the type HDAC1, HDAC2, HDAC3, or HDAC8, or a combination thereof.
- the HDACi is a Class Ila HDAC inhibitor of the type HDAC4, HDAC5, HDAC7, or HDAC9, or a combination thereof.
- the HDACi is a Class lib HDAC inhibitor of the type HDAC6 or HDAC 10, or a combination thereof.
- the HDACi is a Class IV HDAC inhibitor of the type HDACI 1.
- the HDACi is a Class I or Class II HDAC inhibitor, or a combination thereof.
- HDAC inhibitors include hydroxamic acids, aliphatic acids, hydroxamates, benzamides, thiophene benzamide, butyrates, sodium butyrate, phenylbutyrate, cyclic tetrapeptide, trapoxin B, depsipeptide, cyclic peptide, electrophilic ketones, dacinostat/LAQ-824, NVP-LAQ824, givinostat/ITF-2357, bufexamac, pyroxamide, sulforaphane, trichostatin A (TSA) and analogs thereof, miglustat/ OGT-918, SAHA/vorinostat/MK-0683/Zolinza, entinostat/MS-275, panobinostat/LBH-589, droxinostat/CMH, quisinostat/JNJ-26481585, PCI-24781/CRA-024781, romidepsin /FK228
- the HDACi is a hydroxamate, hydroxamic acid, or combination thereof.
- the HDACi is a hydroxamate, hydroxamic acid, vorinostat (SAHA), belinostat/PXDIOl, LAQ824, panobinostat/LBH-589, givinostat/ITF2357, pyroxamide, trichostatin A, CBHA, or any combination thereof.
- SAHA vorinostat
- belinostat/PXDIOl belinostat/PXDIOl
- LAQ824 panobinostat/LBH-589
- givinostat/ITF2357 pyroxamide
- trichostatin A CBHA, or any combination thereof.
- the HDACi is vorinostat.
- the dosage amount of the hydrophobic drug is not particularly limiting. In some embodiments,
- the hydrophobic drug may be administered in an amount ranging from 0.1 - 500 mg/kg. This range includes all values and subranges therebetween, including 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg/kg, or any combination thereof.
- the dosage amount is based on a 50 mg/kg murine dose, and may be scaled for human treatment, as is known. For example, a 50 mg/kg 2
- murine dose may scale to 150 mg/m in children. Such scaling is well within the skill of the artisan and may be suitably applied to any dosage for any compound or compounds herein.
- cyclodextrin is not particularly limiting.
- Some non-limiting examples of cyclodextrin include one or more of hydroxypropyl-P-cyclodextrin, 2-hydroxypropyl-P-cyclodextrin, dimethyl- ⁇ - cyclodextrin, hydroxypropyl-a-cyclodextrin, hydropropyl-Y-cyclodextrin, or any combination thereof.
- the cyclodextrin is ⁇ -cyclodextrin.
- the cyclodextrin is hydroxypropyl-P-cyclodextrin.
- the cyclodextrin is 2-hydroxypropyl-P-cyclodextrin.
- the cyclodextrin may have any average molecular weight ranging, for example from about 970 to 6,000 Da depending, for example, on the type of cyclodextrin ( ⁇ , ⁇ , or ⁇ ) and whether it is crosslinked or uncrosslinked, substituted or unsubstituted, the degree of substitution, and the like, as is known in the art. Accordingly, the cyclodextrin may be crosslinked or uncrosslinked, substituted or unsubstituted, or any combination thereof.
- the aforementioned range includes all values and subranges therebetween, including about 970, 972, 980, 990, 1000, 1010, 1030, 1050, 1070, 1090, 1100, 1120, 1140, 1160, 1180, 1200, 1250, 1300, 1350, 1370, 1380, 1390, 1395, 1400, 1410, 1420, 1430, 1440, 1460, 1480, 1500, 1600, 1800, 2000, 2500, 3000, 3500, 4000, 5000, 6000 Da, or combination thereof.
- the cyclodextrin is 2-hydroxypropyl-P-cyclodextrin and may have an average molecular weight of 1396 Da.
- the cyclodextrin is a- cyclodextrin and may have an average molecular weight of 973 Da. In some embodiments, the cyclodextrin is ⁇ -cyclodextrin and may have a molecular weight of 1 135 Da. In some embodiments, the cyclodextrin is ⁇ -cyclodextrin and may have a molecular weight of 1297 Da.
- the cyclodextrin may have a degree of substitution, or average number of substituents per glucopyranose unit, ranging from 0.5 to 3. This range includes any value or subrange therebetween, including 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, or any combination thereof.
- the cyclodextrin is preferably water soluble.
- the cyclodextrin may have a water solubility at 25 °C from about 10 mg/ml and higher. This range includes all values and subranges therebetween, including about 10, 20, 40, 60, 100, 200, 300, 400, 500, 600 mg/ml and higher.
- the cyclodextrin is 2-hydroxypropyl-P-cyclodextrin, having an average molecular weight of 1396 Da and an average degree of substitution of 0.67 hydroxypropyl groups per glucopyanose unit.
- the dosage amount of the cyclodextrin is not particularly limiting.
- the cyclodextrin may be administered in an amount ranging from 1000 - 40,000 mg/kg.
