RESUMEN
Engaging patients as partners in biomedical research has gradually gained consensus over the last two decades. They provide a different perspective on health priorities and help to improve design and outcomes of clinical studies. This paper describes the relationship established between scientists and members of a large family at genetic risk of very rare lethal disease, fatal familial insomnia (FFI). This interaction led to a clinical trial based on the repurposing of doxycycline - an antibiotic with a known safety profile and optimal blood-brain barrier passage - which in numerous preclinical and clinical studies had given evidence of its potential therapeutic effect in neurodegenerative disorders, including prion diseases like FFI. The design of this trial posed several challenges, which were addressed jointly by the scientists and the FFI family. Potential participants excluded the possibility of being informed of their own FFI genotype; thus, the trial design had to include both carriers of the FFI mutation (10 subjects), and non-carriers (15 subjects), who were given placebo. Periodic clinical controls were performed on both groups by blinded examiners. The lack of surrogate outcome measures of treatment efficacy has required to compare the incidence of the disease in the treated group with a historical dataset during 10 years of observation. The trial is expected to end in 2023. Regardless of the clinical outcome, it will provide worthwhile knowledge on the disease. It also offers an important example of public engagement and collaboration to improve the quality of clinical science.
Asunto(s)
Insomnio Familiar Fatal , Enfermedades por Prión , Humanos , Insomnio Familiar Fatal/tratamiento farmacológico , Insomnio Familiar Fatal/genética , Mutación , Enfermedades por Prión/genéticaRESUMEN
Fatal familial insomnia (FFI) is a dominantly inherited prion disease linked to the D178N mutation in the gene encoding the prion protein (PrP). Symptoms, including insomnia, memory loss and motor abnormalities, appear around 50 years of age, leading to death within two years. No treatment is available. A ten-year clinical trial of doxycycline (doxy) is under way in healthy individuals at risk of FFI to test whether presymptomatic doxy prevents or delays the onset of disease. To assess the drug's effect in a tractable disease model, we used Tg(FFI-26) mice, which accumulate aggregated and protease-resistant PrP in their brains and develop a fatal neurological illness highly reminiscent of FFI. Mice were treated daily with 10 mg/kg doxy starting from a presymptomatic stage for twenty weeks. Doxy rescued memory deficits and restored circadian motor rhythmicity in Tg(FFI-26) mice. However, it did not prevent the onset and progression of motor dysfunction, clinical signs and progression to terminal disease. Doxy did not change the amount of aggregated and protease-resistant PrP, but reduced microglial activation in the hippocampus. Presymptomatic doxy treatment rescues cognitive impairment and the motor correlates of sleep dysfunction in Tg(FFI-26) mice but does not prevent fatal disease.
Asunto(s)
Ritmo Circadiano/efectos de los fármacos , Doxiciclina/farmacología , Doxiciclina/uso terapéutico , Insomnio Familiar Fatal/tratamiento farmacológico , Memoria/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacos , Animales , Encéfalo/patología , Progresión de la Enfermedad , Insomnio Familiar Fatal/genética , Insomnio Familiar Fatal/patología , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacosRESUMEN
BACKGROUND: Sporadic fatal insomnia (sFI) is a rapid progressive neurodegenerative disease characterised by gradual to perpetual insomnia, followed by dysautonomia, coma and death. 1 The cause of sFI was recently mapped to a mutation in a protein, the prion, found in the human brain. It is the unfolding of the prion that leads to the generation of toxic oligomers that destroy brain tissue and function. Recent studies have confirmed that a methionine mutation at codon 129 of the human Prion is characteristic of sFI. Current treatment slows down the progression of the disease, but no cure has been found, yet. METHODS: We used Molecular Docking and Molecular Dynamics simulation methods, to study the toxic Fatal-Insomnia-prion conformations at local unfolding. The idea was to determine these sites and to stabilise these regions against unfolding and miss-folding, using a small ligand, based on a phenothiazine "moiety". CONCLUSION: As a result we here discuss current fatal insomnia therapy and present seven novel possible compounds for in vitro and in vivo screening.
