US20190111041A1 - Arimoclomol for treating glucocerebrosidase associated disorders - Google Patents

Arimoclomol for treating glucocerebrosidase associated disorders Download PDF

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US20190111041A1
US20190111041A1 US16/092,070 US201716092070A US2019111041A1 US 20190111041 A1 US20190111041 A1 US 20190111041A1 US 201716092070 A US201716092070 A US 201716092070A US 2019111041 A1 US2019111041 A1 US 2019111041A1
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gba
pharmaceutical ingredient
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Anders Mørkeberg Hinsby
Thomas Kirkegaard Jensen
Catherine Kolster Fog-Tonnesen
Nikolaj Havnsøe Torp Petersen
Claus Bornaes
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Zevra Denmark AS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof (arimoclomol), for use in a method of treating a glucocerebrosidase (GBA)-associated disorder other than Gaucher's disease (GD), including GBA-associated alpha-synucleinopathies such as GBA-associated Parkinson's disease (PD), GBA-associated dementia with Lewi bodies (DLB) and GBA-associated multiple system atrophy (MSA).
  • GBA glucocerebrosidase
  • PD glucocerebrosidase
  • DLB GBA-associated dementia with Lewi bodies
  • MSA GBA-associated multiple system atrophy
  • Gaucher's disease is the most common of the lysosomal storage diseases characterized by an accumulation of glucocerebrosides. It is a form of sphingolipidosis as it involves dysfunctional metabolism of sphingolipids. To date, up to 300 mutations in the GBA gene are known and linked to Gaucher disease. GBA mutations can be categorized as mild (causing GD type I, nonneuronopathic) or severe (causing GD types II and III). Homozygous GBA mutations as well as compound heterozygous mutations cause GD.
  • GBA mutation carriers having one mutated GBA gene
  • GBA mutation carriers having one mutated GBA gene
  • Mutations in GBA are now considered one of the main genetic risk factors for Parkinson's disease. It has been estimated that at least 8% of patients with Parkinson's disease have mutations in the GBA gene, both mild and severe GBA mutations, including L444P heterozygotes. Also secondary deficiencies of GBA activity may be linked to Parkinson's disease.
  • WO 2014/071282 discloses a recombinant self-complementary adeno-associated viral vector encoding human glucocerebrosidase (AAV-GBAI) in models to support glucocerebrosidase augmentation therapies for PD and related synucleinopathies and tauopathies.
  • AAV-GBAI human glucocerebrosidase
  • WO 2013/148333 discloses salicylic acid derivatives as glucocerebrosidase activators for treating Gaucher's disease and inhibiting the onset of Gaucher's disease symptoms in a patient having a GBA gene mutation and for treating Parkinson's disease.
  • WO 2009/155936 discloses heat shock protein 70 and inducers thereof for treating lysosomal storage diseases, including Gaucher's disease.
  • WO 2005/041965 discloses use of the heat shock inducer arimoclomol for protecting neurons in neurodegenerative diseases, including Parkinson's disease.
  • Arimoclomol is a heat shock protein amplifier currently under evaluation in the treatment of paediatric lysosomal storage disorders and amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • arimoclomol increases GBA levels and increases GBA activity, not only in GBA homozygotes (presenting with Gaucher's disease and markedly reduced GBA activity), but also in mutant GBA heterozygotes (carriers). Specifically, arimoclomol increases GBA activity in GBA homozygotes (Gaucher patient) to clinically unaffected activity level. Furthermore, arimoclomol increases GBA activity in GBA heterozygotes (clinically unaffected), and increases GBA enzyme amount (total level and matured/post-ER GBA).
  • the present inventors also show herein that arimoclomol increases GBA activity in Parkinson's disease patients with mutated GBA alleles (heterozygous or homozygous, clinically unaffected re Gaucher's disease).
  • an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride (arimoclomol), its stereoisomers and the acid addition salts thereof, for use in a method of treating a glucocerebrosidase (GBA)-associated disorder.
  • GAA glucocerebrosidase
  • said GBA-associated disorder is associated with reduced GBA enzyme levels and/or reduced GBA enzyme activity. In one embodiment said GBA-associated disorder is associated with one or more GBA gene mutations, including heterozygous and homozygous GBA gene mutations.
  • said GBA-associated disorder is a GBA-associated alpha-synucleinopathy, such as selected from the group consisting of GBA-associated Parkinson's disease (PD), GBA-associated dementia with Lewi bodies (DLB) and GBA-associated multiple system atrophy (MSA).
  • PD GBA-associated Parkinson's disease
  • DLB GBA-associated dementia with Lewi bodies
  • MSA GBA-associated multiple system atrophy
  • said GBA-associated Parkinson's disease is associated with a genetically high-risk Parkinson's disease GBA genotype.
  • an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of increasing GBA levels and/or
  • FIG. 1 Arimoclomol-induced dose-dependent increase in ER Hsp70 (BiP) in primary cells (human fibroblasts) from individual with a heterozygous GBA allele containing the L444P, A456P, V460V mutations in cis (carrier, clinically unaffected re. Gaucher's disease). See Example 1.
  • FIG. 2 Arimoclomol-induced dose-dependent increase in GBA enzyme amount in primary cells (human fibroblasts) from individual with a heterozygous GBA allele containing the L444P, A456P, V460V mutations in cis (carrier, not affected with Gaucher's disease). See Example 1.
  • FIG. 3 Arimoclomol-induced dose-dependent increase in GBA activity in L444P/L444P, A456P, V460V Gaucher TII patient. Level increased to clinically unaffected activity level (dashed line). See Example 2.
  • FIG. 4 Arimoclomol-induced dose-dependent increase in GBA activity in L444P, A456P, V460V Heterozygote (carrier; clinically unaffected parent of Gaucher disease patient, genetically high-risk Parkinson's disease genotype). Level increased by more than 2-fold. See Example 2.
  • FIG. 5 Arimoclomol-induced dose-dependent increase in GBA activity in primary cells from Gaucher disease patients of type I (N370S/V394L and N370S/1-BP ins 84G), type II (E326K, L444P/E326K, L444P and G325R/C342G and P415R/L444P) or type Ill (L444P/L444P). See Example 3.
  • FIG. 6 Arimoclomol-induced dose-dependent increase in GBA activity in primary cells from Parkinson Disease patient with a heterozygous GBA allele containing the N370S mutation (N370S/+). See Example 4.
  • FIG. 7 Arimoclomol-induced dose-dependent increase in GBA activity in human fibroblasts from non-symptomatic healthy individuals with no GBA mutation (+/+). See Example 5.
  • FIG. 8 Arimoclomol-induced increase in labeling of active GBA by ME569 in primary cells from Gaucher disease patients of type I (N370S/V394L), type II (G325R/C342G) and type III (L444P/L444P). See Example 6.
  • FIG. 9 Arimoclomol-induced dose-dependent increase in ER Hsp70 (BiP) in primary cells from Gaucher disease patient of type I (N370S/V394L). Vinculin was used as loading control. See Example 7.
  • FIG. 10 Arimoclomol-induced dose-dependent increase in ER Hsp70 (BiP) in primary cells from Gaucher disease patient of type I (N370S/1-BP ins 84G). RPA was used as loading control. See Example 7.
  • FIG. 11 Arimoclomol-induced dose-dependent increase in GBA protein level in primary cells from Gaucher disease patient of type I (N370S/1-BP ins 84G). RPA was used as loading control. See Example 7.
  • FIG. 12 Arimoclomol-induced dose-dependent increase in ER Hsp70 (BiP) in primary cells from Gaucher disease patient of type II (L444P/P415R). RPA was used as loading control. See Example 8.
  • FIG. 13 Arimoclomol-induced increase in ER Hsp70 (BiP) in primary cells from Gaucher disease patient of type II (G325R/C342G). Vinculin was used as loading control. See Example 8.
  • FIG. 14 Arimoclomol-induced dose-dependent increase in GBA protein level in primary cells from Gaucher disease patient of type II (L444P/P415R). Vinculin was used as loading control. See Example 8.
  • FIG. 15 Arimoclomol-induced dose-dependent increase in GBA protein level in primary cells from Gaucher disease patient of type II (G325R/C342G). RPA was used as loading control. See Example 8.
  • FIG. 16 Arimoclomol-induced dose-dependent increase in ER Hsp70 (BiP) in primary cells from Gaucher disease patient of type III (L444P/L444P). Vinculin was used as loading control. See Example 9.
  • FIG. 17 Arimoclomol-induced dose-dependent increase in GBA protein level in primary cells from Gaucher disease patient of type III (L444P/L444P). RPA was used as loading control. See Example 9.
  • FIG. 18 Arimoclomol-induced dose-dependent increase in ER Hsp70 (BiP) in primary cells from a PD-GBA (N370S/N370S) individual. Vinculin was used as loading control. See Example 10.
  • FIG. 19 Arimoclomol does not affect neuronal differentiation of MASCs from GD individuals with the indicated GBA mutations.
  • Cells were either treated with mock (PBS) or 400 ⁇ M arimoclomol (Ari) for 9 days.
  • FIG. 20 Arimoclomol-induced increase in GBA activity in primary neronal-like cells from GD individuals with the indicated GBA mutations. Skin-derived fibroblasts from individual with GDTIII (L444P/L444P) were included as control. Cells were either treated with mock (PBS) or 400 ⁇ M arimoclomol (Ari). See Example 11.
  • Beta-glucocerebrosidase or glucocerebrosidase (UniProt entry P04062, GLCM_HUMAN, also called glucosylceramidase, acid beta-glucosidase, D-glucosyl-N-acylsphingosine glucohydrolase, GCase or GBA) is an enzyme with glucosylceramidase activity that cleaves, by hydrolysis, the beta-glucosidic linkage of glucocerebroside, an intermediate in glycolipid metabolism:
  • GBA requires saposin C and anionic phospholipids for activity. It is localized in the lysosome. It is encoded by the GBA gene (official name: glucosidase, beta, acid; Gene/Locus MIM number 606463; EC 3.2.1.45). Alternative splicing results in multiple transcript variants.
