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(2) Patent Application Publication (10) Pub. No.: US 2013/0251671 A1 Kaufman Et Al

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(2) Patent Application Publication (10) Pub. No.: US 2013/0251671 A1 Kaufman Et Al US 20130251671A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2013/0251671 A1 Kaufman et al. (43) Pub. Date: Sep. 26, 2013 (54) GABA AGONISTS IN THE TREATMENT OF Publication Classification DISORDERS ASSOCIATED WITH METABOLIC SYNDROME AND GABA (51) Int. Cl. COMBINATIONS IN TREATMENT OR A61R 31/197 (2006.01) PROPHYLAXIS OF TYPE I DLABETES A61 K 39/00 (2006.01) A61 K 38/20 (2006.01) A61R 39/39 (2006.01) (75) Inventors: Daniel Kaufman, Los Angeles, CA (52) U.S. CI. (US); Jide Tian, Los Angeles, CA (US) CPC ............... A61K31/197 (2013.01); A61K.39/39 (2013.01); A61K39/0008 (2013.01); A61 K (73) Assignee: THE REGENTS OF THE 38/2013 (2013.01) UNIVERSITY OF CALIFORNLA, USPC ........................ 424/85.2: 514/561; 424/184.1 Oakland, CA (US) (57) ABSTRACT (21) Appl. No.: 13/876,147 In certain embodiments methods are provided for the thera peutic or prophylactic amelioration of one or more symptoms (22) PCT Filed: Sep. 28, 2011 or disorders associated with metabolic syndrome. In various embodiments the methods involve administering to a subject (86) PCT No.: PCT/US11/53732 in need thereof, a GABA receptor agonist, in an amount § 371 (c)(1), sufficient to ameliorate said one or more symptoms. In certain (2), (4) Date: Jun. 10, 2013 embodiments methods are provided for the prophylaxis or treatment of type I diabetes and related pathologies that involve the use of GABA or GABA agonists in combination Related U.S. Application Data with certain other compounds (e.g., one more antigens (e.g., (60) Provisional application No. 61/387,398, filed on Sep. GAD) that have a therapeutic effect in type I diabetes and/or 28, 2010, provisional application No. 61/433,089, an anti-CD3 antibody, an anti-CD20 antibody, exendin-4, filed on Jan. 14, 2011. and/or or a pro-insulin therapeutic). Patent Application Publication Sep. 26, 2013 Sheet 1 of 14 US 2013/0251671 A1 Food intake per mouse weekly 3{} –Vehicle 25 ——GAEA i {} 5 * {} 15 20 Week on HFæ Fig. 1 Patent Application Publication Sep. 26, 2013 Sheet 2 of 14 US 2013/0251671 A1 Water intake per mouse weekiy | {} 5 ºf 0 45 2ü Week of HFE Fig. 2 Patent Application Publication Sep. 26, 2013 Sheet 3 of 14 US 2013/0251671 A1 Oral GABA improves Glucose Tolerance in HFD-fed mice s º — — G à B à *::::: _--" º$ - …”Al-` f - ...” __* * ...” .* - ... --~~~~ _.--~~~~ -, ** * sº ~ ...~~~ --~~~~ {} 4. 8 $2 ºf 6 20 Week on HFD Fig. 3 Patent Application Publication Sep. 26, 2013 Sheet 4 of 14 US 2013/0251671 A1 Oral GABA increases insuffin Sensitivity in HFE 3-fed fºice 20 -e-GABA --- ! -º-Vehicle Time after injection (min) Fig. 4 Patent Application Publication Sep. 26, 2013 Sheet 5 of 14 US 2013/0251671 A1 Oral GABA reduces fasting blood glucose level in HFE-fed mice * 65 sºmº, -º-Vehicle —d +3 5, 140 E. # §£º 420--- - E Ö 3 100 & 㺠> 85 {} 4 8 12 46 23 Week or HFº Fig. 5 Patent Application Publication Sep. 26, 2013 Sheet 6 of 14 US 2013/0251671 A1 Oral GABA reduces fasting body weight gains in HFD-fed mice {{} -º-Vehicle * : ; 45 —º-GABA * _-s-sº s— -- {} 4. 8 42 ºf 6. 20 Week on HFD Fig. 6 Patent Application Publication Sep. 26, 2013 Sheet 7 of 14 US 2013/0251671 A1 Oenigøu]p[n]OL ood Z S Fig. 7 Patent Application Publication Sep. 26, 2013 Sheet 8 of 14 US 2013/0251671 A1 5 {}0. No Treatment º: 400R H–F–F–F–F–F–F–i, Time of Post Transplantation (Week) Fig. 8A GAE] §§ § § 3. 3. 300+ A : -----4---------------- § 100] i-H-I-H, Time of Post Transpiantation (Week) Fig. 8B Patent Application Publication Sep. 26, 2013 Sheet 9 of 14 US 2013/0251671 A1 §§ § § - H–F–F–F–F–F–F–F–I, Time of Post Transplantation {Week} Fig. 8C GAD + GABA 3.§ -H-I-H-H, Time of Post Transplantation {Week} Fig. 8D Patent Application Publication Sep. 26, 2013 Sheet 10 of 14 US 2013/0251671 A1 Ær flo Treatment Time Post Treatment (Week} Fig. 9A 5 Ú G. 28}{} . º 3 5 6 Time Post Treatment (Week) Fig. 9B Patent Application Publication Sep. 26, 2013 Sheet 11 of 14 US 2013/0251671 A1 GAD + GABA Time Post Treatment (Week) Fig. 9C ml 6 mg/ml Ba cl ofen GABA C | 2 mg/ml 6 mg/ml Ba cl ofen GABA GABA Fig. 10B atent Application Publication Sep. 26, 2013 Sheet 13 of 14 US 2013/0251671 A1 ·–LIË º ::|=$| 6 mg/ml ÇA?A Fig. 10C (s??unKueu??que) Control 2 mg/ml 6 mg GABA Fig. 10D Patent Application Publication Sep. 26, 2013 Sheet 14 of 14 US 2013/0251671 A1 §§ § $8; §§ º º §§ 3& Time post initiai injection iday} Fig. 11 US 2013/025 1671 A1 Sep. 26, 2013 GABA AGONISTS IN THE TREATMENT OF ease have higher risk for cardiovascular diseases, heart attack, DISORDERS ASSOCIATED WITH stroke, type 2 diabetes (T2D) and