DEVELOPMENT OF A THERAPY BASED ON THE SELECTIVE ACTIVATION OF VIA CANONICA WNT FOR THE TREATMENT OF ACUTE SPINAL INJURY. (Q3136883): Difference between revisions
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39°51'21.85"N, 4°1'26.26"W
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Revision as of 08:50, 9 October 2021
Project Q3136883 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | DEVELOPMENT OF A THERAPY BASED ON THE SELECTIVE ACTIVATION OF VIA CANONICA WNT FOR THE TREATMENT OF ACUTE SPINAL INJURY. |
Project Q3136883 in Spain |
Statements
116,160.0 Euro
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145,200.0 Euro
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80.0 percent
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1 January 2019
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31 December 2022
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FUNDACION DEL HOSPITAL NACIONAL DE PARAPLEJICOS
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39°51'21.85"N, 4°1'26.26"W
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45168
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RETO Y POTENCIAL IMPACTO EN SALUD: HASTA 7 MILLONES DE PERSONAS Y 130.000 NUEVOS CASOS POR AÑO VIVEN EN EL MUNDO CON SECUELAS INCAPACITANTES POR LESION MEDULAR (LM). LA LM REPRESENTA EL INICIO DE UNA ENFERMEDAD CON SECUELAS CRONICAS Y CONSTITUYE UNA CATASTROFE INDIVIDUAL Y SOCIOECONOMICA PARA LA QUE NO EXISTE CURA. TODO ESTO JUSTIFICA LA NECESIDAD DE APROXIMACIONES MULTIDISCIPLINARES DIRIGIDAS A DESARROLLAR ESTRATEGIAS TERAPEUTICAS INNOVADORAS, PREFERENTEMENTE BASADAS EN DIANAS YA IDENTIFICADAS EN HUMANOS Y COMUNES A MODELOS ANIMALES DE LM, Y CUYO TRATAMIENTO HAYA SIDO DEMOSTRADO EFICAZ EN LM U OTRAS PATOLOGIAS._x000D_ HIPOTESIS Y OBJETIVOS: EVIDENCIAS EXPERIMENTALES APORTAN UN SOPORTE SOLIDO A LA HIPOTESIS DE QUE LA POTENCIACION DE LA VIA DE SEÑALIZACION CANONICA WNT, MEDIANTE LA ADMINISTRACION EXOGENA DE LIGANDOS WNT CANONICOS O EL BLOQUEO DE SUS INHIBIDORES, PERMITIRA REDUCIR EL DAÑO SECUNDARIO Y PROMOVER LA RECUPERACION FUNCIONAL A TRAVES DE: 1) NEUROPROTECCION; 2) REDUCIR LA INFILTRACION DE CELULAS INFLAMATORIAS HEMATOGENAS; 3) RESTAURAR LA BARRERA HEMATOESPINAL (BHE) Y CON ELLO LA HOMEOSTASIS; 4) RESOLUCION DE LA INFLAMACION VIA PROMOCION DE UN FENOTIPO M2 FACILITADOR DE LA REPARACION TISULAR; 5) RECUPERACION FUNCIONAL POR FORMACION DE NUEVAS SINAPSIS Y REMIELINIZACION._x000D_ NUESTROS RESULTADOS HAN PERMITIDO IDENTIFICAR EL EJE WNT1/FRIZZLED1 Y EL INHIBIDOR CANONICO DKK1 COMO POTENCIALES DIANAS TERAPEUTICAS DURANTE LA FASE AGUDA DE LA LESION MEDULAR. SIN EMBARGO, LAS TERAPIAS WNT SE HALLAN LIMITADAS POR SU CORTA VIDA MEDIA Y RIESGO INTRINSECO PARA INDUCIR CARCINOGENESIS CUANDO SE ADMINISTRAN SISTEMICAMENTE. EN CONSECUENCIA, SE PLANTEA EL USO