  • GBA gene which encodes the lysosomal enzyme that is deficient in Gaucher's disease, are important and common risk factors for Parkinson's disease and related disorders. This association was first recognised in the clinic, where parkinsonism was noted, albeit rarely, in patients with Gaucher's disease and more frequently in relatives who were obligate carriers (an individual who may be clinically unaffected but who must carry a gene mutation based on analysis of the family history).
  • Alpha-synuclein is a synuclein protein of unknown function primarily found in neural tissue. It can aggregate to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Alpha-synuclein is the primary structural component of Lewy body fibrils.
  • Arimoclomol is a small-molecule inducer of the heat shock proteins including Hsp70. It is currently being investigated for treatment of amyotrophic lateral sclerosis (ALS) and the lysosomal storage disorder Niemann-Pick disease type C. Induction of the heat shock proteins including Hsp70 protects lysosomal membranes and increases activity of lysosomal enzymes responsible for degradation of lysosomal substrate.
  • ALS amyotrophic lateral sclerosis
  • Niemann-Pick disease type C Niemann-Pick disease type C.
  • Induction of the heat shock proteins including Hsp70 protects lysosomal membranes and increases activity of lysosomal enzymes responsible for degradation of lysosomal substrate.
  • arimoclomol increases GBA activity in cells from a patient with Gaucher's disease type III (e.g. L444P/L444P) to clinically unaffected activity levels (in some instances same levels as GBA mutation carriers). Also shown herein is that arimoclomol surprisingly increases GBA activity in cells from a GBA mutation carrier (e.g. L444P heterozygous) more than 2-fold of clinically unaffected activity levels. Furthermore, arimoclomol increases N370S GBA activity in cells from a PD patient. Thus, GBA activity—and levels—can be increased also in cells from mutant GBA heterozygotes (carriers), and in cells from mutant GBA homozygotes who are clinically unaffected re Gaucher's disease.
  • Gaucher's disease type III e.g. L444P/L444P
  • arimoclomol increases GBA activity in cells from a GBA mutation carrier (e.g. L444P heterozygous) more than 2-fold of
  • Arimoclomol-induced increase in GBA levels and/or activity may thus provide useful for treating a range of proteinopathic disorders wherein GBA levels and/or activity is compromised.
  • Arimoclomol is defined herein as an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof.
  • arimoclomol for use in the treatment of GBA deficiencies.
  • said GBA deficiency does not include Gaucher's disease (GD) per se/as such.
  • GD Gaucher's disease
  • arimoclomol for use in the treatment of a glucocerebrosidase (GBA)-associated disorder other than Gaucher's disease (GD).
  • GBA glucocerebrosidase
  • GD Gaucher's disease
  • said treatment is prophylactic, curative or ameliorating.
  • said treatment is prophylactic.
  • said treatment is curative.
  • said treatment is ameliorating.
  • arimoclomol for the manufacture of a medicament for the treatment of a glucocerebrosidase (GBA)-associated disorder other than Gaucher's disease (GD).
  • GAA glucocerebrosidase
  • GD Gaucher's disease
  • Also provided herewith is a method of treating a glucocerebrosidase (GBA)-associated disorder other than Gaucher's disease (GD), said method comprising administering an effective amount of arimoclomol to an individual in need thereof.
  • GAA glucocerebrosidase
  • GD Gaucher's disease
  • “Individual” or “subject” refers to vertebrates, in particular a member of a mammalian species, preferably primates including humans.
  • an individual as used herein is a human being, male or female, of any age.
  • an “individual in need thereof” refers to an individual who may benefit from the present invention.
  • said individual in need thereof is a diseased individual, wherein said disease is a GBA-associated disorder.
  • arimoclomol as defined herein, for use in the treatment of a GBA-associated disorder encompasses any one of the below conditions.
  • a GBA-associated disorder as defined herein may refer to any disorder which has an association with GBA levels and/or GBA activity.
  • reduced levels and/or reduced activity of GBA is associated with a GBA-associated disorder as defined herein.
  • Associated with in one embodiment means predisposes for (or increases risk of developing; or presenting with).
  • the GBA-associated disorder is not Gaucher's disease. In one embodiment the GBA-associated disorder is not Gaucher's disease type I. In one embodiment the GBA-associated disorder is not Gaucher's disease type II. In one embodiment the GBA-associated disorder is not Gaucher's disease type III. In one embodiment the GBA-associated disorder is not Gaucher's disease types II or III.
  • the GBA-associated disorder is associated with reduced GBA enzyme levels.
  • the GBA-associated disorder is associated with reduced GBA enzyme activity.
  • Reduced GBA enzyme levels and/or GBA activity may also be defined as impaired GBA enzyme levels and/or GBA activity; insufficient GBA enzyme levels and/or GBA activity; or deficient GBA enzyme levels and/or GBA activity.
  • the GBA-associated disorder is referred to as a GBA-deficiency.
  • the GBA-associated disorder has a GBA activity and/or enzyme level which is reduced yet sufficient to remain clinically unaffected with respect to Gaucher's disease (i.e. does not have and is not diagnosed with Gaucher's disease). In one embodiment the GBA-associated disorder has a GBA activity and/or enzyme level which is reduced compared to wild type activity levels.
  • the GBA-associated disorder is associated with one or more individual GBA gene mutations. In one embodiment the GBA-associated disorder is an individual having one or more GBA gene mutations who remain clinically unaffected re Gaucher's disease.
  • the GBA-associated disorder is associated with one or more mild GBA gene mutations (associated with GD type I; TI).
  • the GBA-associated disorder is associated with one or more severe GBA gene mutations (associated with GD type II; TII, and GD type III; TIII).
  • the GBA-associated disorder is associated with one or more heterozygous GBA gene mutations, wherein said heterozygous GBA gene mutations do not cause or result in the development of Gaucher's disease.
  • the GBA-associated disorder is an individual having one or more heterozygous GBA gene mutations who remain clinically unaffected re Gaucher's disease.
  • the GBA-associated disorder is associated with one or more homozygous GBA gene mutations and/or compound heterozygous GBA gene mutations, wherein said GBA gene mutations do not cause or result in the development of Gaucher's disease.
  • the GBA-associated disorder is an individual having one or more homozygous and/or compound heterozygous GBA gene mutations who remain clinically unaffected re Gaucher's disease.
  • GBA gene that may affect the activity of the GBA protein include L444P, D409H, D409V, E235A, E340A, E326K, N370S, N370S/1-BP ins 84G, V394L, A456P, V460V, C342G, G325R, P415R, Y133*, F213I, N188S and IVS2+1G>A/N188S.
  • the GBA-associated disorder is associated with (or comprises, presents with) one or more mutations in the GBA gene selected from the group consisting of L444P, D409H, D409V, E235A, E340A, E326K, N370S, N370S/1-BP ins 84G, V394L, A456P, V460V, C342G, G325R, P415R Y133*, F213I, N188S and IVS2+1G>A/N188S.
  • Said one or more mutations in the GBA gene can be heterozygous, compound heterozygous or homozygous mutations.
  • the GBA-associated disorder is an individual having one or more GBA gene mutations selected from the group consisting of L444P, D409H, D409V, E235A, E340A, E326K, N370S, N370S/1-BP ins 84G, V394L, A456P, V460V, C342G, G325R, P415R Y133*, F213I, N188S and IVS2+1G>A/N188S who remain clinically unaffected re Gaucher's disease.
  • Said one or more mutations in the GBA gene can be heterozygous, compound heterozygous or homozygous mutations.
  • the GBA-associated disorder is associated with the L444P GBA gene mutation (L444P/, L444P/+ or L444P/L444P).
  • L444P/+ A heterozygous GBA allele containing the L444P mutation may be referred to as L444P/+.
  • the GBA-associated disorder is associated with the D409H GBA gene mutation.
  • the GBA-associated disorder is associated with the D409V GBA gene mutation.
  • the GBA-associated disorder is associated with the E235A GBA gene mutation.
  • the GBA-associated disorder is associated with the E340A GBA gene mutation.
  • the GBA-associated disorder is associated with the E326K GBA gene mutation.
  • the GBA-associated disorder is associated with the N370S GBA gene mutation.
  • a homozygous GBA allele containing the N370S mutation may be referred to as N370S/N370S.
  • a heterozygous GBA allele containing the N370S mutation may be referred to as N370S/+.
  • the GBA-associated disorder is associated with the N370S/1-BP ins 84G GBA gene mutation.
  • the GBA-associated disorder is associated with the V394L GBA gene mutation.
  • the GBA-associated disorder is associated with the A456P GBA gene mutation.
  • the GBA-associated disorder is associated with the V460V GBA gene mutation.
  • the GBA-associated disorder is associated with the C342G GBA gene mutation.
  • the GBA-associated disorder is associated with the G325R GBA gene mutation.
  • the GBA-associated disorder is associated with the P415R GBA gene mutation.
  • the GBA-associated disorder is associated with the Y133* GBA gene mutation.
  • the GBA-associated disorder is associated with the F213I GBA gene mutation.
  • the GBA-associated disorder is associated with the N188S and/or IVS2+1G>A/N188S GBA gene mutation.
  • the GBA-associated disorder is associated with one or more GBA gene mutations without accompanying reduction in GBA enzyme activity.
  • the GBA-associated disorder is associated with reduced GBA enzyme activity and said GBA gene is wild-type. In one embodiment the GBA-associated disorder is associated with idiopathic reduced GBA enzyme activity.
  • a wild type GBA allele may be referred to as (+/+) (no GBA mutation).
  • the GBA-associated disorder is associated with reduced GBA activity due to suppression of activity of the protein.
  • the GBA-associated disorder is associated with reduced GBA activity due to repression of transcription or translation of the gene/protein.
  • the GBA-associated disorder is associated with reduced GBA activity and said GBA gene is wild-type, and the reduction in GBA activity is due to suppression of activity of the protein and/or repression of transcription or translation of the gene/protein.