Asunto(s)
Antipsicóticos/uso terapéutico , Clorpromazina/química , Diseño de Fármacos , Insomnio Familiar Fatal/tratamiento farmacológico , Fenotiazinas/uso terapéutico , Encéfalo/metabolismo , Humanos , Insomnio Familiar Fatal/metabolismo , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Mutación/genética , Fenotiazinas/química , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Desplegamiento ProteicoRESUMEN
The text describes a preventive clinical trial with drug treatment in a very rare neurodegenerative disease (Fatal familial Insomnia, FFI) designed with the help of individuals at genetic risk of developing the disease, asymptomatic carriers, who have agreed to be exposed over a 10-year period to doxycycline, an antibiotic with anti-prion activity. At least 10 carriers of the FFI mutation over 42 y old will be treated with doxycycline (100 mg/die) and the incidence of the disease will be compared to that of an historical dataset. For ethical reasons a randomized, double-blind, placebo-controlled trial was not feasible, however the study design and the statistical analysis ensure the scientific value of the results. This approach might represent an important breakthrough in terms of potential therapy and knowledge of rare diseases that could give some hopes to these neglected patients.
Asunto(s)
Insomnio Familiar Fatal , Adulto , Ensayos Clínicos como Asunto , Doxiciclina/uso terapéutico , Humanos , Insomnio Familiar Fatal/tratamiento farmacológico , Insomnio Familiar Fatal/genética , Insomnio Familiar Fatal/prevención & control , Persona de Mediana EdadAsunto(s)
Insomnio Familiar Fatal/complicaciones , Insomnio Familiar Fatal/patología , Imagen por Resonancia Magnética/métodos , Síndrome de Leucoencefalopatía Posterior/complicaciones , Síndrome de Leucoencefalopatía Posterior/patología , Adulto , Antihipertensivos/uso terapéutico , Femenino , Humanos , Insomnio Familiar Fatal/tratamiento farmacológico , Síndrome de Leucoencefalopatía Posterior/tratamiento farmacológico , Resultado del TratamientoRESUMEN
A young patient with FFI was started on agomelatine 25 mg to medicate nocturnal insomnia. Under this treatment sleep efficiency was improved, slow wave sleep was high and awakenings during sleep period time were far less than before. Clinically the patient was less restless during nighttime.
Asunto(s)
Acetamidas/uso terapéutico , Hipnóticos y Sedantes/uso terapéutico , Insomnio Familiar Fatal/tratamiento farmacológico , Adulto , Epilepsia/etiología , Resultado Fatal , Femenino , Humanos , Insomnio Familiar Fatal/fisiopatología , Índice de Severidad de la Enfermedad , Fases del Sueño/efectos de los fármacos , Resultado del TratamientoRESUMEN
Fatal familial insomnia (FFI) is a hereditary prion disease caused by a mutation in codon 178 of the prion protein gene PRNP on chromosome 20. It is characterized by disturbed night sleep, resulting in daily vigilance perturbations and a variety of other neurological symptoms. We present the case of a 46-year-old woman deteriorating despite immunosuppressive treatment which was initiated suspecting cerebral vasculitis as the cause of her progressive neurological symptoms. The correct diagnosis was established only post mortem. Based on the case presented here, we discuss typical clinical symptoms and imaging findings. In particular, we outline how modern diagnostic methods such as positron emission tomography with [(15)O]H(2)O and [(18)F]FDG and single photon emission computed tomography can add valuable information to results from conventionally performed imaging techniques and genetic testing.
Asunto(s)
Fluorodesoxiglucosa F18 , Inmunosupresores/uso terapéutico , Insomnio Familiar Fatal/diagnóstico , Insomnio Familiar Fatal/tratamiento farmacológico , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada de Emisión de Fotón Único/métodos , Agua , Resultado Fatal , Femenino , Humanos , Persona de Mediana Edad , Radioisótopos de Oxígeno , RadiofármacosAsunto(s)
Clorpromazina/uso terapéutico , Síndrome de Creutzfeldt-Jakob/tratamiento farmacológico , Insomnio Familiar Fatal/tratamiento farmacológico , Quinacrina/uso terapéutico , Adulto , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Síndrome de Creutzfeldt-Jakob/fisiopatología , Análisis Mutacional de ADN , Antagonistas de Dopamina/uso terapéutico , Quimioterapia Combinada , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Insomnio Familiar Fatal/genética , Insomnio Familiar Fatal/fisiopatología , Masculino , Persona de Mediana Edad , Mutación/genética , Insuficiencia del TratamientoRESUMEN
Prion diseases are invariably fatal. Recently, quinacrine and chlorpromazine have been suggested as immediate candidates for the treatment of Creutzfeldt-Jakob disease and other prion diseases. The objective of this paper was to report on 2 fatal familial insomnia patients whose overall condition worsened despite quinacrine and chlorpromazine treatment.