ES2552843T3 - Terapia anaplerótica de enfermedad de Huntington y otras enfermedades de poliglutamina - Google Patents
Terapia anaplerótica de enfermedad de Huntington y otras enfermedades de poliglutamina Download PDFInfo
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- ES2552843T3 ES2552843T3 ES07847692.6T ES07847692T ES2552843T3 ES 2552843 T3 ES2552843 T3 ES 2552843T3 ES 07847692 T ES07847692 T ES 07847692T ES 2552843 T3 ES2552843 T3 ES 2552843T3
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- polyglutamine diseases
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Classifications
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/035—Organic compounds containing oxygen as heteroatom
- A23L29/04—Fatty acids or derivatives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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Abstract
Precursor de propionil-CoA seleccionado del grupo que consiste en ácido graso de siete carbonos, triheptanoína, heptanoato, 3-cetovalerato y 3-hidroxivalerato para su uso en un método para tratar y/o prevenir una enfermedad por poliglutamina.
Description
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en una etapa temprana de la enfermedad y portadores premanifiestos. Por consiguiente, los BCAA en plasma pueden considerarse biomarcadores relevantes para enfermedad de Huntington. Deben ayudar a detectar la aparición de la enfermedad y monitorizar su progresión en vista de ensayos terapéuticos. Para conocimiento de los presentes inventores, este es el primer biomarcador accesible identificado en enfermedad de Huntington y, más ampliamente, el primer biomarcador periférico demostrado en un trastorno neurodegenerativo.
Solo algunos estudios metabonómicos han conducido a la identificación de biomarcadores que pueden usarse rutinariamente para el seguimiento de pacientes (Sabatine et al. 2005). Se sabe que la variabilidad inter-individual complica tales análisis en los líquidos del cuerpo humano, limitando así los estudios metabonómicos esencialmente a modelos animales (Wagner et al. 2006). Sesgos experimentales y analíticos comunes en seres humanos incluyen ingesta dietética, tiempo de recogida de muestras, acondicionamiento de muestras y desplazamientos químicos debido a cambios en el pH (Cloarec et al. 2005; Teahan et al. 2006; Walsh et al. 2006). En el presente estudio, cada uno de estos parámetros se controló rigurosamente. Esto explica probablemente la exactitud de los hallazgos de RMN de los presentes inventores.
La implicación de BCAA en el metabolismo intermedio mitocondrial, tanto en el cerebro como en tejidos periféricos, soporta adicionalmente una función importante para el déficit de energía en EH. Se mostró una reducción en la producción de ATP en cerebro de ratones con EH, que incluyen ratones presintomáticos (Gines et al. 2003). Una reducción significativa en los niveles de ATP y respiración mitocondrial también se demostró en células estriatales de ratones con EH, aunque los complejos de la cadena respiratoria no se alteraron (Milakovic y Johnson 2005). En pacientes con EH, hay una fuerte evidencia de hipometabolismo en el cerebro en el que se reduce el consumo de glucosa, especialmente en los ganglios basales, incluso en portadores de mutación presintomáticos (Grafton et al. 1992; Kuwert et al. 1993; Antonini et al. 1996). La causa subyacente de este déficit de energía temprano en cerebro con EH es actualmente desconocida, pero la glicólisis alterada (Browne y Beal 2004), el ciclo del ácido cítrico (Tabrizi et al. 1999) y/o la fosforilación oxidativa (Milakovic y Johnson 2005) pueden participar. Recientemente, se mostró que la huntingtina mutada reducía la expresión de PGC-1α (co-activador-1α del receptor gamma activado por proliferadores del peroxisoma) en el estriado de ratones y pacientes con EH, mediante una inhibición transcripcional