WO2007131329A1 - Traitement des troubles liés au dysfonctionnement du système ubiquitine-protéasome - Google Patents

Traitement des troubles liés au dysfonctionnement du système ubiquitine-protéasome Download PDF

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WO2007131329A1
WO2007131329A1 PCT/CA2007/000786 CA2007000786W WO2007131329A1 WO 2007131329 A1 WO2007131329 A1 WO 2007131329A1 CA 2007000786 W CA2007000786 W CA 2007000786W WO 2007131329 A1 WO2007131329 A1 WO 2007131329A1
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phosphatidylglycerol
disease
particles
liposomes
presenting
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PCT/CA2007/000786
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English (en)
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Arkady Mandel
Anthony Ernest Bolton
Yvonne Mairead Nolan
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Vasogen Ireland Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • This invention relates to medical treatments and compositions useful therein. More particularly, it relates to treatments of neurological disorders in which proteasome inhibition in neuronal cells is a significant causative factor, and compositions useful therein.
  • a normally functioning mammalian cellular system involves constant synthesis and degradation of intracellular proteins.
  • Eukaryotic cells are believed to have three different systems for accomplishing protein degradation.
  • There is the mitochondrial protease system by means of which mitochondrial proteases degrade most of the mitochondrial proteins.
  • mitochondrial protease system by means of which mitochondrial proteases degrade most of the mitochondrial proteins.
  • lysosome system through which lysosomes degrade membrane and endocytosed proteins
  • the ubiquitin-proteasome system which degrades most of the normal and abnormal intracellular proteins. Because it accounts for the degradation of at least 80% of all intracellular proteins, the ubiquitin-protease system is regarded as the major pathway of intracellular protein degradation. Accordingly, it is of great significance for cell biology.
  • Ubiquitin formerly known as "ubiquitous immunopoietic polypeptide, is an 8.5 kDa polypeptide, originally isolated from bovine thymus, as capable of inducing differentiation of thymus-derived T cells and bone marrow derived B cells. It was subsequently found in various cell types, and discovered to be the heat-stable polypeptide essential for the activity of the ATP-dependent proteolytic system in reticulocytes.
  • ubiquitin-proteasome system of protein degradation multiple moieties of ubiquitin first become enzymatically activated and attach to cellular proteins generating a polyubiquitin chain. Then the so-labeled proteins are recognized and degraded by the 26S proteasome complex.
  • the ubiquitin-proteasome system is highly specific and tightly regulated, primarily by ubiquitin protein ligases (E3) in the cell.
  • the ubiquitin-proteasome system affects a number of both positive and negative cell cycle regulators, and has been related to inflammation and to apoptosis. As regards inflammation, the ubiquitin-proteasome system has a major role in the activation of the transcription factor nuclear factor kappa beta (MF K ⁇ ), which leads to the expression of a number of inflammation related genes.
  • MF K ⁇ transcription factor nuclear factor kappa beta
  • Inhibitors of proteasome activity are known and have been proposed for therapeutic uses. They are of a variety of classes, including both synthetic and natural materials. Both in vitro and in vivo studies have shown antiproliferative effects of proteasome inhibitors, attributed to an increase in the activity of pro-apoptotic factors such as p53, p21 and Bax (see Adams, J., Palombella V. J., and Elliott P. J., Proteasome Inhibition: a New Strategy in Cancer Treatment, Invest. New Drugs, 2000; 18; 109-121 ). Examples include epoxomycin, a natural product, and MG-132, a peptide aldehyde inhibitor. They are proposed for use, for the most part, as cancer therapy adjuncts.
  • compositions of the present invention show potential effectiveness in the treatment of neurological disorders, in mammalian patients who have dysfunction of the ubiquitin-proteasome system as significant underlying factor.
  • These neurological disorders include dementia with Lewy bodies, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, frontotemporal dementia, Gerstmann-Straussler- Scheinker disease, spinocerebellar ataxias, spinal and bulbar muscular ataxia, dentatorubral and pallidoluysian ataxia, and Lafora disease.
  • a ubiquitin-proteasome system dysfunction related disorder selected from dementia with Lewy bodies, Pick's disease, progressive supranuclear palsy, corticobasal degeneration,
  • a ubiquitin- proteasome system dysfunction related disorder selected from dementia with Lewy bodies, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker disease, spinocerebellar ataxias, spinal and bulbar muscular ataxia, dentatorubral and pallidoluysian ataxia, and Lafora disease in a mammalian patient, of pharmaceutically acceptable phosphatidylglycerol-presenting bodies, of a size resembling that of apoptotic cells or apoptotic bodies.
  • a ubiquitin- proteasome system dysfunction related disorder selected from dementia with Lewy bodies, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker disease, spinocerebell
  • FIGURE 1 illustrates the time line of the in vivo animal experiment reported in the specific Example described below;
  • FIGURES 2A and 2B are graphical presentations of the results of the Rota- rod test to which the animals were subjected as reported in the Example below;
  • FIGURE 3 is a graphical presentation of the results of the open field behavior test to which the animals were subjected as reported in the Example below.
