WO2010041288A1 - Use of l-kynurenine and derivatives thereof for the prevention and treatment of diabetes mellitus type 1 - Google Patents
Use of l-kynurenine and derivatives thereof for the prevention and treatment of diabetes mellitus type 1 Download PDFInfo
- Publication number
- WO2010041288A1 WO2010041288A1 PCT/IT2009/000451 IT2009000451W WO2010041288A1 WO 2010041288 A1 WO2010041288 A1 WO 2010041288A1 IT 2009000451 W IT2009000451 W IT 2009000451W WO 2010041288 A1 WO2010041288 A1 WO 2010041288A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- kynurenine
- receptor
- ligand
- toll
- treatment
- Prior art date
Links
- 230000002265 prevention Effects 0.000 title claims abstract description 10
- 206010012601 diabetes mellitus Diseases 0.000 title abstract description 21
- YGPSJZOEDVAXAB-UHFFFAOYSA-N (R)-Kynurenine Natural products OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 claims abstract description 67
- YGPSJZOEDVAXAB-QMMMGPOBSA-N L-kynurenine Chemical compound OC(=O)[C@@H](N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-QMMMGPOBSA-N 0.000 claims abstract description 28
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- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims abstract description 13
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- 108010060818 Toll-Like Receptor 9 Proteins 0.000 claims description 15
- 108091034117 Oligonucleotide Proteins 0.000 claims description 10
- VCKPUUFAIGNJHC-UHFFFAOYSA-N 3-hydroxykynurenine Chemical group OC(=O)C(N)CC(=O)C1=CC=CC(O)=C1N VCKPUUFAIGNJHC-UHFFFAOYSA-N 0.000 claims description 8
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Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- L-kynurenine and derivatives thereof for the prevention and treatment of diabetes mellitus type 1
- the present invention concerns the use of L- kynurenine and natural or synthetic derivatives thereof, alone or in combination with a ligand of TLR receptor, for the prevention and treatment of type 1 diabetes mellitus.
- Type 1 diabetes mellitus is a disease caused by the autoimmune destruction of insulin producing pancreas ⁇ -cells.
- the mechanism this aggression is based on is an unsuitable activation of T- lymphocyte immune response against components of these cells to which the immune system would be “tolerant” . It would be desirable to find substances suitable to direct the immune response towards said "tolerance” condition.
- pancreas ⁇ - cells It is thought that the destruction of pancreas ⁇ - cells occurs progressively through the activation of an autoimmune response, resulting in the clinical onset of the disease (hyperglycaemia) when the number of ⁇ -cells is highly but not totally reduced.
- This preclinical phase identifiable for the presence of expressed insulin antibodies directed against ⁇ -cell expressed antigens, offers the possibility to develop a therapeutic treatment to prevent the disease onset or modify advantageously the course thereof.
- IDO indoleamine- 2 , 3-dioxygenase
- IDO an enzyme that at the same time degrades essential amino acid tryptophan and produces several catabolites (known as kynurenines) able to control the immmune response and induce apoptosis of T- lymphocytes .
- IDO is an ubiquitous enzyme although high levels of expression thereof are found in particular cells of the immune system, i.e. dendritic cells mainly after stimulation with ⁇ -interferon (INF-g) .
- IDO-mediated significant immunoregulating effects already have been demonstrated during the pregnancy, where IDO allows an immunity tolerance condition between mother and fetus [1] to be conserved, like also in autoimmunity [2] and allergy [3] .
- the authors of present the invention have demonstrated in previous studies that dendritic cells of NOD female mice (developing a pathology very similar to type 1 human diabetes) express IDO at much lower levels than normal mice, also as a result of INF- ⁇ stimulation ( [2] , [4] ) . This defect results in inability to control the autoimmune reactivity in NOD mice towards ⁇ -cell expressed autologous antigen.
- Kynurenines are a family of tryptophan metabolites formed by L- tryptophan metabolic degradation through IDO enzyme controlled kynurenine pathway (see Figure 1) . Although neuro-active properties of some of these metabolites are known, none of said matabolites has been considered as performing a physiological function significant at the level of the peripheral organs ( [6] , [7]) .