- This range includes all values and subranges therebetween, including 1000, 1200, 1400, 1600, 1800, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3500, 4000, 5000, 6000, 7000, 8000, 9000, 10,000, 20,000, 30,000, 40,000 mg/kg, or any combination thereof.
- the dosage amount is based on a 2000 mg/kg murine dose, and may be scaled for human treatment, as is known.
- polyrotaxanes are a new class of supramolecular materials in which ⁇ -cyclodextrins are threaded along a polymer chain capped with bulky terminal moieties. Polyrotaxanes are known and have been cited in the literature as potentially useful therapeutics to combat cholesterol accumulation in the treatment of NPC.
- Non- limiting examples of polyrotaxanes include 2- hydroxypropyl-P-cyclodextrin/plurionic-based polyrotaxanes, biocleavable plurionic/p-cyclodextrin polyrotaxanes, and the like. These and other examples of polyrotaxanes are disclosed in Tamura, A. & N. Yui, Scientific Reports 4: 4356 (2014) and Mondjinou, Y.A., et al, Biomacromolecules 14: 4189-4197 (2013), incorporated herein by reference.
- polyethylene glycol and propylene glycol are not particularly limiting. In some embodiments, polyethylene glycol is used.
- the molecular weight of the polyethylene glycol or polypropylene glycol is not particularly limiting.
- the average molecular weight may range from 100 to 6000 Da. This range includes all values and subranges therebetween, including 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1200, 1400, 1600, 1800, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3500, 4000, 5000, 6000 Da, or any combination thereof.
- polyethylene glycol is used, and the average molecular weight may range from 100 to 6000 Da. This range includes all values and subranges therebetween, including 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1200, 1400, 1600, 1800, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3500, 4000, 5000, 6000 Da, or any combination thereof.
- polyethylene glycol having an average molecular weight of 100 - 1000 Da is used. In some embodiments, polyethylene glycol having an average molecular weight of 200-600 is used. In some embodiments, polyethylene glycol having an average molecular weight of 400 is used.
- the amount of polyethylene glycol is not particularly limiting.
- the amount of polyethylene glycol may suitably range from 1 to 80% of the composition by weight. This range includes all values and subranges therebetween, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80%, or any combination thereof, based on the weight of the composition.
- hydrophobic drug : cyclodextrin polyethylene glycol or propylene glycol
- the hydrophobic drug : cyclodextrin polyethylene glycol or propylene glycol molar ratio
- Each of these ranges independently includes all values and subranges therebetween.
- the 1-100 range given for the hydrophobic drug independently includes all values and subranges therebetween, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, or any combination thereof.
- the 1-1000 range given for the polyethylene glycol or polypropylene glycol independently includes all values and subranges therebetween, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, or any combination thereof.
- the hydrophobic drug : cyclodextrin : polyethylene glycol or propylene glycol molar ratio may be 1-100 : 1-100 : 1-1000.
- Each of these ranges independently includes all values and subranges therebetween.
- the 1-100 range given for the hydrophobic drug independently includes all values and subranges therebetween, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, or any combination thereof.
- the 1-100 range given for the cyclodextrin independently includes all values and subranges therebetween, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, or any combination thereof.
- the 1-1000 range given for the polyethylene glycol or polypropylene glycol independently includes all values and subranges therebetween, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, or any combination thereof.
- the composition has a hydrophobic drug : cyclodextrin : polyethylene glycol molar ratio of 1-10 : 1-1000 : 1-1000. In some embodiments, the composition has a hydrophobic drug : cyclodextrin : polyethylene glycol molar ratio of 1-10 : 1-100 : 1-1000. In some embodiments, the composition has a hydrophobic drug : cyclodextrin : polyethylene glycol molar ratio of 1 : 1-100 : 1-500. In some embodiments, the composition has a hydrophobic drug : cyclodextrin : polyethylene glycol molar ratio of l : 1-10 : 1-100.
- the composition has a hydrophobic drug : cyclodextrin : polyethylene glycol molar ratio of 1 : 5-100 : 10-100. In some embodiments, the composition has a hydrophobic drug : cyclodextrin : polyethylene glycol molar ratio of 1 : 5-10 : 10-100.
- the composition includes HDACi, cyclodextrin, and polyethylene glycol in a HDACi : cyclodextrin : polyethylene glycol molar ratio of 1-100 : 1-1000 : 1-1000. In some embodiments, the composition includes HDACi, cyclodextrin, and polyethylene glycol in a HDACi : cyclodextrin : polyethylene glycol molar ratio of 1-100 : 1-100 : 1-1000.
- the composition includes HDACi, 2-hydroxypropyl-P-cyclodextrin, and polyethylene glycol 400 in a HDACi : 2-hydroxypropyl-P-cyclodextrin : polyethylene glycol 400 molar ratio of 1-100 : 1-1000 : 1-1000.
- the composition includes HDACi, 2- hydroxypropyl-P-cyclodextrin, and polyethylene glycol 400 in a HDACi : 2-hydroxypropyl-P- cyclodextrin : polyethylene glycol 400 molar ratio of 1-100 : 1-100 : 1-1000.