  • Lewy bodies are neuronal cells with pigmented inclusion bodies. Dementia with Lewy bodies (DLB) is probably the second most common form of dementia after Alzheimer's disease. It is a form of dementia that shares characteristics with both Alzheimer's and Parkinson's diseases.
  • the presence of Lewy bodies in the brain disrupts the brain's normal functioning, interrupting the action of important chemical messengers such as acetylcholine and dopamine.
  • These Lewy bodies contain abnormally accumulated aggregates of proteins such as ⁇ -synuclein.
  • Characteristic symptoms of DLB sufferers include fluctuation of abilities on a daily and even hourly basis, fainting, falls or experiencing vague weaknesses of arms or legs, experiencing detailed and convincing hallucinations, falling asleep easily by day and having restless disturbed nights with confusion, nightmares and hallucinations.
  • the main requirement for its diagnosis is progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function.
  • Progressive supranuclear palsy is a condition related, but distinct from, Parkinson's disease. Patients present with parkinsonian symptoms, including slow movement, postural instability leading to falls, rigidity and tremor. PSP sufferers have additional symptoms including trouble with eyesight and eye movement, as well as breathing and swallowing. Other psychiatric symptoms may include problems with information processing and concept formation. Personality and behavioural changes, as well as sleep disturbances are also fairly common. Patients with PSP rarely develop the resting tremor and stooped posture characteristic of Parkinsonism. The pathology of the disease occurs in the subcortical regions of the brain, including the subthalamic nucleus, globus pallidus and the substantia nigra.
  • the characteristic microscopic feature of PSP is the "tufted astrocyte", which possesses fibrous aggregates, visualised by staining for tau and glial fibrillary acidic protein.
  • Cells in the subcortical regions to which the pathology spreads develop neurofibrillary tangles, composed of an abnormally phosphorylated, polymerised form of the microtubule-associated protein tau.
  • a mutant form of ubiquitin-B protein (UBB+1 ) has been shown to accumulate in persons suffering from PSP, indicating that impairment of the ubiquitin-proteasome system may be involved in this disorder (Fischer et al., Disease-specific Accumulation of Mutant Ubiquitin as a Marker for Proteasomal Dysfunction in the Brain, FASEB J., 2003 Nov.; 17(14): 2014-24).
  • MRI magnetic resonance imaging
  • Diffusion weighting can differentiate PSP from Parkinsonism based on increased diffusion coefficients in the putamen. Such differentiation, however, is not difficult for the experienced clinician. Limitation or slowing of vertical saccades (rapid movement of the eye between fixation points) is a strong diagnostic indicator of PSP.
  • Corticobasal degeneration is a relatively rare disorder, but relatively straightforward to diagnose. It often has a distinct set of syndromes. Disease onset is usually after 60 years of age. The disease progresses relatively slowly. Problems are usually noted unilaterally, on one side of the body initially, and later spread. Symptoms include parkinsonianism as well as difficulties with speech, articulation, balance and muscle control in the face. The disease causes degeneration in multiple areas of the brain, including areas of the cortex and basal ganglia, but especially in the outer, cortical areas of the brain.
  • Symptoms associated specifically with CBD are alien hand syndrome, in which the patient does not recognize his hand as being part of his own body and cannot control its movements; apraxia (loss of ability to make familiar, purposeful movements) and difficulty with spatial orientation; and acalculia (difficulty with simple calculations).
  • Microscopic examination of brain sections reveals loss of neurons and glia. Characteristic brain pathology includes ballooned neurons and astrocytic plaques.
  • An electroencephalogram (EEG) may show changes in brain function over time that are consistent with the neurodegeneration.
  • CT Computerized tomography
  • MRI scans can also be used in this way, to provide images of asymmetric atrophy of the fronto-parietal regions of the brain's cortex, the regions most frequently involved in the disease.
  • ubiquitin in achromatic neuronal cells in corticobasal degeneration (Halliday et al., Ubiquitin-positive Achromatic Neurons in Corticobasal Degeneration, Acta Neuropathol (Berl)., 1995;90(1 ):68-75).
  • Argyrophilic grain disease is a sporadic, late-onset form of dementia characterised by a neurodegenerative process mainly affecting limbic structures (amygdala, hippocampus and mediobasal temporal/entorhinal cortex). Its symptoms include reduction of short-term memory, disorders of word finding, disorders of reading and writing, disorientation and behavioural disturbances.
  • Argyrophilic grains which are granular or punctuate deposits that are highly variable in size and shape, together with the presence of coiled bodies, are diagnostic hallmarks of AGD in the absence of additional neurodegenerative brain lesions sufficient to meet diagnostic criteria for Alzheimer's disease (Zhukareva, V., et a/., American Journal of Pathology, Vol. 61 , No. 4, October 2002, page 1135).