nomalcoholic liver disease. METABOLIC SYNDROME AND GABA COMBINATIONS IN TREATMENT OR SUMMARY OF THE INVENTION PROPHYLAXIS OF TYPE I DIABETES [0006] In certain embodiments a method of ameliorating one or more symptoms or disorders associated with metabolic CROSS-REFERENCE TO RELATED syndrome is provided. The method typically involves admin APPLICATIONS istering, or causing to be administered, to a mammal in need [0001] This application claims benefit of and priority to thereof GABA, and/or a GABA receptor agonist, and/or a U.S. Ser. No. 61/387,398, filed on Sep. 28, 2010, and to U.S. GABA potentiator, and/or a GABA prodrug and/or a GABA Ser. No. 61/433,089, filed Jan. 14, 2011, both of which are agonist prodrug in an amount sufficient to ameliorate said one incorporated herein by reference in their entirety for all pur or more symptoms. In certain embodiments the symptoms or poses. disorders comprise insulin resistance, and/or glucose intoler ance, and/or hypertension, and/or fatty liver disease, and/or STATEMENT OF GOVERNMENTAL SUPPORT macrophage infiltrates into adipose tissue, and/or chronic kidney disease, and/or obesity. [0002] This work was supported in part by Grant No [0007] In certain embodiments a method of slowing or DK075070 awarded by the National Institutes of Health. The stopping the progression from a pre-diabetic condition in a government has certain rights in this invention. mammal or from a non-diabetic condition in a mammal at risk for type II diabetes to type II diabetes. The method typically BACKGROUND OF THE INVENTION involves administering to said mammal GABA, and/or a GABA receptoragonist, and/or a GABA potentiator, and/or a [0003] Type I, or insulin-dependent, diabetes mellitus is GABA prodrug and/or a GABA agonist prodrug, in an known to occur spontaneously in humans, rats and mice amount sufficient to slow or stop progression of the mammal (Castao and Eisenbarth (1990) Ann. Rev. Immunol. 8:647 from a pre-diabetic or a non-diabetic condition to type II 679). There is a genetic susceptibility to type I diabetes asso diabetes. ciated with certain haplotypes of Class II antigens of the [0008] Also provided is a composition comprising GABA, major histocompatability complex (MHC), i.e., HLA-DR3, and/or a GABA receptor agonist, and/or a GABA potentiator, -DR4 and -DQ3.2 in humans (see e.g., Platz et al. (1981) and/or a GABA prodrug and/or a GABA agonist prodrug Diabetologia 21:108-115; Toddetal. (1987) Nature 329:599 receptor agonist for use in: ameliorating one or more symp 604); RT1* in Bio-Breeding (BB) rats (see e.g., Colle (1990) toms or disorders associated with metabolic syndrome; and/ Clin. Immunol. & Immunopathol. 57: 1-9; Parfrey et al. or slowing or stopping the progression from a pre-diabetic (1989) Crit. Rev. Immunol. 9:45-65) and H-247 in non-obese condition in a mammal or from a non-diabetic condition in a diabetic (NOD) mice (see e.g., Kikutani and Makino in Adv. mammal at risk for type II diabetes to type II diabetes. Immunol. (Dixon, F. J., ed.), pp. 285-323, New York, N.Y.: [0009] In certain embodiments in any of the foregoing Academic Press, Inc., 1992). The pathology of type I diabetes methods and/or compositions the composition comprises involves the progressive inflammatory infiltration of pancre GABA and/or the composition administered is GABA. In atic islets (i.e., insulitis) containing immunocytes targeted certain embodiments in any of the foregoing methods and/or specifically to insulin-secreting 5-cells (see e.g., Bottazzo et compositions the GABA agonist is a GABAA-specificagonist al. (1985) N. Eng. J. Med. 313: 353–360; Foulis et al. (1991) and/or GABA, preferential and/or a GABAA-specific and/or J. Pathol. 165: 97-103; Hanenberg et al. (1991) Diabetologia a GABAA-preferential agonist. In certain embodiments in any 32: 126-134). This pathology develops over an indeterminate of the foregoing methods and/or compositions the GABA period of time (months to years). receptor agonist comprises a compound selected from the [0004] Over one half million people in the United States group consisting of thiopental, thiamylal, pentobarbital, suffer from insulin-dependent diabetes. Prior to 1921, people secobarbital, hexobarbital, butobarbital, amobarbital, bar who developed type I diabetes were not expected to live much bital, mephobarbital, phenobarbital, primidone, midazolam, more than a year after diagnosis. Afflicted individuals suf triazolam, lometazepam, flutazolam, nitrazepam, fluri fered from clinical signs of chronic hyperglycemia (e.g., trazepam, nimetazepam, diazepam, medazepam, oxazolam, excessive thirst and urination, rapid weight loss) as a conse prazeam, tofisopam, rilmazafonoe, lorazepam, temazepam, quence of abnormal carbohydrate metabolism.
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