- L-kynurenine is captured by murine dendritic cells and transformed through intracellular metabolism into quinolinate.
- the overcoming of the IDO enzyme dependent block by- means of upstream administration of a quinolinate precursor activates the pathway and suppressive properties [8] .
- IDO upstream enzymes of kynurenine pathway contribute to the tolerogenesis through mechanisms which are added to the cytostatic effect of Trp deprivation.
- L-kynurenine and derivatives thereof, natural or synthetic can be advantageously used for the prevention and precocious intervention in the treatment of type 1 diabetes.
- the authors have found that the administration of molecules as L-kynurenine leads to a physiological re-balance of the immune response in diabetic animal resulting in the formation of new islands, leading to a true pancreatic regeneration.
- prevention means to avoid or delay the onset of type 1 diabetes in at risk subjects;
- precocious participation means innovative therapies aiming to prevent from the autoimmune attack residual viable ⁇ -cells in subjects suffering from recently detected diabetes .
- kynurenine in form of single sustained release tablet prevents the diabetes development for 80% of the animals. If the tablet is administered at diabetes onset (250-350 mg/dL of glycaemia values) , the kynurenine alone is 40% successful in the treatment of NOD mice, as evidenced by basal glycaemia values of about 200 mg/dL. Treated mice are still alive after 7 months since the disease onset without exogenous insulin administration.
- Kynurenine associations with ligands of toll -like 9 receptor (TLR9) like CpG oligonucleotide have been also tested.
- the treatment is 60% successful for diabetic mice with further decrease of basal glycaemia values to about 170 mg/dL.
- Pancreas histological analysis of some treated mice reveals at 6 months the presence of several insulin positive islands, although less large than normal ones.
- TLR9 Toll-like receptor
- said ligand of Toll-like receptor 9 is CpG oligonucleotide.
- Said oligonucleotide preferably is administered in the form of phosphorothioate ester.
- L- kynurenine derivatives and derivatives thereof mean 3- hydroxykynurenine , kynurenine salts (for example kynurenine sulfate) , or pro-medicaments thereof like kynurenine esters or amides .
- TLR to be used in medical field.
- said ligand is CpG oligonucleotide
- CpG concentration ratio is from 1:2 to 1:4.
- a preferred treatment schedule suggests administration doses of 5-10 mg of kynurenine/kg by intraperitoneal route for 20 days and two doses of 2,5 mg of CpG/kg at day 0 and day +3.
- a pharmaceutical composition comprising, as active principle, L-kynurenine or a natural or synthetic derivative thereof, or a combination as above defined together with one or more pharmaceutically acceptable adjuvant and/or excipient.
- L-kynurenine is administered in an amount from 100 mg to 200 mg.
- said composition is suitable to the subcutaneous administration of active principles, as kynurenine, having a short half life thus avoiding daily administration.
- said pharmaceutical composition is in a form of sustained release pellet, preferably active for 20- 30 days.
- the pharmaceutical composition or combination as above defined can be administered in a form of subcutaneous implant .
- the invention concerns a kit of parts for the simultaneous, sequential or separated administration of L-kynurenine or a natural or synthetic derivative thereof, and a ligand of Toll -like receptor (TLR) for the treatment of type 1 diabetes mellitus.
- said ligand is CpG oligo- nucleotide (preferably in the form of phosphorothioate ester) for the Toll -like 9 receptor (TLR9) .
- Figure 1 shows the pathway of kynurenines and tryptophan metabolic product, i.e. L-kynurenine (L- kyn) , anthranilic acid, 3-hydroxykynurenine, 3- hydroxyanthranilic acid and quinolinic acid (Quin Acid) , generally known as "Kynurenines" (KYNS) .
- EXAMPLE 1 Immunoregulating and trophic effects of kynurenines on the pancreatic ⁇ -cells of diabetic NOD mice
- Autoimmune diabetes develops in 80% of 24 week old NOD/Mrk female mice.