  • a mutant form of ubiquitin-B protein (UBB+1 ) has been shown to accumulate in persons suffering from AGD, indicating that impairment of the ubiquitin-proteasome system may be involved in this disorder (Fischer et al., supra).
  • Frontotemporal dementia primarily affects the frontal and anterior temporal lobes of the brain, the areas which control "executive functions" such as reasoning, social behaviour, movement, speech, language and certain aspects of memory. It is believed to account for perhaps 3% of all dementia cases. FTD sufferers have some motor difficulties similar to those seen in Parkinson's disease, including rigidity, lack of balance, and stiffness of movement, but not the trembling of arms and legs at rest that are characteristic of Parkinson's. Because of its symptoms, FTD may be misdiagnosed as a psychiatric problem or as Alzheimer's disease (AD), but a skilled health care professional can detect features that rule out other diagnoses as well as pinpoint those that indicate FTD.
  • AD Alzheimer's disease
  • FTD is characterized by a gradual onset of changes in personality, social behaviour and language ability.
  • the brain areas affected are the frontal and temporal lobes, whereas in AD it is the medial and temporal area, usually in the hippocampus, which is initially affected, with subsequent spreading to other areas of the brain.
  • Formation of amyloid plaques is characteristic of AD, whereas amyloid plaques do not form in FTD.
  • AD begins with memory loss and proceeds to an inability to orient to time and place, whereas memory is preserved early on in FTD, which begins with personality and behaviour changes, such as loss of empathy towards others, lack of insight into proper social conduct, and compulsive eating and oral fixations. (Connections, Vol. 9 Number 4, Alzheimer's Disease Educations Referral Center).
  • a mutant form of ubiquitin- B protein (UBB+1 ) has been shown to accumulate in persons suffering from FTD, indicating that impairment of the ubiquitin-proteasome system may be involved in this disorder (Fischer et al., supra).
  • Pick's disease is one of the group of FTDs. It is a relatively rare type of presenile dementia. It is characterised by specific lesions named Pick bodies, made up of tau proteins that are found in the hippocampus and in the neocortex. It is characterised by slow deterioration in social skills and changes in personality, along with impairment of intellect, memory and language.
  • a mutant form of ubiquitin-B protein (UBB+1 ) has been shown to accumulate in persons suffering from Pick's disease, indicating that impairment of the ubiquitin- proteasome system may be involved in this disorder (Fischer et al., supra).
  • FTD- 17 hereditary frontotemporal dementia with parkinsonism-17
  • FTDP- 17 hereditary frontotemporal dementia with parkinsonism-17
  • Diagnosis depends on a combination of clinical findings, neuroimaging studies and family history. Its symptoms are those of FTD noted above. Gene testing is available.
  • FTDP - 17 can be definitively diagnosed by demonstration of one of the many missense mutations or splice donor site mutations in the MAPT (tau) gene or through a research protocol that documents linkage to chromosome 17q, along with support from behavioural characteristics.
  • Gerstmann-Straussler-Scheinker disease GSS is a familial neurological disorder characterized by amyloid deposition in the cerebrum and the cerebellum. Proteinase-K (PK) resistant prion protein fragments of 7-15 kD accumulate in the brain. It is clinically characterized by postural abnormalities and dementia. It appears to be inherited with an autosomal dominant pattern. It results from a lesion in the left parietal area. Patients are unable to point or name different fingers, have confusion between right and left sides of the body, and are unable to calculate or write. Diagnosis is described by Ghetti, B. et.al., Brain Pathology, 1995; 5:61-75.
  • SCA Spinocerebellar ataxias
  • SCA1, SCA2, SCA3, SCA6, SCA7, SCA17 also appear to have ubiquitin- proteasome system dysfunction (Gatchel J. R. and Zoghbi H.Y., Diseases of Unstable Repeat Expansion: Mechanisms and Common Principles, Nat. Rev. Genet. 2005 Oct;6(10):743-55).
  • SBMA Spinal and bulbar muscular ataxia
  • the onset of weakness is usually between 30 and 50 years and is often preceded by non-specific symptoms such as tremor, muscle cramps, and fatigue.
  • SBMA serotonin-proteasome
  • Dentatorubral and pallidoluysian ataxia is an autosomal dominant spinocerebellar degeneration. Patients may experience symptoms including myoclonus, seizures, choreiform movements, cerebellar ataxia, dementia, and psychiatric disturbance (Ito et al., Corneal Endothelial Degeneration in Dentatorubral-Pallidoluysian Atrophy, Arch. Neurol., Feb. 2002, 59; 289-291. This condition has a relatively high prevalence in Japan (0.2-0.7 per 100,000) but is rare in Western countries. DPA is also associated with an impaired ubiquitin-proteasome system (Gatchel et al., supra).
  • Lafora Disease is a form of epilepsy, inherited as an autosomal recessive condition, that occurs during early adolescence and is characterized by seizures and progressive neurological degeneration, with the disease often resulting in death within a decade of the first symptoms. The onset of the condition is often late childhood or adolescence. LD has no known cure. The condition appears to affect males and females equally, with a higher prevalence in the Mediterranean countries of Southern Europe, Northern Africa, and the Middle East, but is rarer in other parts of the world. Although there is no known cure, anti-epileptic drugs are often used at the beginning stages of the disease.
