Grupos Investigadores

Líneas de Investigación

  • Enfermedad de Dravet y otras enfermedades raras neuropediatricas.
  • Neuromodulación de la actividad cerebral en las enfermedades neurodegenerativas y psiquiátricas (E. Parkinson, Esquizofrenia, Alzheimer y epilepsia).

Palabras Clave

  • Acinesia
  • Alzheimer
  • Dravet
  • Epilepsia
  • Esquizofrenia
  • Estimulación cerebral profunda
  • Movimientos anormales
  • Neurofisiología
  • Neuromodulación
  • Oscilaciones
  • Parkinson

Publicaciones Científicas desde 2018

  • Autores: Marlin Rodriguez, Elías; Valencia Ustárroz, Miguel; Peregrín Pastor, Nuria; et al.
    Revista: BRITISH JOURNAL OF PHARMACOLOGY
    ISSN: 1476-5381 Vol.181 N° 3 2024 págs. 495-508
    Resumen
    BACKGROUND AND PURPOSE: The integrated stress response (ISR) regulates translation in response to diverse stresses. ISR activation has been documented in amyotrophic lateral sclerosis (ALS) patients and ALS experimental models. In experimental models, both ISR stimulation and inhibition prevented ALS neurodegeneration; however, what mode of ISR regulation would work in patients is still debated. We previously demonstrated that the ISR modulator ISRIB (an eIF2B activator) enhances survival of neurons expressing the ALS neurotoxic allele SOD1 G93A. Here, we tested the effect of two ISRIB-like eIF2B activators (2BAct and PRXS571) in the disease progression of transgenic SOD1G93A mice.EXPERIMENTAL APPROACH: After a biochemical characterization in primary neurons, SOD1G93A mice were treated with 2BAct and PRXS571. Muscle denervation of vulnerable motor units was monitored with a longitudinal electromyographic test. We used a clinical score to document disease onset and progression; force loss was determined with hanging-wire motor test. Motor neuronal survival was assessed by immunohistochemistry.KEY RESULTS: In primary neurons 2BAct and PRXS571 relieve the ISR-imposed translational inhibition while maintaining high ATF4 levels. Electromyographic recordings evidenced an earlier and more dramatic muscle denervation in treated SOD1G93A mice that correlated with a decrease in motor neuron survival. Both compounds anticipated disease onset and shortened survival time.CONCLUSION AND IMPLICATIONS: 2BAct and PRXS571 anticipate disease onset, aggravating muscle denervation and motor neuronal death of SOD1G93A mice. This study reveals that the ISR works as a neuroprotective pathway in ALS motor neurons and reveals the toxicity that eIF2B activators may display in ALS patients.
  • Autores: de Pedro Baena, S.; Sariego Jamardo, A.; Castro, P.; et al.
    Revista: MOVEMENT DISORDERS CLINICAL PRACTICE
    ISSN: 2330-1619 Vol.10 N° 11 2023 págs. 1671 - 1679
    Resumen
    Background: Rho-related BTB domain-containing protein 2 (RHOBTB2) is a protein that interacts with cullin-3, a crucial E3 ubiquitin ligase for mitotic cell division. RHOBTB2 has been linked to early infantile epileptic encephalopathy, autosomal dominant type 64 (OMIM618004), in 34 reported patients.Methods: We present a case series of seven patients with RHOBTB2-related disorders (RHOBTB2-RD), including a description of a novel heterozygous variant. We also reviewed previously published cases of RHOBTB2-RD.Results: The seven patients had ages ranging from 2 years and 8 months to 26 years, and all had experienced seizures before the age of one (onset, 4-12 months, median, 4 months), including various types of seizures. All patients in this cohort also had a movement disorder (onset, 0.3-14 years, median, 1.5 years). Six of seven had a baseline movement disorder, and one of seven only had paroxysmal dystonia. Stereotypies were noted in four of six, choreodystonia in three of six, and ataxia in one case with multiple movement phenotypes at baseline. Paroxysmal movement disorders were observed in six of seven patients for whom carbamazepine or oxcarbazepine treatment was effective in controlling acute or paroxysmal movement disorders. Four patients had acute encephalopathic episodes at ages 4 (one patient) and 6 (three patients), which improved following treatment with methylprednisolone. Magnetic resonance imaging scans revealed transient fluid-attenuated inversion recovery abnormalities during these episodes, as well as myelination delay, thin corpus callosum, and brain atrophy. One patient had a novel RHOBTB2 variant (c.359G>A/p.Gly120Glu).Conclusion: RHOBTB2-RD is characterized by developmental delay or intellectual disability, early-onset seizures, baseline movement disorders, acute or paroxysmal motor phenomena, acquired microcephaly, and episodes of acute encephalopathy. Early onsets of focal dystonia, acute encephalopathic episodes, episodes of tongue protrusion, or peripheral vasomotor disturbances are important diagnostic clues. Treatment with carbamazepine or oxcarbazepine was found to be effective in controlling acute or paroxysmal movement disorders. Our study highlights the clinical features and treatment response of RHOBTB2-RD.
  • Autores: Fadila, S.; Beucher, B.; Gonzalez Dopeso-Reyes, I.; et al.