- the composition includes vorinostat, 2-hydroxypropyl-P-cyclodextrin, and polyethylene glycol 400 in a vorinostat : 2-hydroxypropyl-P-cyclodextrin : polyethylene glycol 400 molar ratio of 1-100 : 1-1000 : 1-1000.
- the composition includes vorinostat, 2-hydroxypropyl-P-cyclodextrin, and polyethylene glycol 400 in a vorinostat : 2- hydroxypropyl-P-cyclodextrin : polyethylene glycol 400 molar ratio of 1-100 : 1-100 : 1-1000.
- the molar ratio of hydrophobic drug : cyclodextrin is not particularly limiting, and may suitably range from 0.001 to 100. This range includes all values and subranges therebeetween, including 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, or any combination thereof.
- the molar ratio of hydrophobic drug : polyethylene glycol is not particularly limiting, and may suitably range from 0.001 to 100. This range includes all values and subranges therebeetween, including 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, or any combination thereof.
- the composition has a hydrophobic drug : cyclodextrin molar ratio of less than 0.2, ⁇ 0.13, less than 0.13, 0.001 to less than 0.2, 0.001 to ⁇ 0.13, 0.001 to less than 0.13, 0.01 to 0.15, 0.01 to ⁇ 0.13, 0.01 to less than 0.13, 0.01 to ⁇ 0.1, 0.01 to less than 0.1, 0.01 to ⁇ 0.065, 0.01 to less than 0.065, about 0.13, or about 0.065 as appropriate.
- the composition has a HDACi : cyclodextrin molar ratio of less than 0.2, ⁇ 0.13, less than 0.13, 0.001 to less than 0.2, 0.001 to ⁇ 0.13, 0.001 to less than 0.13, 0.01 to 0.15, 0.01 to ⁇ 0.13, 0.01 to less than 0.13, 0.01 to ⁇ 0.1, 0.01 to less than 0.1, 0.01 to ⁇ 0.065, 0.01 to less than 0.065, about 0.13, or about 0.065 as appropriate.
- the composition has a vorinostat : 2-hydroxypropyl-P-cyclodextrin molar ratio of less than 0.2, ⁇ 0.13, less than 0.13, 0.001 to less than 0.2, 0.001 to ⁇ 0.13, 0.001 to less than 0.13, 0.01 to 0.15, 0.01 to ⁇ 0.13, 0.01 to less than 0.13, 0.01 to ⁇ 0.1, 0.01 to less than 0.1, 0.01 to ⁇ 0.065, 0.01 to less than 0.065, about 0.13, or about 0.065 as appropriate.
- the composition has a hydrophobic drug : polyethylene glycol or propylene glycol molar ratio of less than 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.15, 0.01, or any combination thereof.
- the composition has a hydrophobic drug : polyethylene glycol molar ratio of less than 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.15, 0.01, or any combination thereof.
- the composition has a HDACi : polyethylene glycol 400 molar ratio of less than 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.15, 0.01, or any combination thereof.
- the composition has a vorinostat: polyethylene glycol 400 molar ratio of less than 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.15, 0.01, or any combination thereof.
- the composition does not contain fibroblasts, other biological organisms, or the like.
- the composition may or may not contain DMSO. In some embodiments, the composition does not contain DMSO.
- the composition may be administered as a single dose, or the composition components may be administered separately.
- cyclodextrin may be administered separately from the hydrophobic drug and polyethylene glycol or polypropylene glycol.
- the method includes administering cyclodextrin before or after administering the hydrophobic drug and polyethylene glycol or polypropylene glycol.
- the method includes administering cyclodextrin before administering the remaining components.
- the method includes administering the hydrophobic drug separately.
- the composition is administered as a single admixture.
- the timing of the administration is not particularly limiting. For example, administering may occur once or more than once.
- the administering is carried out periodically or substantially periodically, for example, daily, weekly, monthly, a multiple thereof, a fraction thereof, or a combination thereof. In some embodiments, the administering is carried out daily, a multiple thereof, a fraction thereof, or a combination thereof. In some embodiments, the administering is carried out weekly, a multiple thereof, a fraction thereof, or a combination thereof. In some embodiments, the administration may occur regularly, e.g., every week throughout the duration of treatment, or it may occur irregularly, e.g., once a week for a few weeks, then twice a week or not at all for a few weeks, etc. Similarly, in some embodiments, a rest period of non-administration may occur between administrations. The rest period may occur regularly or irregularly.