  • DPA is also associated with an impaired ubiquitin-proteasome system (Gentry et a/., Insights into Lafora Disease: MaNn is an E3 Ubiquitin Ligase that Ubiquitinates and Promotes the Degradation of Laforin, Proc. Natl. Acad. Sci. U S A., 2005 Jun 14; 102(24):8501 -6).
  • PG-presenting particles useful in the present invention, and their preparation can be found in aforementioned International patent application publication no. WO/03/061667 Vasogen Ireland Limited, and its U.S. counterpart U. S. S. N. 10/348,601 Bolton and Mandel, filed January 21 , 2003, incorporated herein by reference in its entirety.
  • the particles have a size resembling the size of apoptotic cells or apoptotic bodies.
  • These pharmaceutically acceptable bodies include synthetic and semi-synthetic bodies having shapes which are typically but not exclusively spheroidal, cylindrical, ellipsoidal, including oblate and prolate spheroidal, serpentine, reniform etc., and sizes from about 20 nm to about 500 ⁇ m in diameter, preferably measured along its longest axis, and comprising phosphate-glycerol groups on the surface thereof.
  • the pharmaceutically acceptable bodies have phosphatidylglycerol groups, or groups capable of conversion in vivo, of predetermined characteristics on the exterior surface.
  • the structure of these groups may be synthetically altered and include all, part of or a modified version of the original phosphatidylglycerol group.
  • the negatively charged oxygen of the phosphate group may be converted to a phosphate ester group (e.g., L-OP(O)(OR')(OR”), where L is the remainder of the phosphatidylglycerol
  • R' is -CH 2 CH(OH)CH 2 OH and R" is alkyl of from 1 to 4 carbon atoms or hydroxyl substituted alkyl of from 2 to 4 carbon atoms, and 1 to 3 hydroxyl groups provided that R" is more readily hydrolyzed in vivo than the R' group; to a diphosphate group including diphosphate esters (e.g., L-OP(O)(OR')OP(O)(OR") 2 wherein L and R' are as defined above and each
  • R" is independently hydrogen, alkyl of from 1 to 4 carbon atoms, or a hydroxyl substituted alkyl of from 2 to 4 carbon atoms and 1 to 3 hydroxyl groups provided that the second phosphate group [-P(O)(OR") 2 ] is more readily
  • triphosphate esters e.g., L-OP(O)(OR')OP(O)(OR")OP(O)(OR") 2 wherein L and R' are defined as above and each R" is independently hydrogen, alkyl of from 1 to 4 carbon atoms, or a hydroxyl substituted alkyl of from 2 to 4 carbon atoms and 1 to 3 hydroxyl groups provided that the second and third phosphate groups are more readily hydrolyzed in vivo than the R' group; and the like.
  • Such synthetically altered phosphate-glycerol groups are capable of expressing phosphate-glycerol in vivo and, accordingly, such altered groups are phosphate-glycerol convertible groups.
  • Phosphatidylglycerol is a known compound. It can be produced, for example, by treating the naturally occurring dimeric form of phosphatidylglycerol, cardiolipin, with phospholipase D. It can also be prepared by enzymatic synthesis from phosphatidylcholine using phospholipase D - see, for example, U. S. Patent 5,188,951 Tremblay, et al. Chemically, it has a phosphate-glycerol group and a pair of similar but different Ci 8 -C 2O fatty acid chains.
  • PG is intended to cover phospholipids carrying a phosphate-glycerol group with a wide range of at least one fatty acid chains provided that the resulting PG entity can participate as a structural component of a liposome.
  • PG compounds can be represented by the Formula I:
  • R and R 1 are independently selected from Ci - C 24 hydrocarbon chains, saturated or unsaturated, straight chain or containing a limited amount of branching wherein at least one chain has from 10 to 24 carbon atoms.
  • the lipid chains R and R 1 form the structural component of the liposomes, rather than the active component. Accordingly, these can be varied to include two or one such lipid chains, the same or different, provided they fulfill the structural function.
  • the lipid chains are from about 10 to about 24 carbon atoms in length, saturated, mono-unsaturated or polyunsaturated, straight-chain or with a limited amount of branching.
  • Laurate (C12), myristate (C14), palmitate (C16), stearate (C18), arachidate (C20), behenate (C22) and lignocerate (C24) are examples of useful saturated lipid chains for the PG for use in the present invention.
  • Palmitoleate (C16) and oleate (C18) are examples of suitable mono-unsaturated lipid chains.
  • Linoleate (C18), linolenate (C18) and arichidonate (C20) are examples of suitable poly-unsaturated lipid chains for use in PG in the liposomes of the present invention.
  • Phospholipids with a single such lipid chain are known as lysophospholipids.