- Glycaemia ⁇ 200 mg/dl (in absence of glycosuria) and 350-400 mg/dl (stable for at least 1 week, in the presence glycosuria) characterize the pre- diabetic (5-6 weeks) and diabetic (>15 weeks) condition.
- NOD mice maintained for 10 days with haematic glucose values of 350-400 mg/dl change their body weight in meaningful way, during the various experiments never they have been treated with exogenous insulin. Haematic glucose concentrations of treated mice have been monitored weekly.
- CD4+ cells have been selected from the pancreatic lymphonodes and analyzed for the expression of specific marker like Foxp3 , RORgt and cytokine production as for example IL- 23, IL- 17, TGF- ⁇ , IL- 6, IL-10, INF- ⁇ .
- the insulin production is meaningfully more elevated in drug treated mice compared to placebo treated controls after the pathology onset (placebo treated controls: 0.3+0.2; drug treated: 0.9 ⁇ 0.25) .
- Pancreas histology 2 months after L-kynurenine (L-kyn) treatment shows the presence of various, small islands of ⁇ -cells surrounded by not aggressive infiltrated lymphocytes.
- L-kynurenine has been administered to mice at the onset stage of the disease (glycaemia values 250-350 mg/dl) . It has been found that a single dose of L-kynurenine reduced the glycaemia to values lower than 250 mg/dl, remaining unchanged for at least 6 months in a significant proportion (-40%) of the animals. Combinations of the L-kynurenine with INF- ⁇ or CTLA-4-Ig, a fusion protein with immunosuppressive activity, do not contribute to further increase the percentage of successfully treated animals.
- CpG belongs to a molecule class belonging to the category of pathogen associated molecules (or PAMP) which are recognized by specific host cells, in particular by dendritic cells, by means of TLR receptors.
- PAMP pathogen associated molecules
- CpG belongs to the category of TLR9 receptor binding PAMPs. It is interesting to note that these PAMP molecules and particularly CpG and TLR9 receptor signal cascade are critically involved in the regulation of IDO enzyme activity.
- IDO enzyme activity modulators as kynurenine, alone or in combination, represents a potential drug for the treatment of autoimmune pathologies, like for example type 1 diabetes mellitus.
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Abstract
Use of L-kynurenine and derivatives thereof for the prevention and treatment of diabetes mellitus type 1 The present invention concerns the use of L- kynurenine or natural or synthetic derivatives thereof, alone or in combination with a ligand of Toll -like receptor for the prevention and treatment of type 1 diabetes mellitus.
Description
Use of L-kynurenine and derivatives thereof for the prevention and treatment of diabetes mellitus type 1
The present invention concerns the use of L- kynurenine and natural or synthetic derivatives thereof, alone or in combination with a ligand of TLR receptor, for the prevention and treatment of type 1 diabetes mellitus.
Type 1 diabetes mellitus is a disease caused by the autoimmune destruction of insulin producing pancreas β-cells. The mechanism this aggression is based on is an unsuitable activation of T- lymphocyte immune response against components of these cells to which the immune system would be "tolerant" . It would be desirable to find substances suitable to direct the immune response towards said "tolerance" condition.
It is thought that the destruction of pancreas β- cells occurs progressively through the activation of an autoimmune response, resulting in the clinical onset of the disease (hyperglycaemia) when the number of β-cells is highly but not totally reduced. This preclinical phase, identifiable for the presence of expressed insulin antibodies directed against β-cell expressed antigens, offers the possibility to develop a therapeutic treatment to prevent the disease onset or modify advantageously the course thereof.