- Non-limiting examples of diseases include one or more of disease of the brain, cerebral injury, brain and systemic disease, brain and systemic disease for which the liver read out, neurological disease, cerebral injury, disease associated with loss or reduction of level of calbindin, neurotoxicity, Niemann-Pick disease, Niemann-Pick Type C disease, neurodegenerative disorder, TBI, autism, Alzheimer's, cutaneous T cell lymphoma, B cell lymphoma, inflammatory disorder, neuroinflammatory disorder, neuroinflammation due to lysosomal storage disorder, lysosomal storage disorder, Sezary syndrome, Gliobastoma multiforme, Myeloddysplastic syndrome, non small cell lung cancer, HIV, non-neurological disease, brain tumor, disease responsive to treatment with histone deacetylase (HDAC) inhibitor, disease involving plasma concentration of vorinostat (SAHA), disease responsive to treatment with SAHA, disease where effect of SAHA is observed in animal model, encephalopathy, epilepsy, cerebrovascular disease
- HDAC histone de
- polydystrophy/mucolipidosis IIIA MPSI Hurler syndrome, MPSI Scheie syndrome, MPS I Hurler- Scheie syndrome, MPS II Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, MPS IX hyaluronidase deficiency, MPS VI Maroteaux-Lamy, MPS VII Sly syndrome, mucolipidosis I/sialidosis, multiple sulfatase deficiency, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, Salla disease, Tay-Sachs, Wolman disease, advanced solid tumors, treatment-resistant multiple myeloma, chronic lymphocytic leukemia or lymphoma, advanced hematological indications, multiple myeloma, solid refractory tumors, polycythemia vera, essential thrombocythemia, myelofibrosis, acute myocardial in
- the composition can be administered to a human or other mammalian patient by itself or in a pharmaceutical composition where it may be mixed with suitable carriers or excipients at doses to treat or ameliorate the disease or symptom thereof for which treatment is administered.
- a therapeutically effective dose may refer to that amount of the composition sufficient to treat or ameliorate the disease or symptom thereof for which treatment is administered, it being understood that such treatment or amelioration may occur at different concentrations such that a person skilled in the art could determine the required dosage of the composition in light of the teachings herein.
- Therapeutically effective doses may be administered alone or as adjunctive therapy in combination with other treatments.
- the route of administration is not particularly limited.
- suitable routes of administration may, for example, include oral, rectal, transmucosal, buccal, intravaginal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, and optionally in a depot or sustained release formulation.
- parenteral delivery including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, and optionally in a depot or sustained release formulation.
- parenteral delivery including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, and optionally in a depot or sustained release formulation.
- one may administer the composition in
- the composition may be administered systemically, whereas in other embodiments the composition may be administered locally.
- systemic administration may be oral, by injection, intravenous, intra-arterial, subcutaneous, intramuscular, intrathecal, or intraperitoneal injection.
- Systemic administration also may include transdermal or inhalational administration.
- the composition may be administered locally.
- local administration may be accomplished by local injection into the body part that is particularly affected, for example by injecting or infusing the composition directly into the CNS or brain, e.g., intrathecally, or into the ocular space.
- local administration may be accomplished by implanting a sustained-release device such as a pump or micropump, or a sustained-release implant, such as a bead or gel that contains the composition and slowly releases it into the desired area over time.
- compositions and/or compounds may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, dragee-making, levitating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
- the pharmaceutical compositions thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds or composition into preparations, which can be used pharmaceutically. Proper formulation may be dependent upon the route of administration chosen.
- a composition intended for ocular administration might include an aqueous carrier and one or more of viscosity agent, ocular buffer, pH buffer, isotonic buffer, and the like.
- any combination of one or more the compounds, salts thereof, resonance forms thereof, prodrugs, metabolites, isotopically-labeled compounds, tautomers, isomers, and/or atropisomers is possible in the composition.
- composition and/or compounds may be formulated in aqueous solutions, preferably in physiologically compatible buffers, such as Hank's solution, Ringer's solution, or physiological saline buffer.
- physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
- penetrants appropriate to the barrier to be permeated may be suitably used in the formulation. Such penetrants are known in the art.
- composition and/or compounds can be formulated readily by combining the active compounds and/or composition with pharmaceutically acceptable carriers well known to those in the art.
- Such carriers enable the compounds and/or composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
- Pharmaceutical preparations for oral use can be obtained by combining the compound and/or composition with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
- Suitable excipients include but are not limited to fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,
- disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
- Dragee cores are provided with suitable coatings.
- suitable coatings may be used in some embodiments, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
- Dyestuffs or pigments may be added to the tablets or dragee coatings if desired for identification or to characterize different combinations of active compound or composition doses.
- compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
- the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- the active compounds and/or composition may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or the like.
- stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
- compositions may take the form of tablets or lozenges formulated in conventional manner.
- the compounds and/or composition may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
- the compounds and/or composition may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
- Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, optionally with an added preservative.
- the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- compositions for parenteral administration include aqueous solutions of the active compounds or composition in water-soluble form.
- suspensions of the active compounds or composition may be prepared as appropriate oily injection suspensions.
- suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
- Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as polyionic block (co)polymer, sodium carboxymethyl cellulose, sorbitol, or dextran.
- the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds.
- the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
- the compounds and/or composition may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
- the compounds and/or composition may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- the compounds and/or composition may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
- compositions also may include suitable solid- or gel- phase carriers or excipients.
- suitable solid- or gel- phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and pharmaceutically acceptable polymers.
- the compounds may be provided as salts with pharmaceutically compatible counterions.
- Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.; or bases.
- Non-limiting examples of pharmaceutically acceptable salts include sodium, potassium, lithium, calcium, magnesium, iron, zinc, hydrochloride, hydrobromide, hydroiodide, acetate, citrate, tartrate and maleate salts, and the like.
- compositions contain the active compound or compounds in an effective amount to achieve their intended purpose.
- a therapeutically effective amount means an amount effective to prevent or inhibit development or progression of a disease in a subject, who is known to have or suspected of having or at risk of having the disease. Determination of the effective amounts is within the capability of those skilled in the art in light of the teachings herein.