  • the present invention also extends to cover use of liposomes in which the active component is the dimeric form of PG, namely cardiolipin but other dimers of Formula I are also suitable.
  • dimers are not synthetically cross-linked with a synthetic cross-linking agent, such as maleimide but rather are cross-linked by removal of a glycerol unit as described by Lehniger, Biochemistry, p. 525 (1970) and depicted in the reaction below:
  • R 2 and R 3 are independently selected from CrC 24 hydrocarbon chains, saturated or unsaturated, straight chain or containing a limited amount of branching wherein at least one chain has from 10-24 carbon atoms.
  • three-dimensional body portions or pharmaceutically acceptable bodies
  • biocompatible synthetic or semi-synthetic entities such as liposomes, solid beads, hollow beads, filled beads, particles, granules and microspheres of biocompatible materials, natural or synthetic, as commonly used in the pharmaceutical industry or known in the art.
  • the beads may be solid or hollow, or filled with biocompatible material.
  • biocompatible refers to substances which, in the amount employed, are either non-toxic or have acceptable toxicity profiles such that their use in vivo is acceptable.
  • pharmaceutically acceptable as used in relation to “pharmaceutically acceptable bodies” refers to bodies comprised of one or more materials which are pharmaceutically acceptable and suitable for delivery in vivo.
  • Such bodies can include liposomes formed of lipids, one of which is PG.
  • the pharmaceutically acceptable bodies can be solid beads, hollow beads, filled beads, particles, granules and microspheres of biocompatible materials, which comprise one or one or more biocompatible materials such as polyethylene glycol, polymethylmethacrylate), polyvinylpyrrolidone, polystyrene and a wide range of other natural, semisynthetic and synthetic materials, with phosphate-glycerol groups attached thereto.
  • compositions of matter are liposomes, which may be composed of a variety of lipids. Preferably, however, none of the lipids are positively charged.
  • phosphatidylglycerol PG may constitute the major portion or the entire portion of the liposome layer(s) or wall(s), oriented so that the phosphate-glycerol group portion thereof is presented exteriorly, to act as the binding group, and the lipid chain or chains form the structural wall.
  • Liposomes are sealed sacs, in the micron or sub-micron range, the walls (monolayer or multilayer) of which comprise suitable amphiphiles. They normally contain an aqueous medium, although for the present invention the interior contents are unimportant, and generally inactive. Accordingly, in a preferred embodiment, the liposomes, as well as other pharmaceutically acceptable bodies, are essentially free of non-lipid pharmaceutically active entities (e.g. ⁇ 1 %) and more preferably are free of non-lipid pharmaceutically active entities. Such liposomes are prepared and treated so that the active groups are presented exteriorly on the liposomal body.
  • a preferred embodiment of this invention provides use in preparation of a medicament for the treatment or prophylaxis of a ubiquitin-proteasome system dysfunction related disorder selected from dementia with Lewy bodies, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, frontotemporal dementia, Gerstmann-Straussler- Scheinker disease, spinocerebellar ataxias, spinal and bulbar muscular ataxia, dentatorubral and pallidoluysian ataxia, and Lafora disease in a mammalian patient, of liposomal bodies which expose or can be treated or induced to expose, on their surfaces, one or more phosphatidylglycerol groups to act as binding groups.
  • a ubiquitin-proteasome system dysfunction related disorder selected from dementia with Lewy bodies, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease,
  • Such lipids should comprise from 10% - 100% of the liposome, with the balance being an inactive constituent, e.g. phosphatidylcholine PC, or one that acts through a different mechanism, e.g. phosphatidylserine PS, or mixtures of such.
  • Inactive co-constituents such as PC are preferred.
  • At least 10% by weight of such liposome is composed of PG, the balance being phosphatidylcholine (PC) or other such biologically acceptable phospholipid(s), preferably at least 50%, more preferably from 60-100% and most preferably from 70-90%, with the single most preferred embodiment being about 75% by weight of PG.
  • PC phosphatidylcholine
  • phospholipid(s) preferably at least 50%, more preferably from 60-100% and most preferably from 70-90%, with the single most preferred embodiment being about 75% by weight of PG.
  • PG-presenting particles comprise less than 50%, preferably less than 40%, still preferably less than 25% and even still preferably less than 10% phosphatidylcholine.
  • non-liposomal bodies for use in the present invention, these as noted include biocompatible solid or hollow beads of appropriate size.
  • the biocompatible non-liposomal synthetic or semi-synthetic bodies may be selected from polyethylene glycol, poly(methylmethacrylate), polyvinylpyrrolidone, polystyrene and a wide range of other natural, semisynthetic and synthetic materials, with phosphatidylglycerol groups attached to the surfaces thereof.
  • Biodegradable polymers are disclosed in the art and include, for example, linear-chain polymers such as polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, and copolymers, terpolymers and combinations thereof.
  • Other biodegradable polymers include, for example, gelatin, collagen, etc.