  • the GBA-associated disorder is an individual with a heterozygous GBA allele containing one or more mutations selected from the group consisting of L444P, D409H, D409V, E235A, E340A, E326K, N370S, N370S/1-BP ins 84G, V394L, A456P, V460V, C342G, G325R, P415R, Y133*, F213I, N188S and IVS2+1G>A/N188S.
  • the GBA-associated disorder is an individual with a heterozygous GBA allele containing the L444P, A456P, V460V mutations in cis.
  • the GBA-associated disorder is a L444P, A456P, V460V Heterozygote.
  • the GBA-associated disorder is heterozygous for the complex GBA allele L444P, A456P, V460V.
  • the GBA-associated disorder is a GBA mutation carrier. In one embodiment the GBA-associated disorder is an obligate carrier. In one embodiment the GBA mutation carrier is clinically unaffected re. Gaucher's disease.
  • the GBA-associated disorder is a clinically unaffected grand-parent, parent, sibling or child of a Gaucher's disease patient.
  • the GBA-associated disorder is a clinically unaffected parent or sibling of a Gaucher's disease patient.
  • the GBA-associated disorder is an individual with a homozygous or compound heterozygous GBA allele containing one or more mutations selected from the group consisting of L444P, D409H, D409V, E235A, E340A, E326K, N370S, N370S/1-BP ins 84G, V394L, A456P, V460V, C342G, G325R, P415R, Y133*, F213I, N188S and IVS2+1G>A/N188S, wherein said individual remain clinically unaffected re Gaucher's disease.
  • the GBA-associated disorder is an individual with a homozygous GBA allele containing the N370S/N370S mutation.
  • an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of treating a glucocerebrosidase (GBA)-associated disorder, such as a glucocerebrosidase (GBA)-associated disorder other than Gaucher's disease (GD).
  • GBA glucocerebrosidase
  • GD Gaucher's disease
  • the glucocerebrosidase (GBA)-associated disorder is GBA-associated parkinsonism.
  • the GBA-associated disorder is a GBA-associated Lewy body disorder, such as a GBA-associated Lewy body disorder selected from the group consisting of GBA-associated Parkinson's disease, GBA-associated dementia with Lewy bodies, and GBA-associated multiple system atrophy.
  • an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of treating a GBA-associated alpha-synucleinopathy.
  • a GBA-associated alpha-synucleinopathy may be defined herein as an alpha-synucleinopathy having an association with the level and/or activity of GBA enzyme.
  • the alpha-synucleinopathy presents with reduced GBA levels and/or activity, which is associated with an increase in alpha-synuclein.
  • the treatment with arimoclomol reduces alpha-synuclein aggregation.
  • the treatment with arimoclomol increases GBA activity and/or levels.
  • an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of treating a GBA-associated alpha-synucleinopathy selected from the group consisting of GBA-associated Parkinson's disease (PD), GBA-associated dementia with Lewi bodies (DLB) and GBA-associated multiple system atrophy (MSA).
  • PD GBA-associated Parkinson's disease
  • DLB GBA-associated dementia with Lewi bodies
  • MSA GBA-associated multiple system atrophy
  • an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of treating Parkinson's disease, in particular GBA-associated Parkinson's disease.
  • the GBA-associated Parkinson's disease is Parkinson's disease associated with reduced GBA enzyme levels and/or activity.
  • the GBA-associated Parkinson's disease is Parkinson's disease associated with one or more GBA gene mutations. In one embodiment the individual with GBA-associated Parkinson's disease remain clinically unaffected re Gaucher's disease.
  • the GBA-associated Parkinson's disease is Parkinson's disease associated with a heterozygous GBA gene mutation.
  • the GBA-associated disorder is an individual having one or more heterozygous GBA gene mutations who remain clinically unaffected re Gaucher's disease.
  • the GBA-associated Parkinson's disease is Parkinson's disease associated with a homozygous GBA gene mutation.
  • the GBA-associated disorder is an individual having one or more homozygous and/or compound heterozygous GBA gene mutations who remain clinically unaffected re Gaucher's disease.
  • the GBA-associated disorder is a genetically high-risk Parkinson's disease GBA genotype. In one embodiment the GBA-associated disorder is GBA-deficient Parkinson's disease (PD-GBA). In one embodiment the GBA-associated disorder is Parkinson's disease patients with heterozygous GBA alleles.). In one embodiment the GBA-associated disorder is Parkinson's disease patients with homozygous GBA alleles, clinically unaffected re Gaucher's disease.
  • PD-GBA GBA-deficient Parkinson's disease
  • the GBA-associated disorder is Parkinson's disease patients with heterozygous GBA alleles.
  • the GBA-associated disorder is Parkinson's disease patients with homozygous GBA alleles, clinically unaffected re Gaucher's disease.
  • the GBA-associated associated Parkinson's disease is Parkinson's disease associated with a GBA gene mutation selected from the group consisting of L444P, D409H, D409V, E235A, E340A, E326K, N370S, V394L, A456P, V460V, C342G, G325R, P415R, Y133*, F213I, N188S and IVS2+1G>A/N188S.
  • Said one or more mutations in the GBA gene can be heterozygous, compound heterozygous or homozygous mutations.
  • the individual presenting with the GBA gene mutation is clinically unaffected re Gaucher's disease.
  • the individual having GBA-associated associated Parkinson's disease has a GBA gene mutation selected from the group consisting of L444P, D409H, D409V, E235A, E340A, E326K, N370S, V394L, A456P, V460V, C342G, G325R, P415R, Y133*, F213I, N188S and IVS2+1G>A/N188S.
  • the GBA-associated associated Parkinson's disease is Parkinson's disease associated with a N370S GBA gene mutation.
  • the GBA-associated associated Parkinson's disease is Parkinson's disease associated with a heterozygous N370S GBA gene mutation (N370S/+).
  • the GBA-associated associated Parkinson's disease is Parkinson's disease associated with a homozygous N370S GBA gene mutation (N370S/N370S).
  • the GBA-associated associated Parkinson's disease is Parkinson's disease associated with a heterozygous L444P GBA gene mutation.
  • the GBA-associated associated Parkinson's disease is Parkinson's disease associated with a heterozygous A456P GBA gene mutation.
  • the GBA-associated associated Parkinson's disease is Parkinson's disease associated with a heterozygous V460V GBA gene mutation.
  • the GBA-associated associated Parkinson's disease is Parkinson's disease associated with a heterozygous E326K GBA gene mutation.
  • the GBA-associated disorder is Parkinson's disease associated with idiopathic reduced GBA activity and/or levels. In one embodiment the GBA-associated disorder is Parkinson's disease with idiopathic reduced GBA activity and/or levels, wherein no GBA gene mutations are identified.
  • an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of one or more of
  • arimoclomol is for use in a method of increasing GBA levels and/or activity in an individual having a GBA-associated disorder, such as a GBA-associated alpha-synucleinopathy, such as GBA-associated Parkinson's disease.
  • a GBA-associated disorder such as a GBA-associated alpha-synucleinopathy, such as GBA-associated Parkinson's disease.
  • said GBA activity is increased to 50% or more of hypothetical wild-type activity levels, such as 50-60%, such as 60-70%, such as 70-80%, such as 80-90%, such as 90-100%, such as 100-110%, such as 110-120%, such as 120-130%, such as 130-140%, such as 140-150% of hypothetical wild-type activity levels.
  • hypothetical wild-type activity levels such as 50-60%, such as 60-70%, such as 70-80%, such as 80-90%, such as 90-100%, such as 100-110%, such as 110-120%, such as 120-130%, such as 130-140%, such as 140-150% of hypothetical wild-type activity levels.
  • said GBA activity is increased to hypothetical wild-type activity levels or more.
  • said GBA activity is increased at least 10%, such as at least 20%, for example at least 30%, such as at least 40%, for example at least 50%, such as at least 60%, for example at least 70%, such as at least 80%, for example at least 90%, such as at least 100%, for example at least 110%, such as at least 120%, for example at least 130%, such as at least 140%, for example at least 150%, such as at least 160%, for example at least 170%, such as at least 180%, for example at least 190%, such as at least 200%, for example at least 210%, such as at least 220%, for example at least 230%, such as at least 240%, for example at least 250%, such as at least 260%, for example at least 200%, such as at least 270%, for example at least 280%, such as at least 290%, for example at least 300%.
  • said GBA level (or amount) is increased to 50% or more of hypothetical wild-type levels, such as 50-60%, such as 60-70%, such as 70-80%, such as 80-90%, such as 90-100%, such as 100-110%, such as 110-120%, such as 120-130%, such as 130-140%, such as 140-150% of hypothetical wild-type levels.
  • hypothetical wild-type levels such as 50-60%, such as 60-70%, such as 70-80%, such as 80-90%, such as 90-100%, such as 100-110%, such as 110-120%, such as 120-130%, such as 130-140%, such as 140-150% of hypothetical wild-type levels.
  • said GBA level is increased to hypothetical wild-type levels or more.
  • said GBA level and/or activity is increased at least 1.5-fold, such as at least 2-fold, for example at least 2.5-fold, such as at least 3-fold.
  • said GBA level is increased at least 10%, such as at least 20%, for example at least 30%, such as at least 40%, for example at least 50%, such as at least 60%, for example at least 70%, such as at least 80%, for example at least 90%, such as at least 100%, for example at least 110%, such as at least 120%, for example at least 130%, such as at least 140%, for example at least 150%, such as at least 160%, for example at least 170%, such as at least 180%, for example at least 190%, such as at least 200%, for example at least 210%, such as at least 220%, for example at least 230%, such as at least 240%, for example at least 250%, such as at least 260%, for example at least 200%, such as at least 270%, for example at least 280%, such as at least 290%, for example at least 300%.
  • an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of reducing alpha-synuclein aggregation.
  • an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of reducing risk in an individual of developing a glucocerebrosidase (GBA)-associated disorder other than Gaucher's disease, wherein said individual has reduced GBA enzyme level and/or activity.
  • GBA glucocerebrosidase
  • said individual has GBA levels and/or activity lower than hypothetical wild-type levels.
  • said individual has GBA levels (or amount) lower than hypothetical wild-type levels.