Previous studies have demonstrated an important immunomodulating and tolerogenic effect of indoleamine- 2 , 3-dioxygenase (IDO), an enzyme that at the same time degrades essential amino acid tryptophan and produces several catabolites (known as kynurenines) able to control the immmune response and induce apoptosis of T-
lymphocytes . IDO is an ubiquitous enzyme although high levels of expression thereof are found in particular cells of the immune system, i.e. dendritic cells mainly after stimulation with γ-interferon (INF-g) . IDO-mediated significant immunoregulating effects already have been demonstrated during the pregnancy, where IDO allows an immunity tolerance condition between mother and fetus [1] to be conserved, like also in autoimmunity [2] and allergy [3] . The authors of present the invention have demonstrated in previous studies that dendritic cells of NOD female mice (developing a pathology very similar to type 1 human diabetes) express IDO at much lower levels than normal mice, also as a result of INF-γ stimulation ( [2] , [4] ) . This defect results in inability to control the autoimmune reactivity in NOD mice towards β-cell expressed autologous antigen.
Kynurenines are a family of tryptophan metabolites formed by L- tryptophan metabolic degradation through IDO enzyme controlled kynurenine pathway (see Figure 1) . Although neuro-active properties of some of these metabolites are known, none of said matabolites has been considered as performing a physiological function significant at the level of the peripheral organs ( [6] , [7]) .
Recently, the authors of the invention have demonstrated that L-kynurenine (L-kyn) is captured by murine dendritic cells and transformed through intracellular metabolism into quinolinate. In the cells
having noή functional IDO, but in the presence of INF- Y, the overcoming of the IDO enzyme dependent block by- means of upstream administration of a quinolinate precursor activates the pathway and suppressive properties [8] .
According to other considerations found in scientific literature ( [9] - [11] ) IDO upstream enzymes of kynurenine pathway contribute to the tolerogenesis through mechanisms which are added to the cytostatic effect of Trp deprivation.
If on one hand the administration of exogenous insulin remains the basis for the treatment of diabetic subjects, on the other the research interest today is highly oriented towards the prevention of the diabetes and development of therapies for recently developed diabetes. A particularly advantageous therapy for type 1 diabetes would have as objective the re -balance of immune tolerance phenomena in combination with a pancreatic regeneration of β islands. In this context the manipulation of NOD mice through the combination of Freund complete adjuvant with semi-allogenic spleen cells and transplant of transient islands leads to regeneration of the host islands, with 67% survival in the long term, due to the differentiation in vivo of spleen transferred stem cells [12] . Various evidences show that β-cells as such represent the most promising source for the generation of new β-cells. Recent experimental approaches directly emphasises in highest way the stimulation of island
cell growth in vivo animals. Several molecules, like glucagon-like peptide-1, β-cellulin, nicotinamide, gastrin, epidermal growth factor 1 and thyroid hormone perform important roles in the onset of endogenous insular cell regeneration. The most credible hypothesis is that these molecules stimulate the insular cell precursors to be subjected to neo-genesis or induce the existing β-cell replication, emphasizing the importance of progenitor or stem cells occurring in the pancreas for the pancreatic islands regeneration [13] .
The authors of the present invention have now found that the L-kynurenine and derivatives thereof, natural or synthetic, can be advantageously used for the prevention and precocious intervention in the treatment of type 1 diabetes. In particular, the authors have found that the administration of molecules as L-kynurenine leads to a physiological re-balance of the immune response in diabetic animal resulting in the formation of new islands, leading to a true pancreatic regeneration.
The term prevention means to avoid or delay the onset of type 1 diabetes in at risk subjects; the term precocious participation means innovative therapies aiming to prevent from the autoimmune attack residual viable β-cells in subjects suffering from recently detected diabetes .
At this end studies in NOD mice have been carried out in order to verify if also in a pathology of autoimmune origin like the type 1 diabetes kynurenine
could exert a therapeutic effect. In fact, the authors had already demonstrated potential therapeutic role of kynurenine in another pathology, i.e. chronic granulomatous disease, characterized by a severe defect in the IPO-mediated tryptophan metabolism [5] .
Unexpected results have been obtained: the administration of kynurenine in form of single sustained release tablet prevents the diabetes development for 80% of the animals. If the tablet is administered at diabetes onset (250-350 mg/dL of glycaemia values) , the kynurenine alone is 40% successful in the treatment of NOD mice, as evidenced by basal glycaemia values of about 200 mg/dL. Treated mice are still alive after 7 months since the disease onset without exogenous insulin administration.