    Revista: JOURNAL OF CLINICAL INVESTIGATION
    ISSN: 0021-9738 Vol.133 N° 12 2023 págs. e159316
    Resumen
    Dravet syndrome (DS), an intractable childhood epileptic encephalopathy with a high fatality rate, is typically caused by loss-of-function mutations in one allele of SCN1A, which encodes NaV1.1, a 250-kDa voltage-gated sodium channel. In contrast to other epilepsies, pharmaceutical treatment for DS is limited. Here, we demonstrate that viral vector-mediated delivery of a codon-modified SCN1A open reading frame into the brain improves DS comorbidities in juvenile and adolescent DS mice (Scn1aA1783V/WT). Notably, bilateral vector injections into the hippocampus and/or the thalamus of DS mice increased survival, reduced the occurrence of epileptic spikes, provided protection from thermally induced seizures, corrected background electrocorticographic activity and behavioral deficits, and restored hippocampal inhibition. Together, our results provide a proof of concept for the potential of SCN1A delivery as a therapeutic approach for infants and adolescents with DS-associated comorbidities.
  • Autores: Ochoa Martínez, José Ángel; Gonzalez-Burgos, I.; Nicolás Apesteguía, María Jesús; et al.
    Revista: BIOENGINEERING
    ISSN: 2306-5354 Vol.10 N° 12 2023 págs. 1350
    Resumen
    Adaptive deep brain stimulation (aDBS) is a promising concept in the field of DBS that consists of delivering electrical stimulation in response to specific events. Dynamic adaptivity arises when stimulation targets dynamically changing states, which often calls for a reliable and fast causal estimation of the phase and amplitude of the signals. Here, we present an open-hardware implementation that exploits the concepts of resonators and Hilbert filters embedded in an open-hardware platform. To emulate real-world scenarios, we built a hardware setup that included a system to replay and process different types of physiological signals and test the accuracy of the instantaneous phase and amplitude estimates. The results show that the system can provide a precise and reliable estimation of the phase even in the challenging scenario of dealing with high-frequency oscillations (similar to 250 Hz) in real-time. The framework might be adopted in neuromodulation studies to quickly test biomarkers in clinical and preclinical settings, supporting the advancement of aDBS.
  • Autores: Ricobaraza Abarquero, Ana; Buñuales Aramendía, María; González Aparicio, Manuela; et al.
    Revista: JOURNAL OF MOLECULAR MEDICINE-JMM
    ISSN: 0946-2716 Vol.101 N° 12 2023 págs. 1587 - 1601
    Resumen
    The SCN1A gene encodes the alpha subunit of a voltage-gated sodium channel (Nav1.1), which is essential for the function of inhibitory neurons in the brain. Mutations in this gene cause severe encephalopathies such as Dravet syndrome (DS). Upregulation of SCN1A expression by different approaches has demonstrated promising therapeutic effects in preclinical models of DS. Limiting the effect to inhibitory neurons may contribute to the restoration of brain homeostasis, increasing the safety and efficacy of the treatment. In this work, we have evaluated different approaches to obtain preferential expression of the full SCN1A cDNA (6 Kb) in GABAergic neurons, using high-capacity adenoviral vectors (HC-AdV). In order to favour infection of these cells, we considered ErbB4 as a surface target. Incorporation of the EGF-like domain from neuregulin 1 alpha (NRG1¿) in the fiber of adenovirus capsid allowed preferential infection in cells lines expressing ErbB4. However, it had no impact on the infectivity of the vector in primary cultures or in vivo. For transcriptional control of transgene expression, we developed a regulatory sequence (DP3V) based on the Distal-less homolog enhancer (Dlx), the vesicular GABA transporter (VGAT) promoter, and a portion of the SCN1A gene. The hybrid DP3V promoter allowed preferential expression of transgenes in GABAergic neurons both in vitro and in vivo. A new HC-AdV expressing SCN1A under the control of this promoter showed improved survival and amelioration of the epileptic phenotype in a DS mouse model. These results increase the repertoire of gene therapy vectors for the treatment of DS and indicate a new avenue for the refinement of gene supplementation in this disease. KEY MESSAGES: Adenoviral vectors can deliver the SCN1A cDNA and are amenable for targeting. An adenoviral vector displaying an ErbB4 ligand in the capsid does not target GABAergic neurons. A hybrid promoter allows preferential expression of transgenes in GABAergic neurons. Preferential expression of SCN1A in GABAergic cells is therapeutic in a Dravet syndrome model.
  • Autores: Besné Villanueva, Guillermo Miguel; Lopez-Iturri, P.; Alegre Esteban, Manuel; et al.
    Revista: IEEE SENSORS JOURNAL
    ISSN: 1530-437X Vol.23 N° 21 2023 págs. 26620 - 26635
    Resumen
    Ambulatory monitoring is of great interest in both clinical and domestic environments. Despite the technological advances, few monitoring solutions are suitable for medical application and diagnosis. Here, we investigate the feasibility of targeting the periauricular area (ear pavilion, ear canal, and the surrounding skin areas) to implement a multimodal system that fulfills the requirements of ergonomics and minimal obstructiveness in the context of epilepsy monitoring. Six physiological signals are selected and explored for their integration in the area of interest and a proof-of-concept prototype integrating the components in a single portable device targeting the selected location is implemented. Results show mixed results where some parameters are highly reliable, and others are impractical or require customized technology to provide clinically relevant information. To enable data acquisition, storage, and processing within the Internet of Medical Things paradigms, wireless body area transceiver integration is also analyzed in terms of coverage/capacity relations, showing feasibility for such device configuration.