- Vo Vorinostat
- PEG polyethylene glycol
- TCF neurobehavioral scoring system
- For molecular, biochemical, histological analyses at least 3-4 mice were used with at least two technical replicates in each assay. Animals were randomly assigned to treatment groups. Equal numbers of males and females were included in each group. Two independent PK experiments in mice were done each containing 5 mice in a group. The reliability and robustness of neurobehavioral scoring system was evaluated by two blinded investigators.
- HPBCD powder HI 07
- PEG400 All fine chemicals including HPBCD powder (HI 07) and PEG400 were obtained from Sigma (St Louis, MO, USA), unless otherwise indicated.
- Vorinostat was from Selleck Chemicals (Houston, TX, USA).
- DMEM and trypsin were from Life Technologies (New York, NY, USA).
- FBS was procured from ATCC.
- Oligonucleotides for qPCR were purchased from Invitrogen (Carlsbad, CA, USA).
- Npcl nm f 164 BALB/c strain carrying an aspartate to glycine mutation at position 1005
- Vorinostat (50mg/Kg)-Vorinostat was first dissolved in DMSO (lOOmg/ml) and then diluted with 9 volume of Polyethylene Glycol 400 (PEG). This drug solution was named as 'solution A'. Solution A was diluted with equal volume of water where the final concentration of each component was as follows; Vorinostat, 5mg/ml; DMSO, 5% and PEG, 45%. Mice were given weekly intraperitoneal (i.p) injections starting at 21 days. Vorinostat (100mg/Kg)- Vorinostat was first dissolved in DMSO (200mg/ml) and then mixed with 9 volumes of PEG. Rest of the methods and injections plan were as described above.
- HPBCD 4000mg/Kg
- HPBCD 40% HPBCD solution prepared in water. Mice were given weekly i.p injections starting at 7 days.
- HPBCD 2000mg/Kg
- HPBCD 20% HPBCD solution prepared in water. Mice were given weekly i.p injections starting at 7 days.
- TCF Vaninostat, 50mg/Kg +HPBCD, 2000mg/Kg, DMSO, 5%+ PEG, 45%
- each component in the formulation was as follows; Vorinsotat, 5mg/ml; DMSO 5%; PEG, 45%; and HPBCD, 20%. Mice were given two i.p doses of HPBCD (2000mg/Kg) at 7 and 15 days. Starting from 21 days mice were given weekly i.p injection of TCF. Vehicle control (5% DMSO and 45% PEG) - It was made by mixing 1 volume of DMSO with 9 volume of PEG and then diluted with equal volume of water. Mice were given weekly i.p injection starting from 21 days. All drug solutions were stored at -80°C. Fresh vials of frozen stock were thawed for injection on different days.
- mice were sacrificed at 100 days and organs were harvested. For survival studies, injections were continued until the death. Death was defined when animal was either found dead or lost >30% of maximum weight or unable to eat or drink even after providing DietGel 7A (Clear H 2 0, Portland, ME). Quantitative PCR
- Quantitative PCR was performed using Power SYBR Green RNA-to-Cx 1-Step Kit and an ABI Prism 7500 Fast real-time PCR system (Applied Biosystems, Grand Island, USA). Gapdh (Glycer aldehyde 3-phosphate dehydrogenase) was used as an endogenous control. The relative amount of transcript was determined using comparative Cx method. Untreated Npcl +/ ⁇ served as a reference.
- mice were sacrificed by asphyxiation using C0 2 .
- Harvested organs were immersed fixed in 10% neutral buffered formalin ( ⁇ 4% formaldehyde) for 24 hrs at RT.
- the organs were
- Paraffin-embedded tissue sections (4-5 ⁇ ) were dewaxed in xylene and alcohol.
- Calbindin antigen retrieval was done by pre- incubating deparaffmized samples with 0.05% proteinase K (Dako, Germany) in 50mM Tris-HCl (pH 7.5) for 8 min at RT.
- CTSS and NPC1 was retrieved by boiling the sections in acidic condition for 30 min. Blocking was done either with 2% goat serum (for calbindin and NPC1) or 2% rabbit serum (for cathepsin S) for 30 min at RT.
- Sections were incubated with anti-calbindin (1 : 1000, C9848, Sigma), anti-cathepsin S (20 ⁇ g/ml, M-19, Santa Cruz Biotechnology), anti-NPCl (custom made against human NPC1 protein, 20 ⁇ g/ml) overnight at 4 °C.
- the appropriate FITC or TRITC- conjugated secondary IgG (MP Biomedicals, Solon, OH, USA) antibodies were used at 1 :200 dilution. Sections were subsequently washed with PBS containing DAPI (O ⁇ g/ml). Vectashield (Vector laboratories) was used as mounting medium and processed for fluorescence microscopy.
- Npcl nmf164 mice (6-7 weeks) were injected with either Vorinostat (50mg/kg) or TCF through i.p route. Mice were sacrificed 1 hpi (1 hour post-injection) by asphyxiation using C0 2 . After homogenization of tissue, Histones were extracted using EpiQuik Total Histone extraction kit (Epigentek, NY, USA) as per manufacturer's instructions. Antibodies to Histone H3 (Lysl4) and H4 (Lys5/8/12/16) from Millipore (CA, USA) were used in western blotting.