Kynurenine associations with ligands of toll -like 9 receptor (TLR9) , like CpG oligonucleotide have been also tested. The treatment is 60% successful for diabetic mice with further decrease of basal glycaemia values to about 170 mg/dL. Pancreas histological analysis of some treated mice reveals at 6 months the presence of several insulin positive islands, although less large than normal ones.
It is therefore an object of the present invention the use of L-kynurenine or natural or synthetic derivative thereof, alone or in combination with a ligand of Toll-like receptor (TLR) , preferably TLR9 receptor, for the preparation of a medicament for the treatment or prevention of type 1 diabetes mellitus.
Preferably, said ligand of Toll-like receptor 9 (TLR9) is CpG oligonucleotide. Said oligonucleotide preferably is administered in the form of phosphorothioate ester.
In the context of the present invention L- kynurenine derivatives and derivatives thereof mean 3- hydroxykynurenine , kynurenine salts (for example kynurenine sulfate) , or pro-medicaments thereof like kynurenine esters or amides .
It is a further object of the invention a combination of L-kynurenine or natural or synthetic derivative thereof with a ligand of Toll-like receptor
(TLR) to be used in medical field. In a particularly preferred embodiment said ligand is CpG oligonucleotide
(preferably in the form of phosphorothioate ester) for toll-like 9 receptor (TLR9) . Preferably at inoculum kynurenine : CpG concentration ratio is from 1:2 to 1:4.
A preferred treatment schedule suggests administration doses of 5-10 mg of kynurenine/kg by intraperitoneal route for 20 days and two doses of 2,5 mg of CpG/kg at day 0 and day +3.
It is a further object of the present invention a pharmaceutical composition comprising, as active principle, L-kynurenine or a natural or synthetic derivative thereof, or a combination as above defined together with one or more pharmaceutically acceptable adjuvant and/or excipient. Preferably L-kynurenine is administered in an amount from 100 mg to 200 mg. Still more preferably said composition is suitable to the subcutaneous administration of active principles, as
kynurenine, having a short half life thus avoiding daily administration. In a particularly preferred embodiment said pharmaceutical composition is in a form of sustained release pellet, preferably active for 20- 30 days. According to another preferred embodiment the pharmaceutical composition or combination as above defined can be administered in a form of subcutaneous implant .
Finally, the invention concerns a kit of parts for the simultaneous, sequential or separated administration of L-kynurenine or a natural or synthetic derivative thereof, and a ligand of Toll -like receptor (TLR) for the treatment of type 1 diabetes mellitus. Preferably, said ligand is CpG oligo- nucleotide (preferably in the form of phosphorothioate ester) for the Toll -like 9 receptor (TLR9) .
The present invention now will be described by an illustrative but not limitative way according to preferred embodiments thereof with particular reference to enclosed figures, wherein:
Figure 1 shows the pathway of kynurenines and tryptophan metabolic product, i.e. L-kynurenine (L- kyn) , anthranilic acid, 3-hydroxykynurenine, 3- hydroxyanthranilic acid and quinolinic acid (Quin Acid) , generally known as "Kynurenines" (KYNS) .
EXAMPLE 1 : Immunoregulating and trophic effects of kynurenines on the pancreatic β-cells of diabetic NOD mice
MATERIALS AND METHODS
Mice
Autoimmune diabetes develops in 80% of 24 week old NOD/Mrk female mice. Glycaemia <200 mg/dl (in absence of glycosuria) and 350-400 mg/dl (stable for at least 1 week, in the presence glycosuria) characterize the pre- diabetic (5-6 weeks) and diabetic (>15 weeks) condition. NOD mice maintained for 10 days with haematic glucose values of 350-400 mg/dl change their body weight in meaningful way, during the various experiments never they have been treated with exogenous insulin. Haematic glucose concentrations of treated mice have been monitored weekly.
