GENIC TRANSFER TO VAS VECTOR-MEDIATED CNS FOR THE STUDY AND TREATMENT OF NEUROINFLAMATION ASSOCIATED WITH DIABETES AND OBESITY (Q3144733)
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Project Q3144733 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | GENIC TRANSFER TO VAS VECTOR-MEDIATED CNS FOR THE STUDY AND TREATMENT OF NEUROINFLAMATION ASSOCIATED WITH DIABETES AND OBESITY |
Project Q3144733 in Spain |
Statements
163,350.0 Euro
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326,700.0 Euro
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50.0 percent
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1 January 2018
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31 December 2020
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UNIVERSIDAD AUTONOMA DE BARCELONA
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42°13'24.28"N, 1°53'31.70"E
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08903
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LA DIABETES TIPO 2 (DT2), LA OBESIDAD Y SUS COMPLICACIONES ASOCIADAS ESTAN CRECIENDO EN PROPORCIONES EPIDEMICAS. DADA LA NATURALEZA CRONICA DE ESTAS ENFERMEDADES, REPRESENTAN UNA PESADA CARGA A LOS SISTEMAS DE SALUD DE TODOS LOS PAISES Y SON ACTUALMENTE EL PROBLEMA DE SALUD MAS IMPORTANTE A NIVEL GLOBAL. DADO EL CRECIMIENTO DEL NUMERO DE PACIENTES, ES EVIDENTE QUE LOS COSTES DE SU CUIDADO SE VOLVERAN INSOSTENIBLES. LOS TRATAMIENTOS ACTUALES A MENUDO PRESENTAN EFECTOS ADVERSOS. POR TANTO, ES IMPRESCINDIBLE ENCONTRAR MEJORES TRATAMIENTOS PARA ESTAS ENFERMEDADES._x000D_ LA EPIDEMIA DE DT2 Y OBESIDAD ES PARALELA AL INCREMENTO EN LA INCIDENCIA DE PATOLOGIAS DEL SISTEMA NERVIOSO CENTRAL (SNC), COMO DEMENCIA, DEPRESION, ACCIDENTES CEREBROVASCULARES Y ENFERMEDAD DE ALZHEIMER. ESTUDIOS RECIENTES SUGIEREN QUE LA OBESIDAD Y LA RESISTENCIA A LA INSULINA ESTAN ASOCIADAS A NEUROINFLAMACION EN AREAS COMO HIPOTALAMO, AMIGDALA, HIPOCAMPO, CORTEX O CEREBELO. ESTUDIOS EN MODELOS ANIMALES Y EN HUMANOS HAN DEMOSTRADO QUE LA OBESIDAD Y LA RESISTENCIA A LA INSULINA ESTAN TAMBIEN ASOCIADAS A DEFICITS EN LA FUNCION COGNITIVA. DADA LA IMPORTANCIA QUE LA NEUROINFLAMACION PARECE TENER EN EL DETERIORO COGNITIVO OBSERVADO EN DIABETES Y OBESIDAD, NUEVAS APROXIMACIONES DEBERIAN DISEÑARSE PARA CONTRARRESTAR LA INFLAMACION DEL SNC. SE HAN IDENTIFICADO VARIOS FACTORES QUE PODRIAN CONTRARRESTAR ESTE PROCESO PATOFISIOLOGICO. SIN EMBARGO, LA DISTRIBUCION DE FARMACOS AL SNC HA REPRESENTADO SIEMPRE UN RETO TERAPEUTICO DEBIDO A LA PRESENCIA DE LA BARRERA HEMATOENCEFALICA (BHE) QUE LIMITA EL ACCESO DE LA MAYORIA DE LOS PRODUCTOS ADMINISTRADOS SISTEMICAMENTE. LA TERAPIA GENICA PERMITIRIA SUPERAR LAS LIMITACIONES IMPUESTAS POR