- Ear pinna was cleaned with 70% alcohol and 2-3 small pieces (3> ⁇ 3 mm) were chopped and placed in 70% alcohol for 2 min and transferred to DMEM. Tissues were cut into small pieces and 2 ml of 0.25%) trypsin were added, vigorously vortexed for 2 min and incubated at 37 °C with vortexing every 10 min. Trypsin was inactivated by adding 2ml of culture media
- fibroblasts (4x l0 4 ) were plated in 24 well plate containing glass slide. Npcl nm ⁇ 164 fibroblasts were treated with 5 ⁇ vorinostat for 48 hrs. Cells incubated with 0.025% DMSO served as vehicle control. Cells were fixed with 4% paraformaldehyde followed by incubation with filipin (100 ⁇ g/ml) to stain cholesterol. Slides were mounted using Vectashield (Vector laboratories) and processed for fluorescence microscopy.
- Photometrix cooled CCD camera (CH350/LCCD) driven by DeltaVision software from Applied Precision (Seattle, WA, USA). DeltaVision software (softWoRx) was used to deconvolve these images. Images are single optical sections. Images were analyzed using ImageJ software (NIH, MD, USA).
- Npcl +/nmf764 mice (age 6-7 weeks) were injected with either vorinostat (50mg/kg) in PEG or TCF through i.p route. Mice were sacrificed 1 hpi by asphyxiation using C0 2 . Total blood was collected through cardiac puncture in the presence of ⁇ heparin and transferred to K 2 EDTA microtainer tubes (VWR International, Chicago, IL, USA). Blood was immediately spun at 1500g at 4°C for 15 min. Plasma was transferred to a separate tube, immediately flash-frozen in liquid nitrogen and stored at -80°C until analyzed.
- the data were acquired in positive electrospray ionization (ESI) mode by monitoring the following transitions for Vorinostat: 265- ⁇ 232 with collision energy of 5 V, 265 172 with collision energy of 5 V, and 265 - 55 with collision energy of 40 V.
- ESI positive electrospray ionization
- data were acquired by monitoring the following transitions: 270- ⁇ 237 with collision energy of 5 V, 270 172 with collision energy of 5 V, and 270- ⁇ 55 with collision energy of 40V.
- the jet stream ESI interface had a gas temperature of 325°C, gas flow rate of 8 L/minute, nebulizer pressure of 45 psi, sheath gas temperature of 275°C, sheath gas flow rate of 7 L/minute, capillary voltage of 4000 V, and nozzle voltage of 1000 V. All data were acquired and analyzed using Agilent MassHunter software (version B.06). In the final drug calculation in mice plasma, contribution of heparin to total volume was subtracted before plotting the numbers.
- Fig. 3A A modified version of previously described method (Carroll et al., 2010) was used for assessing the neurobehavioral functions in mice.
- Six different parameters (Fig. 3A) associated with neurobehavioral functions of mice were assessed. Each mouse was assessed individually in an observation box (length, 31.8 cm, width, 19.8 cm and height, 10.5 cm) with a grid floor.
- a mouse was assessed for tremor (0 and 2), body position (0, 1 and 2), gait (0, 1 and 2), grooming (0, 1 and 2), limb tone (0,1 and 2), and weight loss (0, 1, 2 and 3). More specific descriptions of the assessments along with the equivalent human symptoms are provided in the Fig. 3A.
- a mouse received a score 0 if no symptom was observed and score 2 when the most severe impairment in the function was seen.
- a mouse was given score 0 for weight loss below 5%, 1 for 5- 10%, 2 for >10 and up to 20%, and 3 for >20 up to 30%>.
- a cumulative score of 0-3 correlate with no neurobehavioral impairment and a score of 13 is the most impaired neurobehavioral function.
- NPC1 a BALB/c strain (Alam et al., 2014) derived from the recently described Npcl nmf764 in C57BL/6J (Maue et al., 2012).
- the mutation is a single nucleotide change (A to G at cDNA bp 3163) resulting in an aspartate to glycine change at position 1005 (D1005G), which destabilizes the protein resulting in partial loss of activity and levels of NPC1.
- Disease progression in this model (monitored over -120 days) closely mimics human disease, where neurodegeneration is the principal cause of death.
- Fig. 1 A skin fibroblasts from mutant Npcl nm ⁇ 164 animals express lower levels of NPC1 protein compared to heterozygote or wild type counterparts. Mutant fibroblasts therefore accumulate high levels of cholesterol, which are reduced in presence of vorinostat (Fig. IB)
- Vorinostat is poorly soluble in aqueous solution and therefore is classified as a
- BCS Biopharmaceutical Classification System
- mice were given a once weekly dose of TCF or 4000 mg/Kg HPBCD (also referred to as 2x HPBCD since it represents twice the levels incorporated in TCF), 50 mg/Kg vorinostat in PEG or a mock injection (PEG+DMSO).
- 2 x HPBCD conferred a minor protection of Purkinje cell, the mechanism for which is unknown but which is not due to HPBCD crossing the BBB.