Study about therapeutic effectiveness of synthetic kynurenines on diabetic NOD mice. Severely diabetic NOD mice (haematic glucose values 350-400 mg/dl for at least 10 days) have been administered with L-kynurenine (L-kyn) pellets
(Innovative Research of America) (100 mg/pellet or 200 mg/pellet) , alone or in combination with TLR ligand (administered by subcutaneous route at different dosages and timing) and monitored for the survival, pancreas histology, island average number in various treatment steps, new island average diameter, insulin production, glucose response. CD4+ cells have been selected from the pancreatic lymphonodes and analyzed for the expression of specific marker like Foxp3 , RORgt and cytokine production as for example IL- 23, IL- 17, TGF-β, IL- 6, IL-10, INF-γ. RESULTS
Results indicate that tryptophan natural catabolite, L-kynurenine (L-kyn) , is suitable to prevent the diabetes onset when administered in single dose in a form of sustained release pellet to about 5 week old female NOD mouse. On the contrary, another tryptophan catabolite, quinolinic acid, when administered results in worsening rather than ameliorating the pathology outline, as demonstrated in the same experimental context . Although the effect of L-kynurenine is not long term - in fact the mice after three months display to be again hyperglyeaemic - glycaemia levels never exceeded 300 mg/dl, the mice have constant body weight and are healthy after 8 months after the treatment. The insulin production is meaningfully more elevated in drug treated mice compared to placebo treated controls after the pathology onset (placebo treated controls: 0.3+0.2; drug treated: 0.9±0.25) . Pancreas histology 2 months after L-kynurenine (L-kyn) treatment shows the presence of various, small islands of β-cells surrounded by not aggressive infiltrated lymphocytes.
According to a therapeutic rather than preventive approach for the control of pathology, L-kynurenine has been administered to mice at the onset stage of the disease (glycaemia values 250-350 mg/dl) . It has been found that a single dose of L-kynurenine reduced the glycaemia to values lower than 250 mg/dl, remaining unchanged for at least 6 months in a significant proportion (-40%) of the animals.
Combinations of the L-kynurenine with INF-γ or CTLA-4-Ig, a fusion protein with immunosuppressive activity, do not contribute to further increase the percentage of successfully treated animals. However, by the administration of the combination of L-kynurenine with a cytosine and guanine rich oligonucleotide (CpG-ODN; a ligand for TLR9 receptor) , a percentage > 60% of female diabetic NOD mice showed glycaemia values lower than 200 mg/dl, this effect lasting over 6 months, as shown in Table 1. This combination is highly contrasting the production of IL- 23 and IL-17 both in the spleen and pancreas of diabetic mice. The reduced production has been observed also in comparison to other cytokines like IL-6, IL-10 and INF-γ concurrently to an increased production of TGF-β and regulating T-cell (Treg) number, mainly in pancreas. On the contrary quinolinic acid proves to be ineffective or even it promotes the pathology under the same experimental conditions. Table 1
Glycaemia
(average ±
% Treatment MST DS)
TREATMENT a CO-TREATMENT b (glycaemia in treated (g)
<250 mg/dl) animals
Placebo None 0 Not 25 determined
L-kyn None 25 225 ± 25 >
100 mg 180
L-kyn None 40 205 ± 35 >
200 mg 180
Placebo INF-g 0 Not 21 determined
L-kyn INF-g 30 230 ± 25 100
200 mg
Placebo CTLA4-Ig 0 Not 21 determined
L-kyn CTLA4-Ig 30 200 ± 45 >
200 mg 180
Placebo CpG-ODN 0 Not 9 determined
L-kyn CpG-ODN 60 175 ± 35 >
200 mg 180
Quinolinic None 15 230 ± 30 90 acid 100 mg
Quinolinic None 0 Not 7 acid 200 mg determined
Quinolinic CTLA4-lg 10 200 ± 25 85 acid 100 mg
Quinolinic CTLA4-Ig 0 Not 10 acid 200 mg determined a subcutaneous single implant at diabetes onset (day 0) b I. p. Co-administration of second agent (INF-γ, 1000 U at day 0,2,7;
CTLA4-Ig, 100 μg at day 0, 2, 7; CpG, 25 μg at day 0,2) c MST: mean survival time (days post-implant) From Table 1 it is apparent the ulterior increase of L-kynurenine (L-kyn) therapeutic effectiveness when administered together with a CpG oligonucleotide. CpG belongs to a molecule class belonging to the category of pathogen associated molecules (or PAMP) which are recognized by specific host cells, in particular by dendritic cells, by means of TLR receptors. CpG belongs to the category of TLR9 receptor binding PAMPs. It is interesting to note that these PAMP molecules and particularly CpG and TLR9 receptor signal cascade are critically involved in the regulation of IDO enzyme activity. The evidence, as reported in Table 1, of the presence of synergic effects in the combined therapeutic use of L-kyn and CpG in NOD mice demonstrates the role of TLR receptor and signal cascade associated to the activation thereof in the modulation of NOD mice autoimmunity.