  • Suitable substances for derivatization to attach the phospholipid(s), or portions thereof with groups or binding groups, to three-dimensional bodies are commercially available e.g. from Polysciences Inc., 400 Valley Road, Warrington, PA 18976, or from Sigma Aldrich Fine Chemicals. Methods for their derivatization are known in the art. Specific preferred examples of such methods are disclosed in International Patent Application PCT/CA02/01398 Vasogen Ireland Limited, which is incorporated herein by reference.
  • Phospholipids are amphiphilic molecules (i.e. amphiphiles), meaning that the compound comprises molecules having a polar water-soluble group attached to a water-insoluble hydrocarbon chain.
  • the amphiphiles serving as the layers of the matrix have defined polar and apolar regions.
  • the amphiphiles can include, in addition to PG in this invention, other, naturally occurring lipids used alone with the phospholipid carrying the active group, or in a mixture with another.
  • the amphiphiles serving as the layer(s) of the liposomes can be inert, structure-conferring synthetic compounds such as polyoxyethylene alkylethers, polyoxyethylene alkylesters and saccharosediesters.
  • PG groups of the present invention are believed to act as ligands, binding to specific sites on a protein or other molecule ("PG receptor") and, accordingly, PG (or derivatives or dimeric forms thereof) are sometimes referred to herein as a "ligand” or a "binding group".
  • PG receptor protein or other molecule
  • PG or derivatives or dimeric forms thereof
  • PG receptor protein or other molecule
  • Liposomes may be prepared by a variety of techniques known in the art, such as those detailed in Szoka et al. (Ann. Rev. Biophys. Bioeng., 9:467 (1980)). Depending on the method used for forming the liposomes, as well as any after-formation processing, liposomes may be formed in a variety of sizes and configurations. Methods of preparing liposomes of the appropriate size are known in the art and do not form part of this invention. Reference may be made to various textbooks and literature articles on the subject, for example, the review article by Yechezkel Barenholz and Daan J. A. Chromeline, and literature cited therein, for example New, R. C. (1990), and Nassander, U. K., et al. (1990), and Barenholz, Y and Lichtenberg, D., Liposomes: Preparation, Characterization, and Preservation, Methods Biochem Anal., 1988, 33:337- 462.
  • Multilamellar vesicles can be formed by simple lipid-film hydration techniques according to methods known in the art. In this procedure, a mixture of liposome-forming lipids is dissolved in a suitable organic solvent. The mixture is evaporated in a vessel to form a thin film on the inner surface of the vessel, to which an aqueous medium is then added. The lipid film hydrates to form MLVs, typically with sizes between about 100-1000 nm (0.1 to 10 microns) in diameter A related, reverse evaporation phase (REV) technique can also be used to form unilamellar liposomes in the micron diameter size range.
  • REV reverse evaporation phase
  • the REV technique involves dissolving the selected lipid components, in an organic solvent, such as diethyl ether, in a glass boiling tube and rapidly injecting an aqueous solution, optionally containing a drug solution to be carried in the interior of the liposome, into the tube, through a small gauge passage, such as a 23-gauge hypodermic needle.
  • a small gauge passage such as a 23-gauge hypodermic needle.
  • the tube is then sealed and sonicated in a bath sonicator.
  • the contents of the tube are alternately evaporated under vacuum and vigorously mixed, to form a final liposomal suspension.
  • the diameters of the PG-presenting liposomes, as well as the other pharmaceutically acceptable bodies, of the preferred embodiment of this invention range from about 20 nm to 500 ⁇ m, more preferably from 20 nm to about 1000 nm, more preferably from about 20 nm to about 500 nm, and most preferably from about 20 nm to about 200 nm.
  • Such preferred diameters will correspond to the diameters of mammalian apoptotic bodies, such as may be apprised from the art.
  • One effective sizing method for REVs and MLVs involves extruding an aqueous suspension of the liposomes through a series of polycarbonate membranes having a selected uniform pore size in the range of 0.03 to 0.2 micron, typically 0.05, 0.08, 0.1 , or 0.2 microns.
  • the pore size of the membrane corresponds roughly to the median size of liposomes produced by extrusion through that membrane, particularly where the preparation is extruded two or more times through the same membrane.
  • This method of liposome sizing is used in preparing homogeneous-size REV and MLV compositions.
  • Patents 4,737,323 and 4,927,637 describe methods for producing a suspension of liposomes having uniform sizes in the range of 0.1-0.4 ⁇ m (100-400 nm) using as a starting material liposomes having diameters in the range of 1 ⁇ m. Homogenization methods are also useful for down-sizing liposomes to sizes of 100 nm or less (Martin, F. J. (1990) In: Specialized Drug Delivery Systems-- Manufacturing and Production Technology, P. TyIe (ed.) Marcel Dekker, New York, pp. 267- 316.). Another way to reduce liposomal size is by application of high pressures to the liposomal preparation, as in a French Press.
  • Liposomes can be prepared to have substantially homogeneous sizes of single, bi-layer vesicles in a selected size range between about 0.07 and 0.2 microns (70-200 nm) in diameter, according to methods known in the art.
