RTI2018-095784-B-I00
Financiado
DESARROLLO DE NUEVAS TERAPIAS EN LAS EPILEPSIAS GENETICAS MEDIANTE EL REPOSICION...
DESARROLLO DE NUEVAS TERAPIAS EN LAS EPILEPSIAS GENETICAS MEDIANTE EL REPOSICIONAMIENTO DE FARMACOS - GECI (GENETIC EPILEPSIES CURE INITAITIVE)
THE EPILEPSIES CONSTITUTE A GROUP OF COMMON (WORLDWIDE PREVALENCE = 1%) AND CHRONIC DISORDERS THAT SEVERELY AFFECT THE QUALITY OF LIFE OF PATIENTS, ESPECIALLY OF THOSE WHO ARE DRUG-RESISTANT, TWO MAIN GROUPS ARE REPRESENTED BY THE...
THE EPILEPSIES CONSTITUTE A GROUP OF COMMON (WORLDWIDE PREVALENCE = 1%) AND CHRONIC DISORDERS THAT SEVERELY AFFECT THE QUALITY OF LIFE OF PATIENTS, ESPECIALLY OF THOSE WHO ARE DRUG-RESISTANT, TWO MAIN GROUPS ARE REPRESENTED BY THE FOCAL EPILEPSIES AND BY THE RARE GENETIC EPILEPSIES, THE FOCAL EPILEPSIES REPRESENT 60% OF ALL EPILEPSIES AND 30-40% OF THEM ARE DRUG RESISTANT, WITH ADVANCES IN NEUROIMAGING AND GENETICS, MALFORMATIONS OF CORTICAL DEVELOPMENT ARE BEING RECOGNIZED AS A MAJOR CAUSE OF AN INCREASING NUMBER OF THESE FOCAL REFRACTORY EPILEPSIES, IN SOME FAMILIAL FOCAL EPILEPSIES, DEPDC5 AND OTHER MEMBERS OF THE MTOR PATHWAY HAVE BEEN FOUND TO BE MUTATED, BOTH FAMILIAL AND SPORADIC CASES AND BOTH GERMLINE AND SOMATIC MUTATIONS HAVE BEEN REPORTED, THE STUDY OF THE GENETIC FOCAL EPILEPSIES IN A MOUSE MODEL OF DEPDC5 EPILEPSY OFFERS A UNIQUE OPPORTUNITY TO GAIN INSIGHT INTO THEIR PATHOGENESIS AND COULD LEAD TO MORE SPECIFIC AND PERSONALIZED THERAPIES OTHER THAN THE KNOWN NON-SPECIFIC ANTIEPILEPTIC DRUGS USED NOWADAYS,AMONG THE RARE GENETIC EPILEPSIES, THE PROGRESSIVE MYOCLONUS EPILEPSIES CONSTITUTE A GROUP OF ESPECIALLY DIFFICULT TO MANAGE NEURODEGENERATIVE EPILEPSIES, LAFORA DISEASE IS PROBABLY THE MOST STRIKING EXAMPLE BECAUSE IT AFFECTS OTHERWISE NORMAL CHILDREN AND ADOLESCENTS WHO, AFTER A PERIOD OF 5-10 YEARS OF REFRACTORY SEIZURES AND COGNITIVE DECLINE, ALMOST INVARIABLY DIE, WE HAVE CHARACTERIZED THE PHENOTYPIC PICTURE OF TWO ANIMAL MODELS OF THIS DISEASE AND STUDIED THE EFFECTS OF SEVERAL COMPOUNDS SUCH AS METFORMIN (ORPHAN DRUG DESIGNATION APPROVED BY EMA AND FDA) AND SODIUM SELENATE, BECAUSE EARLY TREATMENT IS IMPORTANT TO AVOID PERMANENT BRAIN DAMAGE, WE PROPOSE TO TEST PREVIOUSLY TESTED COMPOUNDS VERY EARLY DURING DEVELOPMENT AND NEW COMPOUNDS THAT COULD DIGEST THE CHARACTERISTIC GLYCOGEN-LIKE LAFORA BODIES,THE MAJOR OBJECTIVE OF THIS PROJECT IS TO DEVELOP NEW THERAPIES FOR FOCAL EPILEPSIES AND FOR LAFORA DISEASE, PREVENTING OR DELAYING THE OCCURRENCE OF NEUROLOGICAL DETERIORATION AND EPILEPTIC SEIZURES, BY USING DRUGS THAT ARE ALREADY AVAILABLE (REPURPOSING DRUGS), FOR THIS PURPOSE WE PROPOSE: 1) TO GENERATE A DEPDC5FLOX/FLOX SYNAPSINI-RTTA TETO-CRE MOUSE LINE THAT WILL ALLOW US TO DELETE THE DEPDC5 GENE IN NEURONS AT DIFFERENT STAGES OF DEVELOPMENT, THUS OBTAINING SEVERAL GROUPS OF MICE WITH DIFFERENT GRADES OF THE DISEASE, 2) TO TEST DRUGS THAT INHIBIT THE MTOR PATHWAY (RAPALOGS) VERY EARLY DURING DEVELOPMENT IN ORDER TO PREVENT THE DEVELOPMENT OF EPILEPSY IN THE INDUCIBLE MOUSE NEURONAL MODEL OF DEPDC5 FOCAL EPILEPSY, 3) TO SEARCH FOR BRAIN BIOMARKERS IN LAFORA DISEASE MOUSE MODELS BY MEANS OF STRUCTURAL AND FUNCTIONAL NEUROIMAGING STUDIES (MRI, [1H]-MR, HR-MAS AND PET) IN ORDER TO FOLLOW THE COURSE OF THE DISEASE AND TO ANALYZE THE EFFECTS OF DIFFERENT TREATMENTS, 4) TO AMELIORATE THE COURSE OF LAFORA DISEASE BY ADMINISTRATING DIFFERENT PHARMACOLOGICAL TREATMENTS IN MONOTHERAPY OR IN COMBINATION VERY EARLY DURING DEVELOPMENT (BEFORE BIRTH), 5) TO ATTEMPT TO ELIMINATE LAFORA BODIES BY MEANS OF AN ENZYMATIC THERAPY (ALGLUCOSIDASE ALPHA, MYOZYME) ADMINISTERED BY INTRACEREBRO-VENTRICULAR INJECTIONS, 6) TO DEFINE THE CLINICAL BIOCHEMISTRY OF LAFORA DISEASE MUTATIONS AND PROVIDE A PERSONALIZED DIAGNOSIS THAT MAY LEAD TO THERAPEUTIC OPTIONS TO TREAT LAFORA DISEASE, ULTIMATELY RESULTING IN A CURE, LAFORA\EPILEPSIA\FOCAL\DEPDC5\EPM2A\EPM2B\MODELOS ANIMALES\TRATAMIENTO PERSONALIZADO TREATMENT\REPOSICIONAMIENTO\NEUROIMAGEN
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Línea de financiación: concedida
El organismo AGENCIA ESTATAL DE INVESTIGACIÓN notifico la concesión del proyecto el día 2018-01-01
Presupuesto
El presupuesto total del proyecto asciende a
172K€
Líder del proyecto
FUNDACION INSTITUTO DE INVESTIGACION SANITARI...
Otra investigación y desarrollo experimental en ciencias naturales y técnicas asociacion
Perfil tecnológico
TRL
4-5
50K
Perfil tecnológico
TRL
4-5
50K