Summarizing, it is possible to conclude that 1) not all kynurenines are protective against diabetes,
namely L-kyn and quinolinic acid being suitable to alleviate and promote the pathology, respectively; 2) using a combination therapy of L-kyn with CpG synergic effects are obtained; 3) the administration dose and timing of L-kyn based drug, alone or in combination, are critical in order to obtain a beneficial rather than detrimental effect.
Therefore, the use of IDO enzyme activity modulators as kynurenine, alone or in combination, represents a potential drug for the treatment of autoimmune pathologies, like for example type 1 diabetes mellitus.
BIBLIOGRAPHY
1. Munn, D. H., M. Zhou, J. T. Attwood, I. Bondarev, S.J. Conway, B. Marshall, C. Brown, and A. L. Mellor. 1998. Science 281:1191-1193. 2. Grohmann, U., F. Fallarino, R. Bianchi, C. Orabona, C. Vacca, M. C. Fioretti, and P. Puccetti. 2003. J. Exp. Med. 198:153-160.
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4. Fallarino F, Bianchi R, Orabona C, Vacca C, Belladonna ML, Fioretti MC, Serreze DV, Grohmann U, Puccetti P. Journal of Experimental Medicine 2004; 200:1051-1062.
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6. Stone, T. W. , and L. G. Darlington. 2002. Nat. Rev. Drug Discov. 1:609-620.
7. Schwarcz, R., and R. Pellicciari. 2002. J. Pharmacol. Exp. Ther. 303:1-10. 8. Belladonna, M. L., U. Grohmann, P. Guidetti, C. Volpi, R. Bianchi, M. C. Fioretti, R. Schwarcz, F. Fallarino, and P. Puccetti. 2006. J Immunol 177:130- 137.
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H. Garren; E. M. Hur, R. Gupta, L. Y. Lee, B. A. Kidd, W. H. Robinson, R. A. Sobel, M. L. Selley, and L. Steinman. 2005. Science 310:850-855.
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Abagyan, D. H. Broide, J. Lee, and E. Raz . 2007. Proc . Natl. Acad. Sci. USA. 104:18619-18624.
11. Romani, L., F. Fallarino, A. De Luca, C. Montagnoli, C. D'Angelo, T. Zelante, C. Vacca, F. Bistoni, M. C. Fioretti, U. Grohmann, B. H. Segal, and P. Puccetti. 2008. Nature 451:211-215.
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Claims
1. Use of L-kynurenine or natural or synthetic derivative thereof, alone or in combination with a ligand of Toll -like receptor (TLR) , for the preparation of a medicament for the treatment and prevention of type 1 diabetes mellitus.
2. Use according to claim 1, wherein said ligand is oligonucleotide CpG for Toll-like receptor 9 (TLR9) .
3. Combination of L-kynurenine or natural or synthetic derivative thereof, with a ligand of Toll- like receptor (TLR) for use in medical field.
4. Combination according to claim 3, wherein said ligand is oligonucleotide CpG for Toll-like receptor 9 (TLR9) .
5. Combination according to claim 4, wherein the active principles are at kynurenine : Cpg ratio from 1:2 to 1:4.
6. Combination according to anyone of claims 3-5 wherein said L-kynurenine derivative is selected from 3 -hydroxy kynurenine, L-kynurenine salts, L-kynurenine esters and amides.
