Q3167120 (Q3167120): Difference between revisions
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(Created claim: summary (P836): Intermittent acute porphyria (IAPA), haploinsufficiency of liver porfobilinogen desaminase (PBGD), is characterised by intermittent abdomino-psychic-neurological crises associated with serum accumulation of hepatic haemo precursors. Trials in PAI mice and in a new rabbit model propose systemic administration of messenger RNA in lipid nanoparticles as a promising etiological treatment for MYP. This therapy works within a few hours and maintains e...) |
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Intermittent acute porphyria (IAPA), haploinsufficiency of liver porfobilinogen desaminase (PBGD), is characterised by intermittent abdomino-psychic-neurological crises associated with serum accumulation of hepatic haemo precursors. Trials in PAI mice and in a new rabbit model propose systemic administration of messenger RNA in lipid nanoparticles as a promising etiological treatment for MYP. This therapy works within a few hours and maintains efficacy after repeated administrations in the mouse. The first objective is to confirm the therapeutic efficacy and safety in single and repeated dosing of mRNA-PBGD in the porphyria model in rabbits and non-human primates. The biodistribution of the vector and the zonal distribution pattern of exogenous PBGD in the liver will also be studied. In the rabbit, the distribution of haemo precursors in urine, blood, and cerebrospinal fluid will also be analysed during the acute attack. Data on the accumulation of haemo precursors in PAI mouse and rabbit will be used to develop a semi-mechanistic computational modeling that provides a quantitative description of the different processes that occur during acute attacks. Thus, the second objective is the design of an in silico model that will allow estimating the response to new treatments, and scaling between species, including extrapolation to the patient, providing an approximation of the exposure required in clinical trials. The PAI mouse shows alterations in glycid and lipid metabolism in the absence of accumulation of haemo precursors that revert when expressing exogenous PBGD in the liver. Since diet and nutritional status is one of the triggers of acute attack, the third objective is to evaluate the lipid and glycid profile of patients with acute porphyria in order to provide personalised dietary advice. (English) | |||||||||||||||
| Property / summary: Intermittent acute porphyria (IAPA), haploinsufficiency of liver porfobilinogen desaminase (PBGD), is characterised by intermittent abdomino-psychic-neurological crises associated with serum accumulation of hepatic haemo precursors. Trials in PAI mice and in a new rabbit model propose systemic administration of messenger RNA in lipid nanoparticles as a promising etiological treatment for MYP. This therapy works within a few hours and maintains efficacy after repeated administrations in the mouse. The first objective is to confirm the therapeutic efficacy and safety in single and repeated dosing of mRNA-PBGD in the porphyria model in rabbits and non-human primates. The biodistribution of the vector and the zonal distribution pattern of exogenous PBGD in the liver will also be studied. In the rabbit, the distribution of haemo precursors in urine, blood, and cerebrospinal fluid will also be analysed during the acute attack. Data on the accumulation of haemo precursors in PAI mouse and rabbit will be used to develop a semi-mechanistic computational modeling that provides a quantitative description of the different processes that occur during acute attacks. Thus, the second objective is the design of an in silico model that will allow estimating the response to new treatments, and scaling between species, including extrapolation to the patient, providing an approximation of the exposure required in clinical trials. The PAI mouse shows alterations in glycid and lipid metabolism in the absence of accumulation of haemo precursors that revert when expressing exogenous PBGD in the liver. Since diet and nutritional status is one of the triggers of acute attack, the third objective is to evaluate the lipid and glycid profile of patients with acute porphyria in order to provide personalised dietary advice. (English) / rank | |||||||||||||||
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| Property / summary: Intermittent acute porphyria (IAPA), haploinsufficiency of liver porfobilinogen desaminase (PBGD), is characterised by intermittent abdomino-psychic-neurological crises associated with serum accumulation of hepatic haemo precursors. Trials in PAI mice and in a new rabbit model propose systemic administration of messenger RNA in lipid nanoparticles as a promising etiological treatment for MYP. This therapy works within a few hours and maintains efficacy after repeated administrations in the mouse. The first objective is to confirm the therapeutic efficacy and safety in single and repeated dosing of mRNA-PBGD in the porphyria model in rabbits and non-human primates. The biodistribution of the vector and the zonal distribution pattern of exogenous PBGD in the liver will also be studied. In the rabbit, the distribution of haemo precursors in urine, blood, and cerebrospinal fluid will also be analysed during the acute attack. Data on the accumulation of haemo precursors in PAI mouse and rabbit will be used to develop a semi-mechanistic computational modeling that provides a quantitative description of the different processes that occur during acute attacks. Thus, the second objective is the design of an in silico model that will allow estimating the response to new treatments, and scaling between species, including extrapolation to the patient, providing an approximation of the exposure required in clinical trials. The PAI mouse shows alterations in glycid and lipid metabolism in the absence of accumulation of haemo precursors that revert when expressing exogenous PBGD in the liver. Since diet and nutritional status is one of the triggers of acute attack, the third objective is to evaluate the lipid and glycid profile of patients with acute porphyria in order to provide personalised dietary advice. (English) / qualifier | |||||||||||||||