  • Autores: Gil-Nagel, A.; Sánchez-Carpintero Abad, Rocío (Autor de correspondencia); Villanueva, V.
    Revista: SCIENTIFIC REPORTS
    ISSN: 2045-2322 Vol.13 N° 1 2023 págs. 3355
    Resumen
    The aim of this study was to describe the profile of patients diagnosed with Dravet syndrome (DS), their clinical management, and the impact of DS on their quality of life (QoL) and family. Data of 80 patients from 11 centres in Spain was collected. Patients (47.5% female) were 12.7 (9.6) years on average (SD, standard deviation). Despite the first episode occurred when patients were a mean (SD) of 0.4 (0.2) years, DS was not diagnosed until they were 6.9 (10.1) years old. The majority (86.7%) had SCN1A gene mutations and 73.4% had seizures during the last year (mostly generalized motor seizures [47.8%]). The mean (SD) number of status epilepticus episodes was 3.6 (8.0) since diagnosis and 0.1 (0.5) in the last year. On the Health Utilities Index Mark (HUI) multi-attribute scale, the mean global score (SD) was 0.56 (0.24) in HUI2 and 0.32 (0.37) in HUI3. The impact of the disease was severe in most patients (HUI2, 81%; HUI3, 83.5%). In the Care-related QoL (CarerQol) the mean (SD) well-being score was 7.2 (2.1). Most caregivers (90%) were satisfied with their caregiving tasks, although 75% had difficulties combining these tasks with daily activities, 68.8% reported mental health problems and 61.2% physical problems.
  • Autores: González Aparicio, Manuela; Buñuales Aramendía, María; Ortiz-de Landazuri, I.; et al.
    Revista: BIOTECHNOLOGY JOURNAL
    ISSN: 1860-6768 Vol.18 N° 3 2023 págs. 2200227
    Resumen
    Background and AimsHigh-capacity adenoviral vectors (HC-AdV) show extended DNA payload and stability of gene expression in vivo due to the absence of viral coding sequences. However, production requires methods to trans-complement viral proteins, usually through Helper Viruses (HV). The Cre/loxP system is frequently employed to remove the packaging signal in HV genomes, in order to avoid their encapsidation. However, chronic exposure to the Cre recombinase in packaging cells is detrimental. We have applied the dimerizable Cre system to overcome this limitation. Methods and Results Cre was split in two fragments devoid of recombinase function (N-terminal 244 and C-terminal 99 amino-acids). In one version of the system, interaction with both moieties was favored by rapamycin-dependent heterodimerization domains (DiCre). Other version contained only Cre sequences (oCre). We generated packaging cells and HVs expressing the complementary fragments and studied their performance for HC-AdV production. We found that both conformations avoided interference with the growth of packaging cells, and the oCre system was particularly suitable for HC-AdV amplification. Conclusions The split-Cre system improves the performance of packaging cells and can reduce the time and cost of HC-AdV amplification up to 30% and 15%, respectively. This may contribute to the standardization of HC-AdV production.
  • Autores: Gonzalez-Burgos, I.; Bainier, M.; Gross, S.; et al.
    Revista: ENEURO
    ISSN: 2373-2822 Vol.10 N° 4 2023 págs. ENEURO.0406-22.2023
    Resumen
    Significance Statement Excitatory-inhibitory balance (EIB) is compromised in neurologic disorders. Our study demonstrates that pharmacologically-induced effects on EIB can be quantified by decomposing the quantitative electroence-phalography (qEEG) power spectrum signal into the oscillatory periodic and the 1/f aperiodic components. MK-801 and diazepam showed distinct signatures across brain regions and EEG components. Specific features of these components are sensitive to relatively small changes in measured exposure. This methodological ap-proach and the features identified as sensitive to EIB modulation could be key for the development of new therapies and functional biomarkers in disorders with excitatory-inhibitory imbalance.Brain function depends on complex circuit interactions between excitatory and inhibitory neurons embedded in local and long-range networks. Systemic GABAA-receptor (GABAAR) or NMDA-receptor (NMDAR) modulation alters the excitatory-inhibitory balance (EIB), measurable with electroencephalography (EEG). However, EEG sig-natures are complex in localization and spectral composition. We developed and applied analytical tools to in-vestigate the effects of two EIB modulators, MK801 (NMDAR antagonist) and diazepam (GABAAR modulator), on periodic and aperiodic EEG features in freely-moving male Sprague Dawley rats. We investigated how, across three brain regions, EEG features are correlated with EIB modulation. We found that the periodic component was composed of seven frequency bands that presented region-dependent and compound-dependent changes. The aperiodic component was also different between compounds and brain regions. Importantly, the parametri-zation into periodic and aperiodic components unveiled correlations between quantitative EEG and plasma con-centrations of pharmacological compounds. MK-801 exposures were positively correlated with the slope of the aperiodic component. Concerning the periodic component, MK-801 exposures correlated negatively with the peak frequency of low -y oscillations but positively with those of high -y and high-frequency oscillations (HFOs). As for the power, 0 and low -y oscillations correlated negatively with MK-801, whereas mid -y correlated posi-tively. Diazepam correlated negatively with the knee of the aperiodic component, positively to f3 and negatively to low -y oscillatory power, and positively to the modal frequency of 0 , low -y , mid -y , and high -y. In conclusion, correlations between exposures and pharmacodynamic effects can be better-understood thanks to the paramet-rization of EEG into periodic and aperiodic components. Such parametrization could be key in functional bio-marker discovery.