  • said individual has GBA activity lower than hypothetical wild-type activity levels.
  • said individual has GBA levels and/or activity higher than clinically affected levels and/or activity in a patient with Gaucher's disease.
  • said individual has GBA levels and/or activity lower than hypothetical wild-type levels and/or activity, yet higher than clinically affected levels and/or activity in a patient with Gaucher's disease.
  • said individual has reduced GBA activity to the same degree as a GBA gene mutation carrier (heterozygous GBA mutation), such as a clinically unaffected carrier, such as an obligate carrier.
  • a GBA gene mutation carrier heterozygous GBA mutation
  • a clinically unaffected carrier such as an obligate carrier.
  • said individual has reduced GBA levels to the same degree as a GBA gene mutation carrier (heterozygous GBA mutation), such as a clinically unaffected carrier, such as an obligate carrier.
  • a GBA gene mutation carrier heterozygous GBA mutation
  • a clinically unaffected carrier such as an obligate carrier.
  • said individual with reduced GBA levels and/or activity has one or more heterozygous GBA gene mutations.
  • said individual with reduced GBA levels and/or activity has one or more homozygous or compound heterozygous GBA gene mutations.
  • said individual has reduced GBA activity and/or level to a certain extent of hypothetical wild type levels.
  • said individual has GBA activity and/or levels of about 5 to 95% or 10 to 90% of hypothetical wild type levels, such as 5 to 10%, such as 10 to 20%, such as 20 to 30%, such as 30 to 40%, such as 40 to 50%, such as 50 to 60%, such as 60 to 70%, such as 70 to 80%, such as 80 to 90%, such as 90 to 95% of hypothetical wild type activity and/or levels.
  • said individual has GBA activity and/or levels of about 25 to 75% of hypothetical wild type levels. In one embodiment said individual has GBA activity and/or levels of about 50% of hypothetical wild type levels.
  • said individual has GBA activity and/or levels of about 10 of hypothetical wild type levels and/or activity, such as 20%, such as 30%, such as 40%, such as 50%, such as 60%, such as 70%, such as 80%, such as 90% of hypothetical wild type levels and/or activity.
  • said GBA-associated disorder is a GBA-associated alpha-synucleinopathy, such as a GBA-associated alpha-synucleinopathy selected from the group consisting of GBA-associated Parkinson's disorder (PD), GBA-associated dementia with Lewi bodies (DLB) and GBA-associated multiple system atrophy (MSA).
  • PD GBA-associated Parkinson's disorder
  • DLB GBA-associated dementia with Lewi bodies
  • MSA GBA-associated multiple system atrophy
  • an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of reducing risk in an individual of developing Parkinson's disease, in particular GBA-associated Parkinson's disease, wherein said individual has reduced GBA enzyme levels and/or activity.
  • said individual has one or more heterozygous GBA gene mutations. In one embodiment said individual has one or more heterozygous GBA gene mutations selected from the group consisting of L444P, D409H, D409V, E235A, E340A, E326K, N370S, N370S/1-BP ins 84G, V394L, A456P, V460V, C342G, G325R, P415R, Y133*, F213I, N188S and IVS2+1G>A/N188S. In one embodiment said individual has a heterozygous L444P GBA gene mutation. In one embodiment said individual has a heterozygous E326K GBA gene mutation. In one embodiment said individual has a heterozygous N370S GBA gene mutation.
  • said individual has one or more homozygous GBA gene mutations.
  • said individual has one or more homozygous GBA gene mutations selected from the group consisting of L444P, D409H, D409V, E235A, E340A, E326K, N370S, N370S/1-BP ins 84G, V394L, A456P, V460V, C342G, G325R, P415R, Y133*, F213I, N188S and IVS2+1G>A/N188S.
  • said individual has a homozygous N370S GBA gene mutation.
  • an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of reducing risk in an individual of developing GBA-associated Parkinson's disease, wherein said individual is a patient with Gaucher's disease, such as Gaucher's disease type I, type II or type III.
  • Glucocerebrosidase activity can be assessed by methods known in the art.
  • the glucocerebrosidase activity may be measured from the cerebral spinal fluid of mammals.
  • the mammal is wild-type for the GBA gene.
  • wild-type refers to a gene or protein with no detectable mutations known to affect the level and/or enzymatic activity of the protein.
  • the reduction in activity may be due to suppression of activity of the protein or repression of transcription or translation of the gene/protein.
  • These mechanisms are well known in the art.
  • the production of the protein may be repressed by aberrant cellular mechanism.
  • the protein may be modified in the cell which causes reduced or loss of enzymatic activity.
  • arimoclomol herein encompasses an active pharmaceutical ingredient (API) selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride (arimoclomol), its stereoisomers and the acid addition salts thereof.
  • API active pharmaceutical ingredient
  • Arimoclomol is further described in e.g. WO 00/50403.
  • Arimoclomol refers to the base compound N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its optically active (+) or ( ⁇ ) enantiomer, a mixture of the enantiomers of any ratio, and the racemic compound, furthermore, the acid addition salts formed from any of the above compounds with mineral or organic acids constitute objects of the present invention. All possible geometrical isomer forms of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride belong to the scope of the invention.
  • stereoisomers of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride refers to all possible optical and geometrical isomers of the compound.
  • N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride or one of its optically active enantiomers can be transformed into an acid addition salt with a mineral or organic acid, by known methods.
  • the active pharmaceutical ingredient is the racemate of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.
  • the active pharmaceutical ingredient is an optically active stereoisomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.
  • the active pharmaceutical ingredient is an enantiomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.
  • the active pharmaceutical ingredient is selected from the group consisting of (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride and ( ⁇ )-(S)—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.
  • the active pharmaceutical ingredient is an acid addition salt of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.
  • the active pharmaceutical ingredient is selected from the group consisting of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (also known as BRX-345), and N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate (also known as BRX-220).
  • the active pharmaceutical ingredient is selected from the group consisting of (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate; ( ⁇ )-S—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate; (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate; and ( ⁇ )-S—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate.
  • compositions such as a pharmaceutical composition, i.e. a pharmaceutically safe composition, comprising an active pharmaceutical ingredient as defined herein.
  • the composition in one embodiment comprises a pharmaceutically and/or physiologically acceptable carriers or excipients.
  • compositions containing a bioactive agent of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 20 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 2000.
  • composition such as a pharmaceutical composition, comprising an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof (arimoclomol), for use in the treatment of a glucocerebrosidase (GBA)-associated disorder other than Gaucher's disease (GD) as defined herein.
  • GAA glucocerebrosidase
  • GD Gaucher's disease
  • An active pharmaceutical ingredient or composition comprising the same as defined herein is in one embodiment administered to individuals in need thereof in pharmaceutically effective doses or a therapeutically effective amount.
  • a therapeutically effective amount of an active pharmaceutical ingredient is in one embodiment an amount sufficient to cure, prevent, reduce the risk of, alleviate or partially arrest the clinical manifestations of a given disease or disorder and its complications.
  • the amount that is effective for a particular therapeutic purpose will depend on the severity and the sort of the disorder as well as on the weight and general state of the subject. An amount adequate to accomplish this is defined as a “therapeutically effective amount”.
  • the composition is administered in doses of 1 ⁇ g/day to 100 mg/day; such as 1 ⁇ g/day to 10 ⁇ g/day, such as 10 ⁇ g/day to 100 ⁇ g/day, such as 100 ⁇ g/day to 250 ⁇ g/day, such as 250 ⁇ g/day to 500 ⁇ g/day, such as 500 ⁇ g/day to 750 ⁇ g/day, such as 750 ⁇ g/day to 1 mg/day, such as 1 mg/day to 2 mg/day, such as 2 mg/day to 5 mg/day, or such as 5 mg/day to 10 mg/day, such as 10 mg/day to 20 mg/day, such as 20 mg/day to 30 mg/day, such as 30 mg/day to 40 mg/day, such as 40 mg/day to 50 mg/day, such as 50 mg/day to 75 mg/day, such as 75 mg/day to 100 mg/day, such as 100 mg/day to 150 mg/day, such as 150 mg/day to 200 mg/day, or such
  • the active pharmaceutical ingredient or composition is administered at a dose of 1 ⁇ g/kg body weight to 100 mg/kg body weight; such as 1 to 10 ⁇ g/kg body weight, such as 10 to 100 ⁇ g/day, such as 100 to 250 ⁇ g/kg body weight, such as 250 to 500 ⁇ g/kg body weight, such as 500 to 750 ⁇ g/kg body weight, such as 750 ⁇ g/kg body weight to 1 mg/kg body weight, such as 1 mg/kg body weight to 2 mg/kg body weight, such as 2 to 5 mg/kg body weight, such as 5 to 10 mg/kg body weight, such as 10 to 20 mg/kg body weight, such as 20 to 30 mg/kg body weight, such as 30 to 40 mg/kg body weight, such as 40 to 50 mg/kg body weight, such as 50 to 75 mg/kg body weight, or such as 75 to 100 mg/kg body weight.
  • 1 ⁇ g/kg body weight to 100 mg/kg body weight such as 1 to 10 ⁇ g/kg body weight, such as 10 to 100 ⁇
  • a dose is administered one or several times per day, such as from 1 to 6 times per day, such as from 1 to 5 times per day, such as from 1 to 4 times per day, such as from 1 to 3 times per day, such as from 1 to 2 times per day, such as from 2 to 4 times per day, such as from 2 to 3 times per day. In one embodiment, a dose is administered less than once a day, such as once every second day or once a week.
  • the preferred route of administration will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated, the location of the tissue to be treated in the body and the active ingredient chosen.
  • the route of administration allows for introducing the bioactive agent into the blood stream to ultimately target the sites of desired action.
  • the routes of administration is any suitable route, such as an enteral route (including the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal and intraperitoneal administration), and/or a parenteral route (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal administration).