COMBINADO DE HIDROGELES DESARROLLADOS POR EL GRUPO BIOFORGE (UNIV. VALLADOLID), BASADOS EN RECOMBINAMEROS TIPO ELASTINA (ELR) DISEÑADOS PARA SER INYECTADOS EN TEJIDOS BLANDOS, CON PROPIEDADES NEUROPROTECTORAS Y REGENERATIVAS, Y MODIFICABLES GENETICAMENTE PARA INCREMENTAR LA VIDA MEDIA Y CONTROLAR LA LIBERACION DE MOLECULAS COMO LAS PROTEINAS WNT._x000D_ EL OBJETIVO FINAL ES EL DESARROLLO DE UNA TERAPIA CON POTENCIAL CLINICO BASADA EN LA ADMINISTRACION, UNICA E INTRAPARENQUIMA A LAS 24 HORAS POST-LESION DURANTE LA CIRUGIA DE DESCOMPRESION, DE UN HIDROGEL ELR QUE CONTENGA WNT1 Y UN ANTICUERPO ANTI-DKK1._x000D_ LA TERAPIA PROPUESTA PERSIGUE UN POTENTE EFECTO NEUROPROTECTOR, RESTAURADOR DE LA BHE Y UNA RESPUESTA INFLAMATORIA RESOLUTIVA EN LAS PRIMERAS SEMANAS POST-LESION, QUE FACILITE LA REPARACION TANTO TISULAR COMO FUNCIONAL DURANTE LOS ESTADIOS SUBAGUDO E INTERMEDIO POST-LESION PROMOVIDA POR EL HIDROGEL ELR INYECTADO EN EL EPICENTRO DE LA MEDULA ESPINAL DAÑADA._x000D_ METODOLOGIA: MEDIANTE EL USO DE UN MODELO DE LM EN RATA EVALUAREMOS LA EFICACIA TERAPEUTICA DE LOS TRATAMIENTOS PROPUESTOS MEDIANTE TECNICAS MOLECULARES (ELISA Y CITOMETRIA DE FLUJO), FUNCIONALES (BBB, CATWALK Y HARGREAVES), HISTOLOGICAS (HISTOQUIMICA, INMUNOFLUORESCENCIA, TRAZADO NEURAL Y PERMEABILIDAD BHE) E IMAGEN POR RESONANCIA MAGNETICA._x000D_ RESULTADOS E IMPACTO ESPERADOS: EN CASO DE EXITO EL ESTABLECIMIENTO DE LA BASE PRECLINICA PARA UNA POTENCIAL TRASLACION CLINICA DE LAS TERAPIAS PROPUESTAS. LA GENERACION DE PATENTES DERIVADO DE LAS TERAPIAS BASADAS EN ELRS PARA ADMINISTRACION INTRAPARENQUIMA DE WNT1 Y BHQ880, EN COLABORACION CON TECHNICAL PROTEINS NANOBIOTECHNOLOGY SL (EPO). FINALMENTE, UN MINIMO DE 3 ARTICULOS EN REVISTAS DE IMPACTO ALTO Y 2 COMUNICACIONES A CONGRESOS NACIONALES/INTERNACIONALES. POSICIONAR EL HNP COMO CENTRO DE REFERENCIA EN LM. (Spanish)
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UNMET MEDICAL NEED AND POTENTIAL HEALTH IMPACT: UP TO 7 MILLION PEOPLE WORLDWIDE AND 130.000 NEW CASES PER YEAR LIVE WITH THE DEBILITATING CONSEQUENCES OF SPINAL CORD INJURY (SCI). THE SCI REPRESENTS THE ONSET OF A LIFELONG DISEASE AND CONSTITUTES AN INDIVIDUAL AND SOCIOECONOMIC CATASTROPHE FOR WHICH THERE IS NO CURE. ALL THE ABOVE JUSTIFY THE NEED FOR MULTIDISCIPLINARY APPROACHES AIMING TO DEVELOP NOVEL OR INNOVATIVE THERAPEUTIC STRATEGIES, PREFERENTIALLY BASED ON TARGETS ALREADY IDENTIFIED IN HUMANS AND COMMON TO RELEVANT ANIMAL MODELS OF SCI, AND WHOSE TREATMENT HAS BEEN SHOWN AS SUCCESSFUL IN SCI OR A DIFFERENT DISEASE._x000D_ HYPOTHESIS AND OBJECTIVES: EVIDENCES, FROM OUR GROUP AND OTHERS, PROVIDE STRONG SUPPORT TO HYPOTHESIZE THAT POTENTIATION OF THE ENDOGENOUS WNT CANONICAL SIGNALING, BY EXOGENOUS ADMINISTRATION OF WNT CANONICAL LIGANDS OR BLOCKING OF ITS INHIBITORS, DURING THE ACUTE STAGE AFTER