- Analyses of three inflammatory markers, GFAP, ⁇ and CD68 suggested that 2 x HPBCD reduced their levels comparably to TCF and better than Vo in the brain (Fig. S2). This is again consistent with prior studies that HPBCD is partially effective in reducing neuroinflammation.
- vorinostat and HPBCD in TCF may act synergistically in reducing neuroinflammation, since the combination is far more efficacious than 2 x HPBCD (expected to be additive relative to HPBCD alone).
- TCF-treated animals can survive up to nine to ten months, which is notable in context that mice in this time frame are well into advanced adulthood.
- the improved survival of TCF-treated animals correlated with the action of the triple combination in stimulating vorinostat activity in the brain and preventing neurodegeneration.
- Clinically NPC disease is defined by major and minor symptomatic domains, whose severity has been scored to monitor the natural history of the disease using at least three different scales. Plasma biomarkers are emerging, but quantitative assessment of symptoms continues to be an important index of disease progression and their aggregation in a cumulative score provides a valuable overall outcomes measure.
- Fig. 3A murine neurobehavioral symptomatic score
- each of the six symptomatic parameters in the mouse was assigned to a major patient disease domain (ambulation, cognition, motor control and dysphagia), scored for severity in an indicated range. The sum of the individual scores provided the cumulate disease score, with a maximal possible disease score of 13.
- Fig. S3 Validation of scoring by independent blinded operators in both diseased and healthy animals is shown in Fig. S3.
- a cumulative score of 3 or higher was found to reliably flag onset of symptomatic disease.
- a threshold of 3 was encountered because older healthy animals often displayed poor grooming (particularly males) and slight impairment in limb tone (from days 100-140 days). It was nonetheless acceptable and using these criteria, an early cumulative disease score of 4- 5 reliably detected the onset of symptomatic disease in untreated animals at 77-84 days (Fig. 3A).
- TCF treatment appeared to delay disease onset by ⁇ 4 weeks reaching scores 4-5 at 105-112 days. At this time, vehicle or vorinostat alone treatment resulted in cumulative scores of 9-11, while
- 2xHPBCD yielded intermediate, cumulative scores of 6-8 (Fig. 3A).
- Vorinostat provided no consistent, significant advantage in any symptomatic read out in context of lifespan.
- TCF reduced the inflammatory markers CD68, ITGAX, ⁇ and CTSD, comparable to HPBCD although the presence of vorinostat in TCF appears to further reduce CD68 transcripts (Fig 4B-E). Vorinostat alone also had significant anti-inflammatory activity. These data suggested that vorinostat may reduce systemic disease without providing neurological benefit. Moreover, in conjunction with the findings in Fig. 2 and 3, they strongly support that vorinostat needs to be administered in the TCF form to also treat neurological disease and improve animal survival.
- mice treated with TCF within 1 hr, the concentrations is plasma were 2-3 fold (p ⁇ 0.05) higher than animals injected with vorinostat alone. Since disease progression extends over 120 days (in absence of treatment) we further examined evidence for direct mechanism of action at 100 days (which our survival and symptomatic data confirm corresponds to late stage disease).
- animals treated with TCF showed higher levels of stably expressed Npcl transcript in the liver at 100 days (Fig. 5B; as expected HPBCD alone had no effect on target Npcl expression).
- the TCF treatment significantly increased levels of Npcl transcript (Fig. 5C). But there was little or no effect on brain Npcl transcript levels after administration of either HPBCD or vorinostat in PEG.
- NPC 1 protein detected in western blots of cultured mouse skin fibroblasts isolated from wild type, Npcl +/nmfm (heterozygous mutant) and Npcl nmfm (NPC) mice, Loading control, tubulin.
- mice were administered with vorinostat at 50mg/kg (Vo, lx) or lOOmg/kg (Vo, 2x), vehicle i.p. once weekly or left uninjected. Number of mice as indicated.
- TCF Triple Combination Formulation
- FIG. 1 Murine neurobehavorial disease score for NPC and effects of the TCF in Npcl nmfl6 mice.
- Vo Vorinostat (50mg/Kg) in 45% PEG; 2xHPBCD, 2-hydroxypropyl beta cylcodextrin (4000mg/Kg); Vo, TCF, Triple Combination Formulation (HPBCD, 2000mg/Kg+ Vorinostat, 50mg/Kg+45% PEG), Vehicle, DMSO (5%)+PEG400 (45%). * p ⁇ 0.05 (treated vs untreated), **p ⁇ 0.05 (TCF vs 2xHPBCD).
- FIG. 4 Comparative analyses of Vo and TCF on liver inflammation in Npcl nmfl64 m ⁇ c .
- A Fluorescence micrographs showing the labeling of macrophages in the liver of Npcl nm ⁇ 164 mice. Liver sections (4-5 ⁇ ) from 100 days old mice were stained with anti-CTSS antibodies to stain macrophages (in red) which are indicated by white arrows. Macrophages were seen in abundance often in clusters in untreated NPC mice. Treatment with Vo reduced the clustering of macrophages. Foamy macrophages were barely seen in HPBCD and TCF treated NPC mice. CTSS, green; DAPI, blue. Original magnifications x40.