7. Pharmaceutical composition comprising L- kynurenine or natural or synthetic derivative thereof or a combination according to anyone of claims 3-6, as active principle together with one or more pharmaceutically acceptable adjuvant and/or excipient.
8. Pharmaceutical composition according to claim
7, wherein said composition is suitable to subcutaneous administration .
9. Pharmaceutical composition according to claim
8, in form of sustained release pellet.
10. Pharmaceutical composition according to claim 8 , in form_ of subcutaneous implant .
11. Composition according to anyone of claims 6- 10, wherein said L-kynurenine derivative is selected from 3 -hydroxy kynurenine, L-kynurenine salts, L- kynurenine esters and amides .
12. kit of parts for the simultaneous, sequential or separated administration of L-kynurenine or a natural or synthetic derivative thereof, and a ligand of Toll-like receptor (TLR) for the treatment of type 1 diabetes mellitus.
13. Kit of parts according to claim 12, wherein said ligand is oligonucleotide CpG for Toll-like receptor 9 (TLR9) .
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CN102258020A (en) * | 2011-06-14 | 2011-11-30 | 北京大学 | Micromolecule inhibitor containing growth hormone TAA1 synthetic pathway capable of inhibiting ethylene induction |
WO2016044922A1 (en) * | 2014-09-26 | 2016-03-31 | The University Of British Columbia | A combination of kynurenine and antigen presenting cells (apc) as therapeutics and methods for their use in immune modulation |
WO2018044724A1 (en) * | 2016-08-31 | 2018-03-08 | Ampio Pharmaceuticals, Inc. | Treatment of disease with n-acetyl kynurenine |
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WO2002016549A2 (en) * | 2000-08-25 | 2002-02-28 | Yeda Research And Development Co. Ltd. | METHODS OF TREATMENT OR PREVENTION OF AUTOIMMUNE DISEASES WITH CpG-CONTAINING POLYNUCLEOTIDE |
EP1369114A1 (en) * | 2002-06-07 | 2003-12-10 | Peter Priv. Doz. Dr. Terness | Use of tryptophan metabolites as pharmaceutical agents |
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2008
- 2008-10-07 IT IT000529A patent/ITRM20080529A1/en unknown
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2009
- 2009-10-06 WO PCT/IT2009/000451 patent/WO2010041288A1/en active Application Filing
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Cited By (7)
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CN102258020A (en) * | 2011-06-14 | 2011-11-30 | 北京大学 | Micromolecule inhibitor containing growth hormone TAA1 synthetic pathway capable of inhibiting ethylene induction |
WO2016044922A1 (en) * | 2014-09-26 | 2016-03-31 | The University Of British Columbia | A combination of kynurenine and antigen presenting cells (apc) as therapeutics and methods for their use in immune modulation |
JP2017528508A (en) * | 2014-09-26 | 2017-09-28 | ザ・ユニバーシティ・オブ・ブリティッシュ・コロンビア | Combinations of kynurenine and antigen presenting cells (APC) as therapeutic agents in immune modulation and methods for their use in immune modulation |
RU2727573C2 (en) * | 2014-09-26 | 2020-07-22 | Ти Юниверсити Оф Бритиш Коламбиа | Combination of kynurenin and antigen-presenting cells (apc) as therapeutic agents and a method for use thereof in immunomodulation |
AU2015321365B2 (en) * | 2014-09-26 | 2021-05-20 | The University Of British Columbia | A combination of kynurenine and antigen presenting cells (APC) as therapeutics and methods for their use in immune modulation |
WO2018044724A1 (en) * | 2016-08-31 | 2018-03-08 | Ampio Pharmaceuticals, Inc. | Treatment of disease with n-acetyl kynurenine |
US11478441B2 (en) | 2016-08-31 | 2022-10-25 | Ampio Pharmaceuticals, Inc. | Treatment of disease with n-acetyl kynurenine |
Also Published As
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