  • Autores: Besné Villanueva, Guillermo Miguel; Horrillo Maysonnial, Alejandro; Nicolás Apesteguía, María Jesús; et al.
    Revista: COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE
    ISSN: 0169-2607 Vol.218 2022 págs. 106728
    Resumen
    A B S T R A C T Background and objective: Despite advances on signal analysis and artificial intelligence, visual inspection is the gold standard in event detection on electroencephalographic recordings. This process requires much time of clinical experts on both annotating and training new experts for this same task. In scenarios where epilepsy is considered, the need for automatic tools is more prominent, as both seizures and interictal events can occur on hours-or days-long recordings. Although other solutions have already been proposed, most of them are not integrated on clinical and basic science environments due to their complexity and required specialization. Here we present a pipeline that arises from coordinated efforts between life-science researchers, clinicians and data scientists to develop an interactive and iterative workflow to train machine-learning tools for the automatic detection of electroencephalographic events in a variety of scenarios.Methods: The approach consists on a series of subsequent steps covering data loading and configuration, event annotation, model training/re-training and event detection. With slight modifications, the combination of these blocks can cope with a variety of scenarios. To illustrate the flexibility and robustness of the approach, three datasets from clinical (patients of Dravet Syndrome) and basic research environments (mice model of the same disease) were evaluated. From them, and in response to researchers' daily needs, four real world examples of interictal event detection and seizure classification tasks were selected and processed.Results: Results show that the current approach was of great aid for event annotation and model development. It was capable of creating custom machine-learning solutions for each scenario with slight adjustments on the analysis protocol, easily accessible to users without programming skills. Final annotator similarity metrics reached values above 80% on all cases of use, reaching 92.3% on interictal event detection on human recordings.Conclusions: The presented framework is easily adaptable to multiple real world scenarios and the interactive and ease-to-use approach makes it manageable to clinical and basic researches without programming skills. Nevertheless, it is conceived so data scientists can optimize it for specific scenarios, improving the knowledge transfer between these fields.
  • Autores: Janz, P. (Autor de correspondencia); Nicolás Apesteguía, María Jesús; Redondo, R. L.; et al.
    Revista: JOURNAL OF NEUROCHEMISTRY
    ISSN: 0022-3042 Vol.161 N° 5 2022 págs. 417 - 434
    Resumen
    Cognitive deficits and impaired sensory processing are hallmarks of several neurodevelopmental and neuropsychiatric disorders. N-methyl-D-aspartate receptor (NMDAR) hypofunction contributes to these deficits by disrupting the excitation-to-inhibition balance in neuronal networks. Although preclinical data suggest that the activation of gamma-Aminobutyric acid B receptors (GABA(B)R) may restore excitation-to-inhibition balance and rescues some behavioral deficits, GABA(B)R agonists have failed to meet their clinical study endpoints, suggesting more complex interactions at play. Here, we studied the effects of Baclofen (a GABA(B)R agonist) and MK-801 (a non-competitive NMDAR antagonist) on the neurophysiology of limbic-auditory circuits in freely-moving rats. The pharmacological effects were assessed using resting-state EEG, auditory-evoked oscillation, and mismatch negativity paradigms. MK-801 elevated resting-state oscillatory power, mainly in the gamma and higher frequency ranges, and impaired auditory-evoked responses. Baclofen partially normalized resting-state oscillations but failed to rescue auditory-evoked oscillatory abnormalities. Coherence analysis indicated that NMDAR hypofunction alters the functional coupling of limbic and thalamocortical circuits in several frequency bands. Baclofen normalized only a fraction of MK-801-induced abnormalities (e.g., theta coherence between frontal cortex and amygdala) while reducing delta-theta and augmenting gamma coherence in thalamocortical circuits. Finally, we report that Baclofen intensified the MK-801-induced deficits in auditory mismatch responses. In summary, while Baclofen partially normalizes MK-801-induced gamma abnormalities, it either fails to rescue or exacerbates deficits in other phenotypes like functional coupling and auditory processing. We hope that the presented complex interactions between pharmacologically induced NMDAR hypofunction and GABABR agonism inspire a new understanding of the therapeutic potential around GABAergic modulation.
  • Autores: Gil-Nagel, A.; Falip, M.; Sánchez-Carpintero Abad, Rocío; et al.