point in time: 12 October 2021
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Revision as of 16:54, 12 October 2021
Project Q3167120 in Spain
| Language | Label | Description | Also known as |
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| English | No label defined |
Project Q3167120 in Spain |
Statements
76,000.0 Euro
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152,000.0 Euro
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50.0 percent
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1 January 2019
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31 March 2022
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FUNDACION INSTITUTO DE INVESTIGACION SANITARIA DE NAVARRA
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42°49'6.42"N, 1°38'39.34"W
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31201
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La porfiria aguda intermitente (PAI), haploinsuficiencia de la porfobilinógeno desaminasa (PBGD) hepática, se caracteriza por crisis abdómino-psíquico-neurológicas intermitentes asociadas a la acumulación sérica de precursores del hemo de origen hepático. Ensayos en ratones PAI y en un nuevo modelo en conejo proponen la administración sistémica de ARN mensajero en nanopartículas lipídicas como un prometedor tratamiento etiológico para la PAI. Esta terapia actúa en pocas horas y mantiene la eficacia tras administraciones repetidas en ratón. El primer objetivo es confirmar la eficacia terapéutica y seguridad en dosificación única y repetida de ARNm-PBGD en el modelo de porfiria en conejo y en primates no-humanos. También se estudiará la biodistribución del vector y el patrón de distribución zonal de la PBGD exógena en el hígado. En el conejo, también se analizará la distribución de precursores del hemo en orina, sangre y líquido cefalorraquídeo durante el ataque agudo. Los datos de acumulación de precursores del hemo en ratón PAI y conejo se utilizarán para desarrollar un modelado semi-mecanístico computacional que proporcione una descripción cuantitativa de los diferentes procesos que se producen durante los ataques agudos. Así, el segundo objetivo es el diseño de un modelo in silico que permitirá estimar la respuesta a nuevos tratamientos, y el escalado entre especies, incluida una extrapolación al paciente, proporcionando una aproximación de la exposición necesaria en ensayos clínicos. El ratón PAI muestra alteraciones en el metabolismo glucídico y lipídico en ausencia de acumulación de precursores del hemo y que revierten al expresar PBGD exógena en el hígado. Dado que la dieta y el estado nutricional es uno de los factores desencadenantes de ataque agudo, el tercer objetivo es evaluar el perfil lipídico y glucídico de pacientes con porfiria aguda con el fin de proporcionar un consejo dietético personalizado. (Spanish)
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Intermittent acute porphyria (IAPA), haploinsufficiency of liver porfobilinogen desaminase (PBGD), is characterised by intermittent abdomino-psychic-neurological crises associated with serum accumulation of hepatic haemo precursors. Trials in PAI mice and in a new rabbit model propose systemic administration of messenger RNA in lipid nanoparticles as a promising etiological treatment for MYP. This therapy works within a few hours and maintains efficacy after repeated administrations in the mouse. The first objective is to confirm the therapeutic efficacy and safety in single and repeated dosing of mRNA-PBGD in the porphyria model in rabbits and non-human primates. The biodistribution of the vector and the zonal distribution pattern of exogenous PBGD in the liver will also be studied. In the rabbit, the distribution of haemo precursors in urine, blood, and cerebrospinal fluid will also be analysed during the acute attack. Data on the accumulation of haemo precursors in PAI mouse and rabbit will be used to develop a semi-mechanistic computational modeling that provides a quantitative description of the different processes that occur during acute attacks. Thus, the second objective is the design of an in silico model that will allow estimating the response to new treatments, and scaling between species, including extrapolation to the patient, providing an approximation of the exposure required in clinical trials. The PAI mouse shows alterations in glycid and lipid metabolism in the absence of accumulation of haemo precursors that revert when expressing exogenous PBGD in the liver. Since diet and nutritional status is one of the triggers of acute attack, the third objective is to evaluate the lipid and glycid profile of patients with acute porphyria in order to provide personalised dietary advice. (English)
12 October 2021
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Pamplona/Iruña
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Identifiers
PI18_00860
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