  • an enteral route including the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal and intraperitoneal administration
  • a parenteral route including subcutaneous, intramuscular, intrathecal, intravenous and intradermal administration.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • Parenteral administration is any administration route not being the oral/enteral route whereby the bioactive agent avoids first-pass degradation in the liver. Accordingly, parenteral administration includes any injections and infusions, for example bolus injection or continuous infusion, such as intravenous administration, intramuscular administration or subcutaneous administration. Furthermore, parenteral administration includes inhalations and topical administration.
  • the active pharmaceutical ingredient or composition is in one embodiment administered topically to cross any mucosal membrane of an animal, e.g. in the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract, or rectum, for example the mucosa of the nose, or mouth, and accordingly, parenteral administration may also include buccal, sublingual, nasal, rectal, vaginal and intraperitoneal administration as well as pulmonal and bronchial administration by inhalation or installation.
  • the bioactive agent is administered topically to cross the skin.
  • the intravenous, subcutaneous and intramuscular forms of parenteral administration are employed.
  • the active pharmaceutical ingredient t or composition is used as a local treatment, i.e. is introduced directly to the site(s) of action. Accordingly, the active pharmaceutical ingredient may be applied to the skin or mucosa directly, or may be injected into the site of action, for example into the diseased tissue or to an end artery leading directly to the diseased tissue.
  • an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof (arimoclomol), for use in a method of treating a glucocerebrosidase (GBA)-associated disorder other than Gaucher's disease (GD), in combination with other treatment modalities.
  • GBA glucocerebrosidase
  • GD Gaucher's disease
  • the active pharmaceutical ingredient is administered to an individual in need thereof in combination with at least one other treatment modality, such as conventional or known treatment modalities for (GBA)-associated disorders including GBA-associated alpha-synucleinopathies such as GBA-associated Parkinson's disease (PD), GBA-associated dementia with Lewi bodies (DLB) and GBA-associated multiple system atrophy (MSA).
  • Administering more than one treatment modality in combination may occur either simultaneously, or sequentially.
  • Simultaneous administration may be two compounds comprised in the same composition or comprised in separate compositions, or may be one composition and one other treatment modality performed essentially at the same time.
  • Sequential administration means that the more than one treatment modalities are administered at different time points, such as administering one treatment modality first, and administering the second treatment modality subsequently.
  • the time frame for administering more than one treatment modality sequentially may be determined by a skilled person in the art for achieving the optimal effect, and may in one embodiment be between 30 minutes to 72 hours.
  • the treatment modalities in the form of chemical compounds may be administered together or separately, each at its most effective dosage. Administering more than one compound may have a synergistic effect, thus effectively reducing the required dosage of each drug.
  • compositions comprising, separately or together, i) an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof (arimoclomol), and ii) other treatment modalities, for use in the treatment of (GBA)-associated disorders including GBA-associated alpha-synucleinopathies such as GBA-associated Parkinson's disease (PD), GBA-associated dementia with Lewi bodies (DLB) and GBA-associated multiple system atrophy (MSA).
  • treatment modalities or conventional or known treatment modalities, are referred to as further active ingredients.
  • the active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof (arimoclomol), is administered in combination with, and/or formulated as a combination product, with one or more further active ingredients.
  • the further active ingredient is selected from one or more active ingredients known and/or employed in the treatment of (GBA)-associated disorders including GBA-associated alpha-synucleinopathies such as GBA-associated Parkinson's disease (PD), GBA-associated dementia with Lewi bodies (DLB) and GBA-associated multiple system atrophy (MSA).
  • GBA GBA-associated alpha-synucleinopathies such as GBA-associated Parkinson's disease (PD), GBA-associated dementia with Lewi bodies (DLB) and GBA-associated multiple system atrophy (MSA).
  • the further active ingredient is a compound used for the treatment of Parkinson's disease.
  • said compound used for the treatment of Parkinson's disease is selected from the group consisting of dopamine, L-DOPA, levodopa, dopamine receptor agonists, carboxylase inhibitors such as carbidopa or benserazide, NMDA antagonists such as for example amatidine (Symmetrel), catechol-O-methyl transferase (COMT) inhibitors such as for example tolcapone and entacapone, MAO-B inhibitors such as for example selegiline and rasagiline, Carbidopa-levodopa, Anticholinergics and Amantadine.
  • the further active ingredient is a compound used for the treatment of Gaucher's disease.
  • the further active ingredient is selected from the group consisting of enzyme replacement therapies, allosteric chaperones, pharmacological chaperones and substrate reduction therapies.
  • said further active ingredient is selected from the group consisting of miglustat (Zavesca), imiglucerase (Cerezyme), eliglustat (Cerdelga), VPRIV, taliglucerase alfa (Elelyso) and velaglurase alpha.
  • Example 1 Dose-Dependent Response in Gaucher Type II Heterozygotes (Parkinsons Disease Genotype)—BiP and GBA Induction
  • fibroblast cell lines were cultured under standard cell culture conditions (37° C. and 5% CO 2 ) in DMEM supplemented with non-essential amino acids (NEAA), 1% Pen-Strep and 12% FCS. They were passaged 1-2 times/week with a split ratio of 1:2 or 1:3. Cells were used for experiments around passage 16-26 where no signs of replicative senescence were observed (visual inspection).
  • NEAA non-essential amino acids
  • FCS 12% FCS
  • Arimoclomol is reported to increase the expression levels of heat-shock proteins, e.g. heat-shock protein 70 (HSP70) (Kieran et al., Nature Medicine, 2004).
  • HSP70 heat-shock protein 70
  • arimoclomol on the ER Hsp70 (BiP) expression level in primary cells
  • human fibroblasts from individual with a heterozygous GBA allele containing the L444P, A456P, V460V mutations in cis carrier, clinically unaffected re. Gaucher's disease
  • Cells were then harvested for western blot analysis.
  • a lysate from untreated normal human fibroblasts was used for control.
  • arimoclomol on GBA protein levels was also evaluated in the human fibroblasts cell line heterozygous for the complex GBA allele L444P, A456P, V460V.
  • a dose-dependent increase in the total level of GBA is seen in arimoclomol-treated cells.
  • fibroblast cell lines were cultured under standard cell culture conditions (37° C. and 5% CO 2 ) in DMEM supplemented with non-essential amino acids (NEAA), 1% Pen-Strep and 12% FCS. They were passaged 1-2 times/week with a split ratio of 1:2 or 1:3. Cells were used for experiments around passage 16-26 where no signs of replicative senescence were observed (visual inspection).
  • NEAA non-essential amino acids
  • FCS 12% FCS
  • GBA activity was measured using the “intact cell” GBA assay using the 4-Methylumbelliferyl beta-D-glucopyranoside (4-MUG) substrate (Mu et al, Cell, 2008). Briefly, fibroblasts were seeded in 12 well plates and treated in biological triplicate with indicated concentrations of arimoclomol for 4 weeks. Medium was replenished with fresh compound every 2-3 days and the cells were split twice during the experiment. After 4 weeks of treatment, cells were transferred to 96 well plates and GBA activity was measured using 4-MUG as substrate at pH 4.0. The released 4-MU fluorophore was quantified as Fluorescence Units (FLU) and normalized to cell density using crystal violet staining of a parallel plate. The normalized data is reported as Arbitrary Units (mean ⁇ SD).
  • FLU Fluorescence Units
  • arimoclomol treatment increased GBA activity in a dose-dependent manner.
  • the increase in GBA activity induced by 50 ⁇ M arimoclomol corresponds to the activity level of cells heterozygous for the L444P, A456P, V460V allele (marked by grey line in FIG. 3 ) from a non-symptomatic individual.
  • arimoclomol also increases the GBA activity in primary fibroblasts that are heterozygous for the L444P, A456P, V460V allele. This result demonstrates that GBA activity can be increased even in cells from mutant GBA heterozygotes (carriers).
  • fibroblast cell lines were cultured under standard cell culture conditions (37° C. and 5% CO 2 ) in DMEM supplemented with non-essential amino acids (NEAA), 1% Pen-Strep and 12% FCS. They were passaged 1-2 times/week with a split ratio of 1:2 or 1:3. Cells were used for experiments around passage 16-26 where no signs of replicative senescence were observed (visual inspection).
  • NEAA non-essential amino acids
  • FCS 12% FCS
  • GBA activity was measured using the “intact cell” GBA assay using the 4-Methylumbelliferyl beta-D-glucopyranoside (4-MUG) substrate (Mu et al, Cell, 2008). Briefly, fibroblasts were seeded in 96 well plates and treated in biological triplicate with indicated concentrations of arimoclomol for 5 days. Medium was replenished with fresh compound every 2-3 days. GBA activity was measured using 4-MUG as substrate at pH 4.0. The released 4-MU fluorophore was quantified as Fluorescence Units (FLU) and normalized to cell density using crystal violet staining of a parallel plate. The normalized data is reported as fold change relative to mock-treated control cells (mean ⁇ SD).
  • FLU Fluorescence Units
  • arimoclomol The effect of arimoclomol on GBA activity in primary cells with additional mutations of GBA was evaluated by treating cells of the indicated genotype with arimoclomol.
  • Our data show that arimoclomol dose-dependently increases GBA activity in two GD type I cell lines: N370S/V394L and N370S/1-BP ins 84G.
  • the 1-BP ins 84G is considered to be a null-allele, these results demonstrate that arimoclomol increases the activity of the N370S mutation.
  • a dose-dependent effect of arimoclomol is also seen for GBA activity in primary cells from GD type II/III patients which are either homozygotes for L444P (L444P/L444P) or compound heterozygotes for the GBA mutations G325R/C342G or P415R/L444P.
  • L444P/L444P homozygotes for L444P
  • compound heterozygotes for the GBA mutations G325R/C342G or P415R/L444P.
  • a less pronounced increase of GBA activity is found in arimoclomol-treated type II GD cells homozygous for the E326K, L444P allele.
  • Example 4 Dose-Dependent Response on GBA Activity in Primary Cells from a Parkinson Disease Patient with a Heterozygous GBA Allele Containing the N370S Mutation
  • the primary human fibroblast cell line was cultured under standard cell culture conditions (37° C. and 5% CO 2 ) in DMEM supplemented with non-essential amino acids (NEAA), 1% Pen-Strep and 12% FCS. The cells were passaged 1 time/week with a split ratio of 1:2. Cells were used for experiments around passage 16-26 where no signs of replicative senescence were observed (visual inspection).