dependiente de CREB (Cui et al. 2006). PGC-1α es un co-activador transcripcional que regula vías metabólicas energéticas clave, tanto en el cerebro como tejidos periféricos (Lin et al. 2005). La posible función de PGC-1α en EH se sospechó inicialmente de la observación de lesiones estriatales selectiva en el ratón inactivado en PGC-1α (Lin et al. 2004). Entonces se mostró que la regulación por disminución de PGC-1α en estriado de EH afectaba el metabolismo de la energía mitocondrial, posiblemente alterando la fosforilación oxidativa (Cui et al. 2006). Además, la inhibición de la succinato deshidrogenasa, por ácido 3-nitropropiónico o malonato, imita la neuropatología de la EH en ratones (Klivenyi et al. 2004), que indica que una ausencia de sustratos para el ciclo del ácido cítrico y la cadena respiratoria participa en el déficit de energía en cerebro con EH. Y, lo que es más importante, la oxidación mitocondrial de BCAA conduce a la producción de acetil-CoA y succinil-CoA, dos productos intermedios clave del ciclo del ácido cítrico. Se excluyó aporte calórico o de proteínas insuficiente en el estudio de los presentes inventores, además de alteración de la vía de oxidación de BCAA, ya que los niveles de ácido orgánico en orina fueron normales. Por tanto, la disminución en BCAA en plasma observada en el grupo de EH probablemente resultó de la activación de un mecanismo compensatorio para proporcionar sustratos de energía al ciclo del ácido cítrico, como se describe en diversas enfermedades productoras de caquexia (Szpetnar et al. 2004; De Bandt y Cynober 2006). La correlación entre los reducidos niveles de BCAA y la pérdida de peso en el estudio de los presentes inventores sugiere que excesiva movilización y oxidación de BCAA para producir energía en músculo está asociada a pérdida de peso y reducida masa corporal delgada. La observación de pérdida de peso antes de la disminución neurocognitiva sugiere que los síntomas neurológicos se agravan cuando los sustratos de la periferia se vuelven insuficientes para compensar el déficit de energía en el cerebro con EH. La tasa normal de consumo de oxígeno recientemente observada después de la infusión estriatal de succinato (Weydt et al. 2006) soporta la idea de que proporcionar energía mediante un aumento en tanto productos intermedios del ciclo del ácido cítrico sistémico como cerebral puede ser un enfoque terapéutico prometedor en EH.
Al nivel patofisiológico, el estudio de los presentes inventores también mostró que los bajos niveles de BCAA en plasma producen bajos niveles de IGF1 en el grupo de EH en comparación con los controles, aunque tienen un mayor aporte de proteínas y calórico. La estrecha conexión entre IGF1 y aminoácidos esenciales se ha estudiado ampliamente (Straus y Takemoto 1988; Harp et al. 1991; Thissen et al. 1994; Gomez-Merino et al. 2004). La disponibilidad de aminoácidos esenciales parece tener un mayor efecto sobre la expresión génica de IGF1 que estímulos hormonales tales como concentraciones de insulina en suero (Maiter et al. 1989). IGF1 también es un indicador más sensible de la saciedad de nutrientes que la albúmina, prealbúmina u orosomucoide, como se observa en el estudio de los presentes inventores. De forma interesante, la huntingtina es un sustrato de la vía de serinatreonina Akt, que se activa por IGF1 (Humbert et al. 2002). Se ha mostrado que la activación alterada de la vía de Akt reduce la fosforilación de la huntingtina mutada, produciendo una elevada toxicidad neuronal (Rangone et al. 2005). Bajos niveles de IGF 1 en pacientes con EH podrían, por tanto, proporcionar una explicación de la alteración en la activación de Akt observada en modelos celulares de EH. Por consiguiente, aumentando los niveles de BCAA para corregir el déficit en IGF1, debe favorecer la fosforilación de huntingtina mutada, disminuyendo así su toxicidad.