    Revista: EPILEPSY AND BEHAVIOR
    ISSN: 1525-5050 Vol.132 2022 págs. 108711
    Resumen
    Introduction: Dravet Syndrome (DS) is a severe, developmental epileptic encephalopathy (DEE) that begins in infancy and is characterized by pharmaco-resistant epilepsy and neurodevelopmental delay. Despite available antiseizure medications (ASMs), there is a need for new therapeutic options with greater efficacy in reducing seizure frequency and with adequate safety and tolerability profiles.Fenfluramine is a new ASM for the treatment of seizures associated with DS as add-on therapy to other ASMs for patients aged 2 years and older. Fenfluramine decreases seizure frequency, prolongs periods of seizure freedom potentially helping to reduce risk of Sudden Unexpected Death in Epilepsy (SUDEP) and improves patient cognitive abilities positively impacting on patients' Quality of Life (QoL).Reflective Multi-Criteria Decision Analysis (MCDA) methodology allows to determine what represents value in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner from the perspective of relevant stakeholders. The aim of this study was to determine the relative value contribution of fenfluramine for the treatment of DS in Spain using MCDA.Method: A literature review was performed to populate an adapted a MCDA framework for orphan-drug evaluation in Spain. A panel of ten Spanish experts, including neurologists, hospital pharmacists, patient representatives and decision-makers, scored four comparative evidence matrices.Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. Results: Dravet syndrome is considered a severe, rare disease with significant unmet needs. Fenfluramine is perceived to have a higher efficacy profile than all available alternatives, with a better safety profile than stiripentol and topiramate and to provide improved QoL versus studied alternatives. Fenfluramine results in lower other medical costs in comparison with stiripentol and clobazam. Participants perceived that fenfluramine could lead to indirect costs savings compared to available alternatives due to its efficacy in controlling seizures. Overall, fenfluramine's therapeutic impact on patients with DS is considered high and supported by high-quality evidence.Conclusions: Based on reflective MCDA, fenfluramine is considered to add greater benefit in terms of effi-cacy, safety and QoL when compared with available ASMs.
  • Autores: Foffani, G. (Autor de correspondencia); Alegre Esteban, Manuel (Autor de correspondencia)
    Revista: HANDBOOK OF CLINICAL NEUROLOGY
    ISSN: 0072-9752 Vol.184 2022 págs. 259 - 271
    Resumen
    Brain oscillations have been associated with Parkinson's disease (PD) for a long time mainly due to the fundamental oscillatory nature of parkinsonian rest tremor. Over the years, this association has been extended to frequencies well above that of tremor, largely owing to the opportunities offered by deep brain stimulation (DBS) to record electrical activity directly from the patients' basal ganglia. This chapter reviews the results of research on brain oscillations in PD focusing on theta (4-7Hz), beta (13-35Hz), gamma (70-80Hz) and high-frequency oscillations (200-400Hz). For each of these oscillations, we describe localization and interaction with brain structures and between frequencies, changes due to dopamine intake, task-related modulation, and clinical relevance. The study of brain oscillations will also help to dissect the mechanisms of action of DBS. Overall, the chapter tentatively depicts PD in terms of "oscillopathy."
  • Autores: Janz, P. (Autor de correspondencia); Bainier, M.; Marashli, S.; et al.
    Revista: TRANSLATIONAL PSYCHIATRY
    ISSN: 2158-3188 Vol.12 N° 1 2022 págs. 455
    Resumen
    Neurexins are presynaptic transmembrane proteins crucial for synapse development and organization. Deletion and missense mutations in all three Neurexin genes have been identified in psychiatric disorders, with mutations in the NRXN1 gene most strongly linked to schizophrenia (SZ) and autism spectrum disorder (ASD). While the consequences of NRXN1 deletion have been extensively studied on the synaptic and behavioral levels, circuit endophenotypes that translate to the human condition have not been characterized yet. Therefore, we investigated the electrophysiology of cortico-striatal-thalamic circuits in Nrxn1 alpha(-/-) rats and wildtype littermates focusing on a set of translational readouts, including spontaneous oscillatory activity, auditory-evoked oscillations and potentials, as well as mismatch negativity-like (MMN) responses and responses to social stimuli. On the behavioral level Nrxn1 alpha(-/-) rats showed locomotor hyperactivity. In vivo freely moving electrophysiology revealed pronounced increases of spontaneous oscillatory power within the gamma band in all studied brain areas and elevation of gamma coherence in cortico-striatal and thalamocortical circuits of Nrxn1 alpha(-/-) rats. In contrast, auditory-evoked oscillations driven by chirp-modulated tones showed reduced power in cortical areas confined to slower oscillations. Finally, Nrxn1 alpha(-/-) rats exhibited altered auditory evoked-potentials and profound deficits in MMN-like responses, explained by reduced prediction error. Despite deficits for auditory stimuli, responses to social stimuli appeared intact. A central hypothesis for psychiatric and neurodevelopmental disorders is that a disbalance of excitation-to-inhibition is underlying oscillatory and sensory deficits. In a first attempt to explore the impact of inhibitory circuit modulation, we assessed the effects of enhancing tonic inhibition via delta-containing GABA(A) receptors (using Gaboxadol) on endophenotypes possibly associated with network hyperexcitability. Pharmacological experiments applying Gaboxadol showed genotype-specific differences, but failed to normalize oscillatory or sensory processing abnormalities. In conclusion, our study revealed endophenotypes in Nrxn1 alpha(-/-) rats that could be used as translational biomarkers for drug development in psychiatric disorders.