  • GBA activity was measured using the “intact cell” GBA assay using the 4-Methylumbelliferyl beta-D-glucopyranoside (4-MUG) substrate (Mu et al, Cell, 2008). Briefly, fibroblasts were seeded in 96 well plates and treated in biological triplicate with indicated concentrations of arimoclomol for 5 days. Medium was replenished with fresh compound every 2-3 days. GBA activity was measured using 4-MUG as substrate at pH 4.0. The released 4-MU fluorophore was quantified as Fluorescence Units (FLU) and normalized to cell density using crystal violet staining of a parallel plate. The normalized data is reported as fold change relative to mock-treated control cells (mean ⁇ SD).
  • FLU Fluorescence Units
  • fibroblast cell lines were cultured under standard cell culture conditions (37° C. and 5% CO 2 ) in DMEM supplemented with non-essential amino acids (NEAA), 1% Pen-Strep and 12% FCS. They were passaged 1-2 times/week with a split ratio of 1:2 or 1:3. Cells were used for experiments around passage 16-26 where no signs of replicative senescence were observed (visual inspection).
  • NEAA non-essential amino acids
  • FCS 12% FCS
  • GBA activity was measured using the “intact cell” GBA assay using the 4-Methylumbelliferyl beta-D-glucopyranoside (4-MUG) substrate (Mu et al, Cell, 2008). Briefly, fibroblasts were seeded in 96 well plates and treated in biological triplicate with indicated concentrations of arimoclomol for 5 days. Medium was replenished with fresh compound every 2-3 days. GBA activity was measured using 4-MUG as substrate at pH 4.0. The released 4-MU fluorophore was quantified as Fluorescence Units (FLU) and normalized to cell density using crystal violet staining of a parallel plate. The normalized data is reported as fold change relative to mock-treated control cells (mean ⁇ SD).
  • FLU Fluorescence Units
  • arimoclomol treatment increased WT GBA activity in a dose-dependent manner in all three cell lines albeit to different magnitude.
  • fibroblast cell lines were cultured under standard cell culture conditions (37° C. and 5% CO2) in DMEM supplemented with non-essential amino acids (NEAA), 1% Pen-Strep and 12% FCS. They were passaged 1-2 times/week with a split ratio of 1:2 or 1:3. Cells were used for experiments around passage 16-26 where no signs of replicative senescence were observed (visual inspection).
  • Active GBA can be selectively labeled with the fluorescent activity-based probe (ABP) ME569 (Witte et al, 2010). Briefly, fibroblasts were seeded in dishes and treated in biological duplicates with the indicated concentrations of arimoclomol for 5 days. Medium was replenished with fresh compound every 2-3 days. Cells were collected in PBS, proteins were extracted and the concentrations were determined using the BCA assay. Equal amount of total protein was incubated with ME569 for 30 minutes at 37° C. Loading buffer was added, samples were incubated for 5 min at 98° C. and then subjected to SDS-PAGE using the TGX gel system (Bio-Rad).
  • ABSP fluorescent activity-based probe
  • arimoclomol The effect of arimoclomol on the amount of GBA labeled with fluorescent ABP was evaluated in primary cells from GD patients of the indicated genotype.
  • Our data show that arimoclomol dose-dependently increases GBA labeling in the GD TI cell line (N370S/V394L) and the GD TII cell line (G325R/C342G). Only the high dose of arimoclomol was evaluated in the GD TII cell line (homozygotes for L444P) and also in this cell line, arimoclomol increases the amount of GBA that can be labeled with fluorescent ABP.
  • Example 7 Dose-Dependent Response in Gaucher Type I—BiP and GBA Induction
  • fibroblast cell lines were cultured under standard cell culture conditions (37° C. and 5% CO 2 ) in DMEM supplemented with non-essential amino acids (NEAA), 1% Pen-Strep and 12% FCS. They were passaged 1-2 times/week with a split ratio of 1:2 or 1:3. Cells were used for experiments around passage 16-26 where no signs of replicative senescence were observed (visual inspection).
  • NEAA non-essential amino acids
  • FCS 12% FCS
  • Cells were collected in PBS and centrifuged at 3500 rpm for 5 min at 4° C. Cell pellets were lysed in lysis buffer (Enzo Life Science) containing protease inhibitors, sonicated and cleared by centrifugation at 13000 rpm for 10 min at 4° C. Protein concentration was measured by the BCA assay. Samples containing approx. 10-20 ⁇ g protein were diluted in glycoprotein denaturing buffer (New England Biolabs) and denatured by incubation for 10 min at 100° C.
  • lysis buffer Enzo Life Science
  • Arimoclomol is reported to increase the expression levels of heat-shock proteins, e.g. heat-shock protein 70 (HSP70) (Kieran et al., Nature Medicine, 2004).
  • HSP70 heat-shock protein 70
  • arimoclomol increases the amount of processed/maturated GBA in the cell.
  • Example 8 Dose-Dependent Response in Gaucher Type II—BiP and GBA Induction
  • fibroblast cell lines were cultured under standard cell culture conditions (37° C. and 5% CO 2 ) in DMEM supplemented with non-essential amino acids (NEAA), 1% Pen-Strep and 12% FCS. They were passaged 1-2 times/week with a split ratio of 1:2 or 1:3. Cells were used for experiments around passage 16-26 where no signs of replicative senescence were observed (visual inspection).
  • NEAA non-essential amino acids
  • FCS 12% FCS
  • Cells were collected in PBS and centrifuged at 3500 rpm for 5 min at 4° C. Cell pellets were lysed in lysis buffer (Enzo Life Science) containing protease inhibitors, sonicated and cleared by centrifugation at 13000 rpm for 10 min at 4° C. Protein concentration was measured by the BCA assay. Samples containing approx. 10-20 ⁇ g protein were diluted in glycoprotein denaturing buffer (New England Biolabs) and denatured by incubation for 10 min at 100° C.
  • lysis buffer Enzo Life Science
  • arimoclomol on the ER Hsp70 (BiP) expression level in primary cells.
  • human fibroblasts from type II Gaucher disease patients were treated with the indicated concentrations of arimoclomol for 5 days. Cells were then harvested for western blot analysis.
  • arimoclomol increases the amount of matured (post-ER) GBA in GD type II cells.
  • NEAA non-essential amino acids
  • Pen-Strep and 12% FCS were passaged 1-2 times/week with a split ratio of 1:2 or 1:3. Cells were used for experiments around passage 16-26 where no signs of replicative senescence were observed (visual inspection).
  • Cells were collected in PBS and centrifuged at 3500 rpm for 5 min at 4° C. Cell pellets were lysed in lysis buffer (Enzo Life Science) containing protease inhibitors, sonicated and cleared by centrifugation at 13000 rpm for 10 min at 4° C. Protein concentration was measured by the BCA assay. Samples containing approx. 10-20 ⁇ g protein were diluted in glycoprotein denaturing buffer (New England Biolabs) and denatured by incubation for 10 min at 100° C.
  • lysis buffer Enzo Life Science
  • arimoclomol on the ER Hsp70 (BiP) expression level in primary cells.
  • human fibroblasts from an individual with type III Gaucher disease (L444P/L444P) were treated with the indicated concentrations of arimoclomol for 5 days. Cells were then harvested for western blot analysis.
  • fibroblast cells Primary human fibroblast cells were cultured under standard cell culture conditions (37° C. and 5% CO 2 ) in DMEM supplemented with non-essential amino acids (NEAA), 1% Pen-Strep and 12% FCS. They were passaged 1-2 times/week with a split ratio of 1:2 or 1:3. Cells were used for experiments around passage 16-26 where no signs of replicative senescence were observed (visual inspection).
  • NEAA non-essential amino acids
  • FCS 12% FCS
  • arimoclomol on the ER Hsp70 (BiP) expression level in primary cells from an individual with GBA-deficient Parkinson Disease (PD-GBA)
  • PD-GBA GBA-deficient Parkinson Disease
  • human fibroblasts from an individual with PD-GBA N370S/N370S were treated with the indicated concentrations of arimoclomol for 5 days. Cells were then harvested for western blot analysis.
  • MASCs Human multipotent adult stem cells
  • the asterisk denotes a frameshift and consequential de novo stop codon
  • MASCs were induced to differentiate along the neuronal lineage at Day 0.
  • cells were treated with mock (PBS) or 400 ⁇ M arimoclomol. Treatment persisted throughout differentiation for a total 9 days.
  • differentiation was evaluated by immunofluorescence of neuronal markers. GBA activity was measured using the fluorogenic substrate 4-MUG.
  • Arimoclomol does not Affect Neuronal Differentiation of Skin-Derived Human Multipotent Adult Stem Cells from GD TI and GDTIII Individuals
  • MASCs from GD individuals were induced to differentiate while treated with mock or arimoclomol.
  • Our results show that the expression of the neuronal markers Tubulin beta 3 and NeuN was not affected by arimoclomol.
  • arimoclomol increases mutant GBA activity in neurons from an individual with GD type I (N370S/Y133*) and in three individuals with GD type Ill (F213I/L444P, L444P/L444P or IVS2+1G>A/N188S).