LA BHE Y LA CORTA VIDA MEDIA DE PROTEINAS TERAPEUTICAS PROPORCIONANDO UNA FUENTE CONTINUA DEL AGENTE TERAPEUTICO EN EL SNC._x000D_ EN ESTE PROYECTO PROPONEMOS DESARROLLAR NUEVAS ESTRATEGIAS BASADAS EN LA TRANSFERENCIA DE GENES AL SNC, MEDIADA POR VECTORES ADENO-ASOCIADOS (AAV), PARA EL ESTUDIO Y TRATAMIENTO DE LA NUEROINFLAMACION Y DEFICITS COGNITIVOS ASOCIADOS A DIABETES Y OBESIDAD. PARA ELLO, PRIMERO CARACTERIZAREMOS RATONES MODELOS DE NEUROINFLAMACION Y ALTERACION COGNITIVA ASOCIADOS A ALIMENTACION CON DIETA ALTA EN LIPIDOS (HFD). SE DETERMINARA EL INICIO Y LA PROGRESION DE LAS ALTERACIONES CENTRALES Y METABOLICAS PERIFERICAS EN RATONES A LOS QUE SE INICIARA LA ALIMENTACION CON DIETA HFD A LOS 8 MESES DE EDAD. ESPERAMOS QUE LOS RESULTADOS EN ESTA PARTE DEL PROYECTO INCREMENTARAN EL CONOCIMIENTO DE LOS MECANISMOS PATOFISIOLOGICOS RESPONSABLES DEL DETERIORO COGNITIVO EN DIABETES. EL SEGUNDO OBJETIVO ESTA CENTRADO EN EL DESARROLLO EN ESTE MODELO ANIMAL DE NUEVAS ESTRATEGIAS TERAPEUTICAS PARA LAS ALTERACIONES COGNITIVAS ASOCIADAS A DIABETES. PROPONEMOS UNA APROXIMACION DE TERAPIA GENICA BASADA EN LA TRANSFERENCIA GENICA MEDIADA POR VECTORES AAV DE GENES POTENCIALMENTE TERAPEUTICOS DIRECTAMENTE AL LIQUIDO CEFALORRAQUIDEO. ENTRE LOS POSIBLES GENES TERAPEUTICOS, SOBRESALEN INSULINA Y LOS MIEMBROS DE LA FAMILIA DE LOS FGF, FGF1 Y FGF21. SIN EMBARGO, SI DURANTE LA CONSECUCION DEL PROYECTO SE IDENTIFICAN NUEVOS CANDIDATOS POTENCIALES, PLANEAMOS INCLUIRLOS EN LOS ESTUDIOS. LA CONSECUCION DE LA PRIMERA PARTE TENDRA UNA IMPORTANTE APLICABILIDAD PRACTICA EN EL DESARROLLO DE NUEVOS MEDICAMENTOS PARA EL TRATAMIENTO DE LA DIABETES. EL EXITO EN EL SEGUNDO OBJETIVO REPRESENTARA, SIN EMBARGO, UNA INNOVACION DISRUPTIVA EN ESTA AREA TERAPEUTICA. (Spanish)
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TYPE 2 DIABETES (T2D) AND OBESITY AND THEIR ASSOCIATED COMPLICATIONS ARE WORLDWIDE GROWING EPIDEMICS. GIVEN THE CHRONIC NATURE OF THESE DISEASES, THEY REPRESENT A MASSIVE BURDEN ON HEALTH-CARE SYSTEMS OF ALL COUNTRIES, AND ARE NOW LEADING GLOBAL PUBLIC HEALTH PROBLEMS. WITH THE PERSPECTIVE OF THE GROWING NUMBER OF AFFECTED INDIVIDUALS, IT SEEMS EVIDENT THAT HEALTH COSTS WILL BECOME UNSUSTAINABLE. CURRENT TREATMENTS OFTEN HAVE IMPORTANT ADVERSE EFFECTS. IT IS THEREFORE MANDATORY FOR OUR SOCIETY TO FIND BETTER TREATMENTS FOR THESE DISEASES._x000D_ THE T2D AND OBESITY EPIDEMICS ARE ALSO CONCOMITANT WITH INCREASED INCIDENCE OF CENTRAL NERVOUS SYSTEM (CNS) PATHOLOGIES SUCH AS DEMENTIA, DEPRESSION, STROKE AND ALZHEIMER¿S DISEASE. RECENT STUDIES SUGGEST THAT OBESITY AND INSULIN RESISTANCE ARE ASSOCIATED WITH INFLAMMATION IN THE BRAIN, OR NEUROINFLAMMATION, IN AREAS SUCH AS