En conclusión, la combinación de una rigurosa evaluación nutricional y herramientas metabonómicas ha proporcionado una nueva perspectiva en EH. Los presentes inventores han demostrado la existencia de una
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Claims (1)
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imagen1
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06291873A EP1929995A1 (en) | 2006-12-04 | 2006-12-04 | Anaplerotic therapy of Huntington disease and other polyglutamine diseases |
EP06291873 | 2006-12-04 | ||
PCT/EP2007/063181 WO2008068230A1 (en) | 2006-12-04 | 2007-12-03 | Anaplerotic therapy of huntington disease and other polyglutamine diseases |
Publications (1)
Publication Number | Publication Date |
---|---|
ES2552843T3 true ES2552843T3 (es) | 2015-12-02 |
Family
ID=37733780
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES07847692.6T Active ES2552843T3 (es) | 2006-12-04 | 2007-12-03 | Terapia anaplerótica de enfermedad de Huntington y otras enfermedades de poliglutamina |
ES15175719T Active ES2778525T3 (es) | 2006-12-04 | 2007-12-03 | Precursor de propionil coenzima A para su uso en el tratamiento de la enfermedad de Huntington y otras enfermedades de poliglutamina |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES15175719T Active ES2778525T3 (es) | 2006-12-04 | 2007-12-03 | Precursor de propionil coenzima A para su uso en el tratamiento de la enfermedad de Huntington y otras enfermedades de poliglutamina |
Country Status (11)
Country | Link |
---|---|
US (5) | US20100063147A1 (es) |
EP (3) | EP1929995A1 (es) |
CY (1) | CY1116938T1 (es) |
DK (1) | DK2097064T3 (es) |
ES (2) | ES2552843T3 (es) |
HK (1) | HK1223829A1 (es) |
HU (1) | HUE026217T2 (es) |
PL (1) | PL2097064T3 (es) |
PT (1) | PT2097064E (es) |
SI (1) | SI2097064T1 (es) |
WO (1) | WO2008068230A1 (es) |
Families Citing this family (8)
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EP1929995A1 (en) | 2006-12-04 | 2008-06-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Anaplerotic therapy of Huntington disease and other polyglutamine diseases |
JP5765839B2 (ja) * | 2009-12-05 | 2015-08-19 | 国立大学法人名古屋大学 | 球脊髄性筋萎縮症治療薬 |
EP2519234B1 (en) * | 2009-12-30 | 2017-06-28 | Baylor Research Institute | Anaplerotic therapy for alzheimer's disease |
MX2012014520A (es) * | 2010-06-14 | 2013-03-05 | Baylor Res Inst | Dieta de triheptanoina para tratamiento de enfermedad del cuerpo de poliglucosano (apbd). |
BR112015013349A2 (pt) * | 2012-12-13 | 2017-07-11 | Baylor Res Institute At Dallas | trieptanoína para o tratamento de deficiência de transportador de glicose 1 |
AU2014348457B2 (en) * | 2013-11-14 | 2019-04-18 | The University Of Queensland | Neurodegenerative disorders and methods of treatment and diagnosis thereof |
WO2016004375A2 (en) * | 2014-07-02 | 2016-01-07 | Ridge Diagnostics, Inc. | Methods and materials for treating pain and depression |
AU2017277005B2 (en) | 2016-06-08 | 2022-12-22 | Sunregen Healthcare Ag | Lipids with odd number of carbon atoms and their use as pharmaceutical composition or nutritional supplement |
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US4025649A (en) | 1974-08-19 | 1977-05-24 | Labaz | Acetic acid derivatives having pharmacological activity and compositions containing the same |
DE3032300A1 (de) | 1980-08-27 | 1982-04-01 | Alfred Ing. Wien Lohninger | Mittel zur parenteralen ernaehrung |
GB2104079B (en) | 1981-08-14 | 1985-08-21 | London Polytech | New aminoacid isomers, their production and their medicinal use |
US4753963A (en) | 1985-09-26 | 1988-06-28 | The Procter & Gamble Company | Nutritional fat suitable for enteral and parenteral products |
JP3486778B2 (ja) | 1993-04-02 | 2004-01-13 | 三菱ウェルファーマ株式会社 | アルツハイマー病予防治療剤 |
US20090253781A1 (en) | 2002-05-24 | 2009-10-08 | Btg International Limited | Therapeutic compositions |