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Family Cites Families (126)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU645243B2 (en) 1988-03-18 1994-01-13 General Hospital Corporation, The Human heat shock factor
US5348945A (en) 1990-04-06 1994-09-20 Wake Forest University Method of treatment with hsp70
EP1221488A1 (en) 1993-06-04 2002-07-10 Whitehead Institute For Biomedical Research Stress proteins and uses therefor
CA2185826C (en) 1994-03-21 2007-06-19 Stephen Mark Anderton Peptide fragments of microbial stress proteins and pharmaceutical composition made thereof for the treatment and prevention of inflammatory diseases
US5837251A (en) 1995-09-13 1998-11-17 Fordham University Compositions and methods using complexes of heat shock proteins and antigenic molecules for the treatment and prevention of neoplastic diseases
US5985270A (en) 1995-09-13 1999-11-16 Fordham University Adoptive immunotherapy using macrophages sensitized with heat shock protein-epitope complexes
US5935576A (en) 1995-09-13 1999-08-10 Fordham University Compositions and methods for the treatment and prevention of neoplastic diseases using heat shock proteins complexed with exogenous antigens
HU222994B1 (hu) 1995-11-02 2004-01-28 BIOREX Kutató és Fejlesztő Rt. Hidroxilaminszármazékok és azok alkalmazása sejtek molekuláris chaperon-termelésének fokozására alkalmas gyógyszerkészítmények előállítására
US5962313A (en) 1996-01-18 1999-10-05 Avigen, Inc. Adeno-associated virus vectors comprising a gene encoding a lyosomal enzyme
US6066716A (en) 1996-09-20 2000-05-23 University Of New Mexico Purified heat shock protein complexes
US7157089B1 (en) 1996-11-26 2007-01-02 Stressgen Biotechnologies Corporation Immune responses using compositions containing stress proteins
US6017540A (en) 1997-02-07 2000-01-25 Fordham University Prevention and treatment of primary and metastatic neoplastic diseases and infectious diseases with heat shock/stress protein-peptide complexes
US5830464A (en) 1997-02-07 1998-11-03 Fordham University Compositions and methods for the treatment and growth inhibition of cancer using heat shock/stress protein-peptide complexes in combination with adoptive immunotherapy
US6007821A (en) 1997-10-16 1999-12-28 Fordham University Method and compositions for the treatment of autoimmune disease using heat shock proteins
US5948646A (en) 1997-12-11 1999-09-07 Fordham University Methods for preparation of vaccines against cancer comprising heat shock protein-peptide complexes
HUP0100241A2 (hu) 1998-01-23 2001-06-28 National Jewish Medical And Research Center Eljárás gyulladásos betegségek hősokk-proteinek alkalmazásával történő kezelésére
CA2321101C (en) 1998-02-20 2014-12-09 University Of Miami Modified heat shock protein-antigenic peptide complex
CA2325735C (en) 1998-03-27 2013-06-04 Gabriele Multhoff Hsp70 protein for the treatment of tumours, cancer or infectious diseases through nk-cell activation
FR2777890B1 (fr) 1998-04-22 2000-12-29 Roussy Inst Gustave Composes peptidiques d'hsp70 utiles dans l'immunotherapie du cancer
US6274597B1 (en) 1998-06-01 2001-08-14 Mount Sinai School Of Medicine Of New York University Method of enhancing lysosomal α-Galactosidase A
US6475490B1 (en) 1998-10-19 2002-11-05 Fordham University Compositions and methods for promoting tissue repair using heat shock proteins
HU226617B1 (en) 1998-12-14 2009-04-28 Cytrx Corp Optically active pyridyl-4h-1,2,4-oxadiazine derivatives, and pharmaceutical composition containing the compound as active ingredient
HUP9900475D0 (en) * 1999-02-26 1999-04-28 Biorex Kutato Fejlesztoe Kft O-(3-piperidino-2-hydroxy-1-propyl)-hiyroximic acid-halogenid derivative, it's use for treating insulin resistance, and pharmaceutical compositions containing them as active component
EP1218030A4 (en) 1999-09-10 2004-09-15 Univ Fordham METHODS AND COMPOSITIONS FOR THE TREATMENT AND PREVENTION OF GRAFT REJECTS USING THERMAL SHOCK PROTEINS
US20020039583A1 (en) 1999-09-30 2002-04-04 Subjeck John R. Stress protein compositions and methods for prevention and treatment of cancer and infectious disease
US20030236300A1 (en) 1999-10-27 2003-12-25 Yale University Conductance of improperly folded proteins through the secretory pathway and related methods for treating disease
AU1582801A (en) 1999-11-05 2001-06-06 Board Of Regents Of The University Of Nebraska, The Methods and compositions for protection against bovine herpesvirus
US6964851B2 (en) 1999-12-07 2005-11-15 Stressgen Biotechnologies Corp. Compositions and methods for detecting stress-inducible proteins
GB9930443D0 (en) 1999-12-22 2000-02-16 King S College London Novel use of heat shock proteins
US20020127219A1 (en) 1999-12-30 2002-09-12 Okkels Jens Sigurd Lysosomal enzymes and lysosomal enzyme activators
US20010034042A1 (en) 2000-01-20 2001-10-25 Srivastava Pramod K. Complexes of peptide-binding fragments of heat shock proteins and their use as immunotherapeutic agents
AU2001227960A1 (en) 2000-01-21 2001-07-31 University Of Connecticut Health Center Heat shock/stress protein complexes as vaccines against neurodegenerative disorders
WO2001052877A1 (en) 2000-01-21 2001-07-26 University Of Connecticut Health Center Compositions and methods to treat neurodegenerative disorders
HUP0001583A2 (hu) 2000-04-18 2002-11-28 BIOREX Kutató és Fejlesztő Rt. Egy piridin-1-oxid-származék és eljárás annak átalakítására gyógyászati hatású vegyületekké
WO2001097829A2 (en) 2000-06-19 2001-12-27 Genzyme Corporation Combination enzyme replacement, gene therapy and small molecule therapy for lysosomal storage diseases
US20020037290A1 (en) 2000-08-07 2002-03-28 Armen Garo H. Compositions comprising heat shock proteins or alpha(2) macroglobulin, antigenic molecules and saponins, and methods of use thereof
US7517948B2 (en) 2000-09-13 2009-04-14 Multimmune Gmbh Hsp70 peptide stimulating natural killer (NK) cell activity and uses thereof
AU2001292674A1 (en) 2000-09-15 2002-04-29 University Of Connecticut Health Center Improved formulations using heat shock/stress protein-peptide complexes
US20020172682A1 (en) 2000-10-20 2002-11-21 University Of Connecticut Health Center Using heat shock proteins to increase immune response
IT1319277B1 (it) 2000-10-24 2003-09-26 Chiesi Farma Spa Proteine di fusione utili per il trattamento di immunizzazione dellamalattia di alzheimer.
WO2002041921A2 (en) 2000-11-03 2002-05-30 The Board Of Regents Of The University Of Nebraska Compositions for protection against bovine viral diseases
EP1209226A3 (en) 2000-11-07 2002-06-05 GSF-Forschungszentrum für Umwelt und Gesundheit GmbH Maturation of dendritic cells by recombinant heat shock protein 70 (hsp70)
US20020142299A1 (en) 2001-01-09 2002-10-03 Davidson Beverly L. PTD-modified proteins
EP1368039A4 (en) 2001-02-20 2006-03-29 Uab Research Foundation AMINOGLYCOSIDE TREATMENT FOR LYSOSOMAL STORAGE DISEASES
JP4384489B2 (ja) 2001-08-20 2009-12-16 ユニバーシティー オブ コネティカット ヘルス センター 癌及び感染性疾患の治療に有用な熱ショックタンパク質又はα−２−マクログロブリンを含む組成物の調製方法
HU0103939D0 (en) 2001-09-27 2001-11-28 Biorex Kutato Fejlesztoe Kft Pharmaceutical composition containing methformin and n-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride
JP2005512517A (ja) 2001-09-27 2005-05-12 イ・デ・エム・イミュノ−デジネ・モレキュル 誘導性Ｈｓｐ７０由来のポリペプチドとこのポリペプチドを含有する医薬組成物
GB0123756D0 (en) 2001-10-03 2001-11-21 King S College London A novel chaperone-type of adjuvant for vaccination - Basic 1
US7125843B2 (en) 2001-10-19 2006-10-24 Neose Technologies, Inc. Glycoconjugates including more than one peptide
ITMI20012573A1 (it) 2001-12-06 2003-06-06 D B P Dev Biotechonologica L P Gli acilsalicilati:una nuova classe di induttori di risposta heat shock
CN1615296A (zh) 2002-01-11 2005-05-11 拜奥列克斯研究发展公司 甲脒衍生物及其在治疗血管疾病中的用途
AU2003218639A1 (en) 2002-01-24 2003-09-02 Universiteit Gent Tumour treatment compositions comprising hsp70 and tumour necrosis factor
JP4632664B2 (ja) 2002-02-13 2011-02-16 デューク ユニバーシティ 非ペプチド結合ストレス応答性ポリペプチドによる免疫応答の調節
IL148401A0 (en) 2002-02-26 2002-09-12 Hadasit Med Res Service Hsp70-derived peptides and uses thereof in the diagnosis and treatment of autoimmune diseases
WO2003086452A2 (en) 2002-04-05 2003-10-23 Genzyme Corporation Methods of enhancing lysosomal storage disease therapy
US6984389B2 (en) 2002-04-25 2006-01-10 University Of Connecticut Health Center Using heat shock proteins to improve the therapeutic benefit of a non-vaccine treatment modality
IL164799A0 (en) 2002-04-25 2005-12-18 Univ Connecticut Using heat shock proteins to improve the therapeutic benefit of a non-vaccine treatment modality
US20040022796A1 (en) 2002-05-02 2004-02-05 University Of Connecticut Health Center Using heat shock proteins and alpha-2-macroglobulins to increase the immune response to vaccines comprising heat shock protein-peptide complexes or alpha-2-macroglobulin-peptide complexes
CA2485098A1 (en) 2002-05-02 2003-11-13 University Of Connecticut Health Center Use of heat shock proteins to enhance efficacy of antibody therapeutics
GB0216414D0 (en) 2002-07-15 2002-08-21 Novartis Ag Organic compounds
EP2444409A2 (en) 2002-09-16 2012-04-25 Genentech, Inc. Compositions and methods for the treatment of immune related diseases
ES2396231T3 (es) 2003-05-21 2013-02-20 Biotech Tools S.A. Complejo peptídico
US7244616B2 (en) 2003-06-27 2007-07-17 Bayer Pharmaceuticals Corporation Use of molecular chaperones for the enhanced production of secreted, recombinant proteins in mammalian cells
HUP0303584A3 (en) * 2003-10-30 2009-12-28 Cytrx Corp Use of a hydroximic acid halide derivative in the treatment of neurodegenerative diseases
EP1531160B1 (en) 2003-11-12 2010-12-29 Alfa Biogene International B.V. Recovery of a heat shock protein
AU2004293115A1 (en) 2003-11-25 2005-06-09 Mount Sinai School Of Medicine Of New York University Chaperone-based therapy for Niemann-Pick disease
EP1706423B8 (en) 2003-12-05 2009-07-08 multimmune GmbH Therapeutic and diagnostic anti-hsp 70 antibodies
US20060009520A1 (en) 2004-05-12 2006-01-12 Tall Alan R Retinoid-based methods for altering macrophage cholesterol
WO2005120558A2 (en) 2004-05-25 2005-12-22 University Of Connecticut Health Center Methods for making compositions comprising heat shock proteins or alpha-2-macroglobulin for the treatment of cancer and infectious disease
AU2005312415B2 (en) 2004-12-10 2012-02-02 Angteq B.V. Heat shock proteins (HSP) and supraventricular arrhythmia
ES2485369T3 (es) 2005-06-08 2014-08-13 Amicus Therapeutics, Inc. Tratamiento de trastornos del SNC asociados con mutaciones en genes que codifican enzimas lisosómicas
WO2007041285A2 (en) 2005-09-29 2007-04-12 Viral Genetics, Inc. Complexes of inactivated pepsin fraction and heat shock protein
HUE032640T2 (en) 2005-11-08 2017-10-30 Vertex Pharma Heterocyclic modulator of ATP-binding cassette transcripts
US20080039400A1 (en) 2006-01-24 2008-02-14 Universiteit Utrecht Uu Holding B.V. Treatment and prevention of inflammatory bowel diseases
NZ570103A (en) 2006-01-26 2011-11-25 Foldrx Pharmaceuticals Inc Compounds and methods for modulating protein trafficking
AU2007253694A1 (en) 2006-05-19 2007-11-29 The Scripps Research Institute Treatment of protein misfolding
MX2009000032A (es) 2006-06-23 2009-01-23 Amicus Therapeutics Inc Metodo para el tratamiento de trastornos neurologicos por la mejora de la actividad de la beta-glucocerebrosidasa.