SCI WILL REDUCE SECONDARY DAMAGE AND RESULT IN FUNCTIONAL RECOVERY THROUGH: 1) NEUROPROTECTION; 2) REDUCED INFILTRATION OF HEMATOGENOUS INFLAMMATORY CELLS; 3) RESTORATION OF THE BSCB AND THUS TISSUE HOMEOSTASIS; 4) RESOLUTION OF THE INFLAMMATORY RESPONSE BY PROMOTING A SWITCH TO A M2 TISSUE REPAIR PROFILE; 5) PROMOTION OF FUNCTIONAL RECOVERY BY THE FORMATION OF NEW SYNAPSES AND REMYELINATION._x000D_ OUR RESULTS HAVE ALLOWED TO IDENTIFY THE WNT1/FRIZZLED1 AXIS AND THE CANONICAL INHIBITOR DKK1 AS POTENTIAL THERAPEUTIC TARGETS DURING THE ACUTE STAGE AFTER SCI. HOWEVER, WNT THERAPIES ARE LIMITED BY THEIR SHORT HALF-LIFE AND INTRINSIC RISK TO INDUCE CARCINOGENESIS WHEN ARE ADMINISTERED SYSTEMICALLY. THEREFORE, WE PROPOSE THE COMBINED USE OF HYDROGELS DEVELOPED BY THE GROUP BIOFORGE (UNIV. VALLADOLID), BASED ON ELASTIN-LIKE RECOMBINAMERS (ELRS) DESIGNED TO BE INJECTED IN SOFT TISSUES, WITH NEUROPROTECTIVE AND REGENERATIVE PROPERTIES, AND MAY BE GENETICALLY MODIFIED TO INCREASE THE HALF-LIFE AND CONTROLLED RELEASE OF MOLECULES SUCH AS THE WNT PROTEINS._x000D_ THE FINAL AIM IS THE DEVELOPMENT OF A THERAPY WITH CLINICAL POTENTIAL BASED ON THE ADMINISTRATION, AS A SINGLE AND INTRAPARENCHYMA INJECTION AT 24 HOURS POST-INJURY DURING THE DECOMPRESSION SURGERY, OF AN ELR HYDROGEL CONTAINING WNT1 AND THE DKK1-NEUTRALIZING ANTIBODY BHQ880._x000D_ THE PROPOSED THERAPY SEEKS A POTENT NEUROPROTECTIVE, BHE RESTORATIVE AND RESOLUTIVE INFLAMMATORY RESPONSE IN THE FIRST WEEKS AFTER SCI, WHICH WILL FACILITATE THE TISSUE AND FUNCTIONAL REPAIR DURING THE SUBACUTE AND INTERMEDIATE STAGES POST-INJURY SUPPORTED BY THE ELR HYDROGEL INJECTED AT THE EPICENTER OF THE DAMAGED SPINAL CORD._x000D_ METHODOLOGY: BY MEANS OF A RAT MODEL OF SCI WE WILL ASSESS THE THERAPEUTIC EFFICACY OF THE PROPOSED THERAPIES THROUGH TECHNIQUES OF MOLECULAR BIOLOGY (ELISA AND FLOW CYTOMETRY), FUNCTIONAL EVALUATION (BBB, CATWALK AND HARGREAVES), HISTOLOGY (NEURAL TRACING, IMMUNOFLUORESCENCE, HISTOCHEMISTRY AND BHE PERMEABILITY), AND MAGNETIC RESONANCE IMAGING._x000D_ EXPECTED RESULTS AND IMPACT: IF SUCCESSFUL, THE OBTAINED RESULTS WILL SET THE EXPERIMENTAL BASIS NEEDED TO SUPPORT A CLINICAL TRANSLATION OF THE PROPOSED THERAPIES. WE ALSO EXPECT THE GENERATION OF IPRS DERIVED OF THE DEVELOPMENT OF ELR-BASED THERAPIES FOR INTRAPARENCHYMA ADMINISTRATION OF WNT1 AND BHQ880, IN COLLABORATION WITH TECHNICAL PROTEINS NANOBIOTECHNOLOGY S.L. AS EPO. FINALLY, A MINIMUM OF 3 MANUSCRIPTS IN HIGH-IMPACT JOURNALS AND 2 COMMUNICATIONS IN NATIONAL/INTERNATIONAL MEETINGS MAY BE EXPECTED. ALTOGETHER TO POSITION THE HNP AS REFERENCE CENTER IN SCI. (English)
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Toledo
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Identifiers
RTI2018-097775-B-I00
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