  • liposomes in this size range are readily able to extravasate through blood vessel epithelial cells into surrounding tissues.
  • a further advantage is that they can be sterilized by simple filtration methods known in the art.
  • PG-presenting particles for use in the present invention is liposomes with PG presented on the external surface thereof, it is understood that the PG-presenting particle is not limited to a liposomal structure, as mentioned above.
  • the pharmaceutically acceptable bodies may be suspended in a pharmaceutically acceptable carrier, such as physiological sterile saline, sterile water, pyrogen-free water, isotonic sterile saline, and phosphate buffer sterile solutions (e.g. sterile aqueous solutions comprising phosphate buffer), as well as other non-toxic compatible substances used in pharmaceutical formulations, such as, for example, adjuvants, buffers, preservatives, and the like.
  • a pharmaceutically acceptable carrier such as physiological sterile saline, sterile water, pyrogen-free water, isotonic sterile saline, and phosphate buffer sterile solutions (e.g. sterile aqueous solutions comprising phosphate buffer), as well as other non-toxic compatible substances used in pharmaceutical formulations, such as, for example, adjuvants, buffers, preservatives, and the like.
  • the pharmaceutically acceptable bodies are constituted into a liquid suspension in a sterile biocompatible liquid such as buffered sterile saline and administered to the patient by any appropriate route which exposes it to one or more components of the immune system, such as topically, intra- arterially, intravenously or most preferably intramuscularly or subcutaneously.
  • a sterile biocompatible liquid such as buffered sterile saline
  • the pharmaceutically acceptable bodies may be freeze- dried or lyophilized so that they may be later re-suspended for administration.
  • a preferred manner of administering the pharmaceutically acceptable bodies to the patient is a course of injections, administered daily, several times per week, weekly or monthly to the patient, over a period ranging from a week to several months or more.
  • the frequency and duration of the course of the administration is likely to vary from patient to patient, and according to the severity of the condition being treated, and whether the treatment is intended as prophylactic, therapeutic or curative. Its design and optimization is well within the skill of the attending physician. Intramuscular injection is most preferred.
  • One particular injection schedule is an injection, of an appropriate amount of bodies on day 1 , a further injection on day 2, a further injection on day 14, and then "booster" injections at monthly intervals, if appropriate.
  • Another injection schedule is 6 daily injections and booster injections every 2- 4 weeks.
  • a dose of 5 x 10 8 vesicles, of the order of the dose used in the specific in vivo examples below, is equivalent to 4.06 x 10 13 lipid molecules.
  • Using Avogadro's number for the number of molecules of lipid in a gram molecule (mole), 6.023 x 10 23 one determines that this represents 6.74 x 10 " 11 moles which, at a molecular weight of 747 for PG is approximately 5.04 x 10 "8 gm, or 50.4 ng of PG for such dosage.
  • the quantities of PG-presenting bodies to be administered will vary depending on the identity and characteristics of the patient. It is important that the effective amount of PG-bodies is non-toxic to the patient. The most effective amounts are unexpectedly small.
  • intra-arterial, intravenous, subcutaneous or intramuscular administration of a liquid suspension of PG-presenting bodies it is preferred to administer, for each dose, from about 0.1 -50 ml of liquid, containing an amount of PG-presenting bodies generally equivalent to 10% -1000% of the number of leukocytes normally found in an equivalent volume of whole blood or the number of apoptotic bodies that can be generated from them.
  • the number of PG-presenting bodies administered per delivery to a human patient is in the range from about 500 to about 10 14 (about 10 mg by weight at the highest end of the range), preferably from about 50,000 to about 50,000,000,000 (about 5 ⁇ g by weight at the highest end of the range), more preferably from about 100,000 to about 100,000,000 (about 100 ng by weight at the highest end of the range), and most preferably from about 200,000 to about 2,000,000 (about 0.2 ng by weight at the highest end of the range).
  • dosages from about 2.6 x 10 9 to about 10 14 PG-carrying bodies.
  • the number of such bodies administered to an injection site for each administration is believed to be a more meaningful quantification than the number or weight of PG-presenting bodies per unit of patient body weight.
  • effective amounts or numbers of PG-presenting bodies for small animal use may not directly translate into effective amounts for larger mammals on a weight ratio basis.
  • the person skilled in the art could readily extrapolate from the data and other information contained herein to arrive at appropriate dosing for other mammals.
  • patients at risk of contracting or evidencing initial symptoms of one of the neurodegenerative diseases treatable according to the present invention are first subjected to detailed diagnosis to determine which of the various disorders is present, and to distinguish them not only from one another, but also from other dementias such as Alzheimers and Parkinson's disease.
  • mice Male Sprague-Dawley rats (200-25Og) were used as test animals. They were pretreated with liposomes according to the invention, and then injected with a proteasome inhibitor. Then their motor-co-ordination was measured using a Rota-rod, and their open field behaviour assessed. Then they were sacrificed. From some animals, brain tissue was micro-dissected out and frozen until required for further analyses. From other animals, transcardial perfusion was effected and the brains subsequently removed and post-fixed for later study.