- Vorinostat 50mg/Kg in 45% PEG
- HPBCD 2-hydroxypropyl beta cylcodextrin (2000mg/Kg)
- TCF Triple Combination Formulation (HPBCD, 2000mg/Kg+ Vorinostat,
- A. Plasma Vo concentration in mice Npcl heterozygous mutant mice (Npcl +/nmf764 ) were injected with Vo or TCF through i.p route. Blood was sampled through cardiac puncture at 1 hpi and concentration of Vo in the plasma was determined by mass spectrometry. The data represent mean ⁇ SEM from two independent experiments (5 mice/group in each experiment). *p ⁇ 0.05, TCF vs Vo.
- B-C Quantitative PCR showing the amount of NPCl transcripts in (B) liver and (C) brain of drug treated Npcl +/nmf764 mice at 100 days. The fold change is relative to untreated healthy control (Npcl +/nmf164 ) mice. Each group consisted of 4-5 mice. *p ⁇ 0.05, TCF vs HPBCD.
- D Immunofluorescence micrograph of cerebellar sections showing labeling of NPCl protein in the Purkinje cells. Brain sections from 100 days old mice were stained using anti-NPCl antibodies. Prominent NPCl staining was seen in the Purkinje cells (stained in green) indicated by white arrows are evident in healthy control (Dl). Slight staining of NPCl was seen in the Vo treated mice (D2). Numerous Purkinje cells expressing NPCl protein were seen in the Purkinje cells of TCF treated mice. Micrographs shown are representative images of IX lobule of the cerebellum from 2 mice in untreated and 4 mice in TCF treated mice. 4 sections from each mouse were analyzed.
- NPCl green; DAPI, blue; original magnifications x40.
- D6 Semi-quantitative analyses of NPCl positive Purkinje cells. Number of NPCl positive Purkinje cells in cerebellar sections (4 sections per mouse, 2 mice in untreated and 4 mice in TCF treated group) was counted. The data represent the percentage of NPCl positive Purkinje cells relative to untreated healthy control mice (Npcl +/nmf764 ) which was set at 100%.
- Vo Vorinostat (50mg/Kg) in 45% PEG; HPBCD, 2-hydroxypropyl beta cylcodextrin (2000mg/Kg); TCF, Triple Combination Formulation (HPBCD, 2000mg/Kg+ Vorinostat,
- FIG. 6 Proposed model for TCF in treating cerebral and systemic disease.
- Vorinostat (Vo) solubilized in PEG when injected into the animals has poor solubility and reduced plasma exposure which significantly limits its penetration across the blood brain barrier (BBB).
- BBB blood brain barrier
- delivery of Vo in TCF leads to better solubility, low precipitation and high plasma exposure.
- TCF may also allow slow release of Vo from the complex.
- TCF also significantly improves its penetration across the blood BBB.
- Vo also directly or indirectly (through involvement of chaperones) stabilize and over express the mutant NPC1 protein.
- HPBCD and Vo in blood stream treat systemic disease whereas PEG helps in reducing endothelial inflammation by promoting plasma membrane repair.
- CBB Coomassie
- FIG. 1 qPCR analysis of various inflammatory markers as indicated in the brain of drug treated Npcl 111 " 164 mice at 100 days. Fold change shown is relative to average levels of transcripts detected in untreated healthy control (Npcl +/nmf764 ) mice. Gapdh was used as endogenous control. Each group consisted of 4-5 mice. The data represent mean ⁇ SEM. Vo, Vorinostat
- mice (6 Npcl nmf164 and 4 Npcl +/nmf164 , all males) from 8 weeks onwards until death.
- Investigators scored the mice on two different days (a day apart).
- Six different parameters namely, tremor, body position, gait, grooming, limb tone, weight were assessed on a cumulative score of 0-13. All parameters were scored on a scale of 0-2 except weight which was assessed on scale of 0-3. Score above 3 (baseline, shown by dotted line) suggested diseased state.
- Histone deacetylase inhibitors are approved as therapies for rare cancers. They are also of interest in neurodegenerative disorders with a paucity of therapies. However, brain function, and particularly cerebellar Purkinje cells require HDAC activity.
- the inventors examined a mouse model of a difficult-to-treat cerebellar disorder, Niemann Pick Type C, administered with a composition (TCF) containing the pan HDACi vorinostat, 2-hydroxylpropyl-beta-cyclodextrin (HPBCD), and polyethylene glycol (PEG).
- TCF composition
- HPBCD 2-hydroxylpropyl-beta-cyclodextrin
- PEG polyethylene glycol
- the TCF presents unique promise as superior therapy integrated to treat both cerebral and systemic disease in Niemann Pick Type C with potential for translation to other challenging disorders.
- any embodiment described herein can be readily accomplished, carried out, and/or further implemented with respect to any use, method, compound, composition, kit, obvious variant thereof, or any combination thereof.
Abstract
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WO2022051631A1 (en) * | 2020-09-03 | 2022-03-10 | University Of Notre Dame Du Lac | Therapy to stimulate hippocampal neural progenitors and adult neurogenesis |
KR20240007191A (en) * | 2021-05-06 | 2024-01-16 | 스페팜 아게 | pharmaceutical preparation |
CN114931630A (en) * | 2022-07-11 | 2022-08-23 | 齐鲁制药有限公司 | Ganglioside composition for subcutaneous injection and its use |
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