US6740679B1 (en) * | 1999-02-05 | 2004-05-25 | Baylor University Medical Center | Nutritional supplement or pharmaceutical preparation comprising triglycerides with seven-carbon fatty acid |
JP4902906B2 (ja) * | 1999-02-05 | 2012-03-21 | ベイラー リサーチ インスティテュート | 炭素数が7である脂肪酸を含むトリグリセリドを含有する栄養補助剤または医薬調製物 |
CA2389623A1 (en) | 1999-11-03 | 2001-05-10 | Juvenon, Inc. | Method of treating benign forgetfulness |
US6835750B1 (en) * | 2000-05-01 | 2004-12-28 | Accera, Inc. | Use of medium chain triglycerides for the treatment and prevention of alzheimer's disease and other diseases resulting from reduced neuronal metabolism II |
ES2323940T3 (es) | 2000-05-01 | 2009-07-28 | Accera, Inc. | Uso de trigliceridos de cadena media para el tratamiento y prevencion de la enfermedad de alzheimer. |
US20060189545A1 (en) * | 2003-03-06 | 2006-08-24 | Henderson Samuel T | Novel chemical entities and methods for their use in treatment of metabolic disorders |
US8399515B2 (en) | 2003-05-20 | 2013-03-19 | Baylor Research Institute | Five and fifteen carbon fatty acids for treating metabolic disorders and as nutritional supplements |
MX2007000304A (es) | 2004-07-02 | 2007-06-15 | Baylor Res Inst | Metodo de tratamiento de enfermedad de almacenamiento de glucogeno o polisacaridos. |
WO2006037069A1 (en) | 2004-09-28 | 2006-04-06 | Allergan, Inc. | Compositions comprising nb-dnj, ne-dnj or d-glucaro-delta-lactam and their uses for the treatment of pain and other neurological conditions |
KR20090003148A (ko) | 2006-04-03 | 2009-01-09 | 액세라인크 | 나이와 관련된 기억 손상의 치료를 위한 케톤 생성조성물의 용도 |
KR20150038525A (ko) | 2006-09-26 | 2015-04-08 | 베일러 리서치 인스티튜트 | 영양물 센서 |
EP1929995A1 (en) | 2006-12-04 | 2008-06-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Anaplerotic therapy of Huntington disease and other polyglutamine diseases |
PT2650380E (pt) | 2007-07-31 | 2016-01-14 | Accera Inc | Utilização de testagem genómica e compostos cetogénicos para o tratamento de função cognitiva reduzida |
WO2009124250A1 (en) | 2008-04-03 | 2009-10-08 | The Trustees Of The University Of Pennsylvania | Compositions and methods for detecting tricarboxylic acid (tca) metabolic flux |
EP2519234B1 (en) | 2009-12-30 | 2017-06-28 | Baylor Research Institute | Anaplerotic therapy for alzheimer's disease |
US20110301238A1 (en) | 2010-06-02 | 2011-12-08 | Borges Karin | Seizure related disorders and therapeutic methods thereof |
MX2012014520A (es) | 2010-06-14 | 2013-03-05 | Baylor Res Inst | Dieta de triheptanoina para tratamiento de enfermedad del cuerpo de poliglucosano (apbd). |
US9872850B2 (en) | 2010-12-23 | 2018-01-23 | Amazentis Sa | Compositions and methods for improving mitochondrial function and treating neurodegenerative diseases and cognitive disorders |
BR112015013349A2 (pt) | 2012-12-13 | 2017-07-11 | Baylor Res Institute At Dallas | trieptanoína para o tratamento de deficiência de transportador de glicose 1 |
AU2014348457B2 (en) | 2013-11-14 | 2019-04-18 | The University Of Queensland | Neurodegenerative disorders and methods of treatment and diagnosis thereof |
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- 2007-12-03 SI SI200731703T patent/SI2097064T1/sl unknown
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DK2097064T3 (en) | 2015-11-23 |
WO2008068230A1 (en) | 2008-06-12 |
ES2778525T3 (es) | 2020-08-10 |
EP1929995A1 (en) | 2008-06-11 |
US9717705B2 (en) | 2017-08-01 |
EP3009135A1 (en) | 2016-04-20 |
US20180021287A1 (en) | 2018-01-25 |
US20100063147A1 (en) | 2010-03-11 |
PL2097064T3 (pl) | 2016-02-29 |
HK1223829A1 (zh) | 2017-08-11 |
US20140364498A1 (en) | 2014-12-11 |
EP2097064B1 (en) | 2015-08-19 |
CY1116938T1 (el) | 2017-04-05 |
HUE026217T2 (en) | 2016-05-30 |
US20190365695A1 (en) | 2019-12-05 |
EP2097064A1 (en) | 2009-09-09 |
US20120165405A1 (en) | 2012-06-28 |
EP3009135B1 (en) | 2020-02-05 |
US10220014B2 (en) | 2019-03-05 |
PT2097064E (pt) | 2015-11-25 |
SI2097064T1 (sl) | 2016-01-29 |
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