  • Autores: Azcona Ganuza, G.; Alegre Esteban, Manuel (Autor de correspondencia)
    Revista: NEUROREPORT
    ISSN: 0959-4965 Vol.33 N° 11 2022 págs. 487 - 494
    Resumen
    There is a growing interest about the effects of static transcranial magnetic stimulation (tSMS) over different cortical areas, being the motor cortex the most widely studied region. Previous experiments have shown that noninvasive magnetic static stimulation of the human brain may change its excitability in a reversible way for a period that outlasts the time of application of the magnetic field. However, evidence about the effects over the auditory cortex are poor and this is the purpose of the present study. Twelve voluntary subjects were studied in two different sessions, immediately before and 20 min after the placement of a magnet or a sham over the left primary auditory cortex, for 30 min. No significant effects of the magnet were observed on auditory responses, including onset and offset potentials and oscillatory responses to stimulus frequency modulation. A reduction in the amplitude of the cortical onset and offset potentials was observed after the two sessions, both with the magnet and with the false magnet (sham). No effects of unilateral static magnetic stimulation on cortical auditory responses have been observed. However, we probe the feasibility and tolerability of the protocol performed and suggest the use of different stimulation protocols.
  • Autores: Aledo-Serrano, A. (Autor de correspondencia); Mingorance, A.; Villanueva, V.; et al.
    Revista: FRONTIERS IN NEUROLOGY
    ISSN: 1664-2295 Vol.13 2022 págs. 975034
    Resumen
    ObjectiveThe appropriate management of patients with Dravet Syndrome (DS) is challenging, given the severity of symptoms and the burden of the disease for patients and caregivers. This study aimed to identify, through a qualitative methodology and a Delphi consensus-driven process, a set of recommendations for the management of DS to guide clinicians in the assessment of the clinical condition and quality of life (QoL) of DS patients, with a special focus on patient- and caregiver-reported outcomes (PROs). MethodsThis study was conducted in five phases, led by a multidisciplinary scientific committee (SC) including pediatric neurologists, epileptologists, a neuropsychologist, an epilepsy nurse, and members of DS patient advocates. In phases 1 and 2, a questionnaire related to patients' QoL was prepared and answered by caregivers and the SC. In phase 3, the SC generated, based on these answers and on a focus group discussion, a 70-item Delphi questionnaire, covering six topic categories on a nine-point Likert scale. In phase 4, 32 panelists, from different Spanish institutions and with a multidisciplinary background, answered the questionnaire. Consensus was obtained and defined as strong or moderate if >= 80% and 67-79% of panelists, respectively, rated the statement with >= 7. Phase 5 consisted of the preparation of the manuscript. ResultsThe panelists agreed on a total of 69 items (98.6%), 54 (77.14%), and 15 (21.43%) with strong and moderate consensus, respectively. The experts' recommendations included the need for frequent assessment of patient and caregivers QoL parameters. The experts agreed that QoL should be assessed through specific questionnaires covering different domains. Likewise, the results showed consensus regarding the regular evaluation of several clinical parameters related to neurodevelopment, attention, behavior, other comorbidities, and sudden unexpected death in epilepsy (SUDEP). A consensus was also reached on the instruments, specific parameters, and caregivers' education in the routine clinical management of patients with DS. ConclusionsThis consensus resulted in a set of recommendations for the assessment of clinical and QoL parameters, including PROs, related to the general evaluation of QoL, neurodevelopment, attention, behavior, other comorbidities affecting QoL, SUDEP, and QoL of caregivers/relatives and patients with DS.
  • Autores: Rius-Rocabert, S.; Arranz-Herrero, J.; Fernández-Valdés, A.; et al.
    Revista: MATERIALS TODAY BIO
    ISSN: 2590-0064 Vol.13 2022 págs. 100191
    Resumen
    Inorganic materials can provide a set of tools to decontaminate solid, liquid or air containing viral particles. The use of disinfectants can be limited or not practical in scenarios where continuous cleaning is not feasible. Physicochemical differences between viruses raise the need for effective formulations for all kind of viruses. In the present work we describe two types of antimicrobial inorganic materials: i) a novel soda-lime glass (G3), and ii) kaolin containing metals nanoparticles (Ag or CuO), as materials to disable virus infectivity. Strong antiviral properties can be observed in G3 glass, and kaolin-containing nanoparticle materials showing a reduction of viral infectivity close to 99% in the first 10 min of contact of vesicular stomatitis virus (VSV). A potent virucidal activity is also present in G3 and kaolin containing Ag or CuO nanoparticles against all kinds of viruses tested, reducing more than 99% the amount of HSV-1, Adenovirus, VSV, Influenza virus and SARS-CoV-2 exposed to them. Virucidal properties could be explained by a direct interaction of materials with viruses as well as inactivation by the presence of virucidal elements in the material lixiviates. Kaolin-based materials guarantee a controlled release of active nanoparticles with antiviral activity. Current coronavirus crisis highlights the need for new strategies to remove viruses from contaminated areas. We propose these low-cost inorganic materials as useful disinfecting antivirals in the actual or future pandemic threats.
  • Autores: Wu, J. Y. (Autor de correspondencia); Cock, H. R.; Devinsky, O.; et al.