HYPOTHALAMUS, AMYGDALA, HIPPOCAMPUS, CORTEX AND CEREBELLUM. STUDIES IN ANIMAL MODELS AND IN HUMANS HAVE DEMONSTRATED THAT OBESITY AND INSULIN RESISTANCE ARE ALSO ASSOCIATED WITH DEFICITS IN COGNITIVE FUNCTION. GIVEN THE IMPORTANCE THAT NEUROINFLAMMATION SEEMS TO PLAY IN THE COGNITIVE DECLINE OBSERVED IN DIABETES AND OBESITY, NEW THERAPEUTIC APPROACHES SHOULD BE DESIGNED TO ADDRESS THE INFLAMMATION OF THE CNS. SEVERAL FACTORS HAVE BEEN IDENTIFIED THAT MAY BE ABLE TO COUNTERACT THIS PATHOPHYSIOLOGICAL PROCESS. HOWEVER, THE DELIVERY OF MEDICINES TO THE CNS HAS ALWAYS REPRESENTED A THERAPEUTIC CHALLENGE, AS THE PRESENCE OF THE BLOOD-BRAIN BARRIER (BBB) LIMITS THE ACCESS TO THE CNS OF MOST PRODUCTS DELIVERED SYSTEMICALLY. GENE THERAPY CAN POTENTIALLY OVERCOME THE LIMITATIONS POSED BY THE BBB AND THE SHORT HALF-LIFE OF PROTEINS BY PROVIDING A CONTINUOUS SOURCE OF THE THERAPEUTIC AGENT WITHIN THE CNS._x000D_ HERE WE PROPOSE TO DEVELOP NEW STRATEGIES BASED ON ADENO-ASSOCIATED VIRAL (AAV) VECTOR-MEDIATED TRANSFER OF KEY GENES TO THE CNS FOR THE STUDY AND TREATMENT OF THE NEUROINFLAMMATION AND COGNITIVE IMPAIRMENT ASSOCIATED WITH DIABETES AND OBESITY. TO THIS END WE WILL FIRST ESTABLISH AND CHARACTERIZE MOUSE MODELS OF NEUROINFLAMMATION AND COGNITIVE IMPAIRMENT ASSOCIATED TO HIGH FAT DIET (HFD) FEEDING. WE WILL DETERMINE THE TIME-COURSE OF THE ONSET AND PROGRESSION OF CENTRAL AND PERIPHERAL METABOLIC ALTERATIONS IN MICE THAT WILL BEGIN TO BE FED A HFD AT THE AGE OF 8 MONTHS. WE EXPECT THAT THE RESULTS OBTAINED FROM THIS PART OF THE PROJECT WILL INCREASE THE KNOWLEDGE ON THE PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING COGNITIVE IMPAIRMENT IN DIABETES. THE SECOND OBJECTIVE FOCUSES ON THE DEVELOPMENT IN THIS ANIMAL MODEL OF NEW THERAPEUTIC STRATEGIES FOR DIABETES-ASSOCIATED COGNITIVE IMPAIRMENT. WE PROPOSE A GENE THERAPY APPROACH BASED ON THE AAV-MEDIATED GENE TRANSFER OF KEY POTENTIAL THERAPEUTIC CANDIDATES DIRECTLY TO THE CEREBROSPINAL FLUID. AMONGST POSSIBLE THERAPEUTIC GENES, INSULIN AND THE MEMBERS OF THE FGF FAMILY FGF1 AND FGF21 STAND OUT. HOWEVER, IF DURING THE CONSECUTION OF THE PROPOSAL NEW POTENTIAL CANDIDATES ARE IDENTIFIED, WE PLAN TO INCLUDE THOSE IN THE TEST PIPELINE. THE FULFILLMENT OF THE FIRST PART OF THIS PROJECT WOULD HAVE AN IMPORTANT PRACTICAL APPLICABILITY IN THE DEVELOPMENT OF NEW MEDICINES FOR THE TREATMENT OF DIABETES. SUCCESS IN THE SECOND OBJECTIVE WOULD, HOWEVER, REPRESENT A DISRUPTIVE INNOVATION IN THIS THERAPEUTIC AREA. (English)
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Sant Julià de Cerdanyola
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Identifiers
SAF2017-86266-R
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