  • the proteasome inhibitor was Z-lle-Glu(OtBu)-Ala-Leu-al (PSI), Peptides Inc, Louisville, KY, USA.
  • the liposomes were 25% phosphatidylcholine, 75% phosphatidylglycerol, particle size 110 ⁇ 10 nanometers.
  • Rats were pretreated intramuscularly (i.m.) with either 150 ⁇ l of sterile saline or liposomes (1.2 x 10 7 particles/ml suspension in sterile saline). Administration with either liposomes or saline was alternated between left and right hind limbs on alternate days to minimize local muscle injury. This treatment was carried out 14, 13 and 1 days before administration of PSI (day 0). NOT FURNISHED UPON FILING
  • the group that received liposomes/PSI lasted for significantly (p ⁇ 0.05) longer times on the rotating rod as compared with the group receiving saline./PSI, and. substantially-equivalent to that of the saline/control group and of the ' groups at the start of the experimeiiit, (Fig. 2A), indicating that the liposomes have counteracted the effect of the PSI.
  • Open field behaviour was assessed on the day prior to predetermined sacrifice.
  • the animals were placed in a large circular arena with walls. Locomotor activity was tracked using a camera and then analysed using Noldus Ethovision software. The distance traveled by the rat in a period of 10 minutes was then measured for each group.

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Abstract

Les troubles liés au dysfonctionnement du système ubiquitine-protéasome sont traités en administrant à un patient mammifère une quantité efficace de corps composés de phosphatidylglycérol d'une taille similaire à celle d'une cellule apoptotique ou d'un corps apoptotique. Ledit corps composé de phosphatidylglycérol peut être liposomique tandis que les troubles liés au dysfonctionnement du système ubiquitine-protéasome comprennent la démence à corps de Lewy, la maladie de Pick, la maladie de Steele-Richardson, la dégénérescence corticobasale, la démence à grains argyrophiles, la démence frontotemporale, le syndrome de Gerstmann-Straussler-Scheinker, les ataxies spinocérébelleuses, l'atrophie musculaire spinale et bulbaire, l'atrophie dentaturo-rubro-pallido-luysienne et la maladie de Lafora.
PCT/CA2007/000786 2006-05-12 2007-05-07 Traitement des troubles liés au dysfonctionnement du système ubiquitine-protéasome WO2007131329A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016005354A1 (fr) * 2014-07-07 2016-01-14 Ga Generic Assays Gmbh Profilage d'auto-anticorps dans aps

Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2003061667A1 (fr) * 2002-01-21 2003-07-31 Vasogen Ireland Limited Corps portant du phosphate-glycerol pharmaceutiquement acceptable
CA2533084A1 (fr) * 2003-07-21 2005-01-27 Vasogen Ireland Limited Traitement de conditions inflammatoires aigues
CA2533136A1 (fr) * 2003-07-21 2005-02-03 Vasogen Ireland Limited Traitement de lesions cerebrales perinatales hypoxiques-ischemiques
CA2572982A1 (fr) * 2004-07-09 2006-01-19 Vasogen Ireland Limited Traitement des alterations de la memoire liees a l'age au moyen de corps porteurs de phosphate-glycerol

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Publication number Priority date Publication date Assignee Title
WO2003061667A1 (fr) * 2002-01-21 2003-07-31 Vasogen Ireland Limited Corps portant du phosphate-glycerol pharmaceutiquement acceptable
CA2533084A1 (fr) * 2003-07-21 2005-01-27 Vasogen Ireland Limited Traitement de conditions inflammatoires aigues
CA2533136A1 (fr) * 2003-07-21 2005-02-03 Vasogen Ireland Limited Traitement de lesions cerebrales perinatales hypoxiques-ischemiques
CA2572982A1 (fr) * 2004-07-09 2006-01-19 Vasogen Ireland Limited Traitement des alterations de la memoire liees a l'age au moyen de corps porteurs de phosphate-glycerol

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MINGHETTI: "Role of inflammation in neurodegenerative diseases", CURRENT OPINION IN NEUROLOGY, vol. 18, 2005, pages 315 - 321 *
QURESHI ET AL.: "The proteasome: A central regulator of inflammation and macrophage function", IMMUNOLOGIC RESEARCH, vol. 31, no. 3, 2005, pages 243 - 260 *
RAMAKRISHNAN ET AL.: "alpha-Synuclein associated with phospathidylglycerol probed by lipid spin labels", BIOCHEMISTRY, vol. 42, 2003, pages 12919 - 12926 *
SHEPHERD ET AL.: "Corticol inflammation in Alzheimer disease but not dementia with Lewy bodies", ARCH. NEUROL., vol. 57, 2000, pages 817 - 822 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016005354A1 (fr) * 2014-07-07 2016-01-14 Ga Generic Assays Gmbh Profilage d'auto-anticorps dans aps

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