    Revista: EPILEPSIA
    ISSN: 0013-9580 Vol.63 N° 5 2022 págs. 1189 - 1199
    Resumen
    Objective: To estimate the timing of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]) onset, we conducted a post hoc analysis of GWPCARE6 (NCT02544763), a randomized, placebo-controlled, phase 3 trial in patients with drug-resistant epilepsy associated with tuberous sclerosis complex (TSC). Methods: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex; 100 mg/ml oral solution) at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or placebo for 16 weeks (4-week titration, 12-week maintenance). Treatment started at 5 mg/kg/day for all groups and reached 25 mg/kg/day on Day 9 and 50 mg/kg/day on Day 29. Percentage change from baseline in TSC-associated seizure (countable focal or generalized) count was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated. Results: Of 224 patients, 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo. Median (range) age was 11.3 (1.1-56.8) years. Patients had discontinued a median (range) of 4 (0-15) antiseizure medications and were currently taking 3 (0-5). Difference in seizure reduction between CBD and placebo emerged on Day 6 (titrated dose, 15 mg/kg/day) and became nominally significant (p < .049) by Day 10. Separation between placebo and CBD in ¿50% responder rate also emerged by Day 10. Onset of AEs occurred during the first 2 weeks of the titration period in 61% of patients (CBD25, 61%; CBD50, 67%; placebo, 54%). In patients with an AE, resolution occurred within 4 weeks of onset in 42% of placebo and 27% of CBD patients and by end of trial in 78% of placebo and 51% of CBD patients. Significance: Onset of treatment effect occurred within 6-10 days. AEs lasted longer for CBD than placebo, but the most common (diarrhea, decreased appetite, and somnolence) resolved during the 16-week trial in most patients.
  • Autores: García, M.; Bonafont, J.; Martínez-Palacios, J.; et al.
    Revista: MOLECULAR THERAPY. METHODS & CLINICAL DEVELOPMENT
    ISSN: 2329-0501 Vol.27 2022 págs. 96 - 108
    Resumen
    Recessive dystrophic epidermolysis bullosa, a devastating skin fragility disease characterized by recurrent skin blistering, scarring, and a high risk of developing squamous cell carcinoma is caused by mutations in COL7A1, the gene encoding type VII collagen, which is the major component of the anchoring fibrils that bind the dermis and epidermis. Ex vivo correction of COL7A1 by gene editing in patients' cells has been achieved before. However, in vivo editing approaches are necessary to address the direct treatment of the blistering lesions characteristic of this disease. We have now generated adenoviral vectors for CRISPR-Cas9 delivery to remove exon 80 of COL7A1, which contains a highly prevalent frameshift mutation in Spanish patients. For in vivo testing, a humanized skin mouse model was used. Efficient viral transduction of skin was observed after excisional wounds generated with a surgical punch on regenerated patient skin grafts were filled with the adenoviral vectors embedded in a fibrin gel. Type VII collagen deposition in the basement membrane zone of the wounded areas treated with the vectors correlated with restoration of dermal-epidermal adhesion, demonstrating that recessive dystrophic epidermolysis bullosa (RDEB) patient skin lesions can be directly treated by CRISPR-Cas9 delivery in vivo.
  • Autores: Baptista Jardín, Peter Michael (Autor de correspondencia); Di Frisco Ramírez, Isberling Madeleine; Urrestarazu Bolumburu, Elena; et al.
    Revista: LIFE
    ISSN: 2075-1729 Vol.12 N° 11 2022 págs. 1737
    Resumen
    Patients with obstructive sleep apnea (OSA) that do not tolerate/accept continuous positive airway pressure (CPAP) are candidates for surgical alternatives. Hypoglossal nerve stimulation (HNS) through the implantation of the Inspire (R) device constitutes a minimally invasive operative option. The main objective of this study is to estimate, under real-world clinical practice conditions, the 3-month impact on the quality of life (IQoL) of the HNS in patients with moderate/severe OSA who do not tolerate or accept CPAP, compared to patients who did not receive HNS. As a baseline, the unadjusted EuroQol utility index was 0.764 (SD:0.190) in the intervention group (IGr) and 0.733 (SD:0.205) in the control group (CGr); three months later, the indexes were 0.935 (SD: 0.101) and 0.727 (SD:0.200), respectively. The positive impact on quality of life was estimated to be +0.177 (95% CI: 0.044-0.310; p = 0.010). All dimensions in the IGr improved compared to CGr, especially for usual activities (p < 0.001) and anxiety/depression (p > 0.001). At the end of the follow-up, there was no significant difference in the quality of life between the general Spanish population and the IGr (difference: 0.012; CI95%: -0.03 to -0.057; p = 0.0578) for the same age range; however, there was a difference concerning the CGr (difference: -0.196; CI95%: -0.257 to -0.135; p < 0.001). In conclusion, patients with moderate/severe OSA implanted with the Inspire (R) device showed a positive IQoL.
  • Autores: Baptista Jardín, Peter Michael; Di Frisco Ramírez, Isberling Madeleine; Urrestarazu Bolumburu, Elena; et al.
    Revista: VALUE IN HEALTH
    ISSN: 1098-3015 Vol.25 N° 12 2022 págs. S391 - S392
  • Autores: Aledo-Serrano, A. (Autor de correspondencia); Gil-Nagel, A.; Isla, J.; et al.