EP3305297A1 (en) 2006-06-30 2018-04-11 Sloan-Kettering Institute for Cancer Research Treatment of neurodegenerative diseases through inhibition of hsp90
US20080044390A1 (en) 2006-08-11 2008-02-21 Xiaowei Jin Methods and compositions for the treatment of neurodegenerative disorders
KR20090045940A (ko) 2006-08-29 2009-05-08 포휴먼텍(주) 세포자멸사의 억제를 위한 약학 조성물, 및 이를 전달하는 방법
US20080227813A1 (en) * 2006-09-26 2008-09-18 Jack Raymond Barber Pharmaceutical compositions and methods for treating diseases associated with neurodegeneration
MX2009005798A (es) 2006-12-01 2009-08-12 Cytrx Corp Recuperacion de apoplejia.
CA2680063A1 (en) 2007-02-23 2008-08-28 University Of Florida Research Foundation, Inc. Compositions and methods for treating glycogen storage diseases
WO2008112525A2 (en) 2007-03-09 2008-09-18 Link Medicine Corporation Treatment of lysosomal storage diseases
GB0705626D0 (en) 2007-03-23 2007-05-02 Royal Veterinary College Method for enhancing sperm survival
CA2682350A1 (en) 2007-04-11 2008-10-23 The Jackson Laboratory Diagnosis and treatment of diseases caused by misfolded proteins
JP5586453B2 (ja) 2007-04-13 2014-09-10 アミカス セラピューティックス インコーポレイテッド 特異的薬理シャペロンによるゴーシェ病の治療および代理マーカーを用いた治療の監視
WO2008134512A1 (en) 2007-04-25 2008-11-06 Cytochroma Inc. Oral controlled release compositions comprising vitamin d compound and waxy carrier
CA2685332A1 (en) 2007-04-26 2008-11-06 Amicus Therapeutics, Inc. Dosing regimens for the treatment of lysosomal storage diseases using pharmacological chaperones
TW200901958A (en) 2007-05-04 2009-01-16 Cytrx Corp Diabetic wound healing
GB0712494D0 (en) 2007-06-27 2007-08-08 Isis Innovation Substrate reduction therapy
US7678764B2 (en) 2007-06-29 2010-03-16 Johnson & Johnson Regenerative Therapeutics, Llc Protein formulations for use at elevated temperatures
WO2009008719A2 (en) 2007-07-06 2009-01-15 Universiteit Utrecht Holding B.V. Treatment and prevention of inflammatory diseases and autoimmune diseases
JP2010538655A (ja) 2007-09-12 2010-12-16 アナフォア インコーポレイテッド 自己免疫疾患についてのｈｓｐ７０に基づく治療
US20100317690A1 (en) 2007-11-21 2010-12-16 Summit Corporation Plc Treatment of protein folding disorders
WO2009073564A1 (en) 2007-11-29 2009-06-11 The Hospital For Sick Children Compositions and methods for treating lysosomal disorders
WO2009099555A2 (en) 2008-01-30 2009-08-13 Corning Incorporated Synthetic surfaces for culturing cells in chemically defined media
WO2009095452A1 (en) 2008-01-31 2009-08-06 Crystax Pharmaceuticals, S.L. Crystal structure of the atpase domain of proteins of the hsp70 family
EP2271213A4 (en) 2008-02-01 2011-06-29 Scripps Research Inst METHOD FOR THE TREATMENT OF A GRADE SUFFERED BY PROTEIN HOMEOSTASIS
EP3778652A1 (en) 2008-05-07 2021-02-17 BioMarin Pharmaceutical Inc. Lysosomal targeting peptides and uses thereof
WO2009137796A2 (en) 2008-05-08 2009-11-12 Northwestern University Method of regulating the heat shock response
GB0809360D0 (en) 2008-05-22 2008-07-02 Isis Innovation Calcium modulation
PL2659904T3 (pl) * 2008-06-26 2016-01-29 Orphazyme Aps Zastosowanie Hsp70 jako regulatora aktywności enzymatycznej
WO2010015816A2 (en) 2008-08-06 2010-02-11 Summit Corporation Plc Treatment of lysosomal storage disorders and other proteostatic diseases
WO2010022461A1 (en) 2008-08-29 2010-03-04 Children, Youth And Women's Health Service Sulphated sugars to increase activity of sulphatases en lysosomal storage disorders
MX2011003249A (es) 2008-09-29 2011-05-19 Vertex Pharma Unidades de dosificacion del acido 3-(6-(1-(2,2-difluorobenzo[d][1 ,3]dioxol-5-il)ciclopropancarboxamido)-3-metilpiridin-2-il)benzoi co.
WO2010053655A2 (en) 2008-11-07 2010-05-14 University Of Kansas Therapeutic methods with withaferin a and analogs
WO2010086418A1 (en) 2009-01-29 2010-08-05 Alfa Biogene International B.V. Functional food product comprising heat shock protein or a hydrolysate thereof
EP2218458A1 (en) 2009-02-13 2010-08-18 Fondazione Telethon Molecules able to modulate the expression of at least a gene involved in degradative pathways and uses thereof
EP2405888B1 (en) 2009-03-10 2018-04-11 Alfa Biogene International B.V. Skin care product
GB0906159D0 (en) 2009-04-09 2009-05-20 Summit Corp Plc Drug combination for the treatment of proteostatic diseases
US8785168B2 (en) 2009-06-17 2014-07-22 Biomarin Pharmaceutical Inc. Formulations for lysosomal enzymes
RU2733466C2 (ru) 2009-07-28 2020-10-01 Шайр Хьюман Дженетик Терапиз Композиции и способы для лечения болезни гоше
WO2011019763A2 (en) 2009-08-10 2011-02-17 The Board Of Trustees Of The University Of Illinois Compositions and methods for the treatment of krabbe and other neurodegenerative diseases
US20110081428A1 (en) 2009-09-16 2011-04-07 The Buck Institute For Age Research Use of thioflavin-like compounds to increase life span and/or health span
US8609416B2 (en) 2009-12-18 2013-12-17 Ventria Bioscience Methods and compositions comprising heat shock proteins
US20120009125A1 (en) * 2010-07-06 2012-01-12 Lombard Jay L Apoe4 and apoj biomarker-based prevention and treatment of dementia
WO2012012656A2 (en) 2010-07-21 2012-01-26 University Of South Florida Materials and methods for treating neurodegenerative diseases
PL2646044T3 (pl) * 2010-11-30 2020-03-31 Orphazyme A/S Sposoby zwiększenia aktywności wewnątrzkomórkowej Hsp70
WO2013006076A1 (en) 2011-07-04 2013-01-10 New York University The use of intranasally administered hsp70 protein to treat neurodegenerative diseases
EP2831039A1 (en) 2012-03-28 2015-02-04 The U.S.A. as represented by the Secretary, Department of Health and Human Services Salicylic acid derivatives useful as glucocerebrosidase activators
AU2013337354A1 (en) * 2012-11-05 2015-05-21 Genzyme Corporation Compositions and methods for treating proteinopathies
US9562110B2 (en) 2012-11-21 2017-02-07 Wuhan Yzy Biopharma Co., Ltd. Bispecific antibody
CA2938577A1 (en) * 2014-02-04 2015-08-13 New York University Progranulin (pgrn) and its derivatives for diagnosis and treatment of lysosomal storage diseases
JP6678676B2 (ja) 2014-09-15 2020-04-08 オーファザイム エー／エス アリモクロモル製剤
EA034524B1 (ru) * 2014-10-10 2020-02-17 Вирджиния Коммонвелт Юниверсити Сульфаты окисленного холестерина для лечения пониженной лептиновой активности

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11707456B2 (en) 2020-11-19 2023-07-25 Kempharm Denmark A/S Processes for preparing arimoclomol citrate and intermediates thereof

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