    Revista: ORPHANET JOURNAL OF RARE DISEASES
    ISSN: 1750-1172 Vol.16 N° 1 2021 págs. 316
    Resumen
    The COVID-19 pandemic is adding an unanticipated concern for those affected by genetic diseases. Most of the new treatment achievements for these patients are made possible as a result of advances in viral-based products. Among them, adenoviruses (AdV) and especially adeno-associated viruses (AAV) are important players. The concerns and the conversation around this issue have increased as COVID-19 vaccines approach the market. What if the viral vectors become the mainstream strategy for vaccine development? Will the immune response elicited against the vector compromise the efficacy of future gene therapies? Patients with genetic diseases and patient advocacy groups are requesting information to the medical community about the potential impact of these vaccines in future gene therapy treatments, and physicians and scientists are not able to provide satisfactory answer yet. Importantly, the frequency of cross-reactivity among different AAV serotypes can be as high as 50%. This would have potential implications for patients with genetic disorders who could benefit from gene therapies, often coming in the form of AAV-based gene therapies. As in many other aspects, this pandemic is challenging our capacity to coordinate, plan ahead and align different medical objectives. In this case, having such conversation early on might allow us to make the right choices while we are still on time.
  • Autores: Ricobaraza Abarquero, Ana (Autor de correspondencia); Mora Jiménez, Lucía; Puerta Ruiz de Azua, Elena; et al.
    Revista: SCIENTIFIC REPORTS
    ISSN: 2045-2322 Vol.11 N° 1 2021 págs. 8437
  • Autores: Buñuales Aramendía, María; Ballesteros-Briones, M. C.; González Aparicio, Manuela; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.22 N° 8 2021 págs. 4176
    Resumen
    Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.
  • Autores: Lumbreras Roche, Sara; Ricobaraza Abarquero, Ana; Baila-Rueda, L.; et al.
    Revista: MOLECULAR THERAPY. METHODS & CLINICAL DEVELOPMENT
    ISSN: 2329-0501 Vol.22 2021 págs. 210 - 221
    Resumen
    Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disease caused by mutations in the CYP27A1 gene, encoding the sterol 27-hydroxylase. Disruption of the bile acid biosynthesis pathway and accumulation of toxic precursors such as cholestanol cause chronic diarrhea, bilateral juvenile cataracts, tissue deposition of cholestanol and cholesterol (xanthomas), and progressive motor/neuropsychiatric alterations. We have evaluated the therapeutic potential of adeno-associated virus (AAV) vectors expressing CYP27A1 in a CTX mouse model. We found that a vector equipped with a strong liverspecific promoter (albumin enhancer fused with the a1 antitrypsin promoter) is well tolerated and shows therapeutic effect at relatively low doses (1.5 x 10(12) viral genomes [vg]/kg), when less than 20% of hepatocytes overexpress the transgene. This vector restored bile acid metabolism and normalized the concentration of most bile acids in plasma. By contrast, standard treatment (oral chenodeoxycholic acid [CDCA]), while reducing cholestanol, did not normalize bile acid composition in plasma and resulted in supra-physiological levels of CDCA and its derivatives. At the transcriptional level, only the vector was able to avoid the induction of xenobiotic-induced pathways in mouse liver. In conclusion, the overexpression of CYP27A1 in a fraction of hepatocytes using AAV vectors is well tolerated and provides full metabolic restoration in Cyp27a1(-/-) mice. These features make gene therapy a feasible option for the etiological treatment of CTX patients.
  • Autores: Mora Jiménez, Lucía; Valencia Ustárroz, Miguel; Sánchez-Carpintero Abad, Rocío; et al.
    Revista: MOLECULAR THERAPY - NUCLEIC ACIDS
    ISSN: 2162-2531 Vol.25 2021 págs. 585 - 602
    Resumen
    Dravet syndrome is a genetic encephalopathy characterized by severe epilepsy combined with motor, cognitive, and behavioral abnormalities. Current antiepileptic drugs achieve only partial control of seizures and provide little benefit on the patient's neurological development. In >80% of cases, the disease is caused by haploinsufficiency of the SCN1A gene, which encodes the alpha subunit of the Nav1.1 voltage-gated sodium channel. Novel therapies aim to restore SCN1A expression in order to address all disease manifestations. We provide evidence that a high-capacity adenoviral vector harboring the 6-kb SCN1A cDNA is feasible and able to express functional Nav1.1 in neurons. In vivo, the best biodistribution was observed after intracerebral injection in basal ganglia, cerebellum, and prefrontal cortex. SCN1A A1783V knockin mice received the vector at 5 weeks of age, when most neurological alterations were present. Animals were protected from sudden death, and the epileptic phenotype was attenuated. Improvement of motor performance and interaction with the environment was observed. In contrast, hyperactivity persisted, and the impact on cognitive tests was variable (success in novel object recognition and failure in Morris water maze tests). These results provide proof of concept for gene supplementation in Dravet syndrome and indicate new directions for improvement.
  • Autores: Mendaza, S.; Fernández-Irigoyen, J.; Santamaría, E. ; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 7 2021 págs. 1739
    Resumen
    Simple Summary Cervical cancer (CC) is managed mainly using subjective and conventional methods. Research about the molecular mechanisms of micro-RNA-877-3p (miR-877-3p) in other cancer types revealed that it interacts with events that are important for CC. Our aim was to understand the role of miR-877-3p in CC. We observed that it was overexpressed in cervical tumors compared with benign lesions, and that it promoted CC cell migration and invasion by modulating cytoskeletal protein folding, which potentiated the effects caused by paclitaxel, one of the most common therapeutic drugs used in CC. We demonstrated a functional link between miR-877-3p and one of its predicted targets, ZNF177. The expression and subcellular location of ZNF177 objectively distinguished two CC entities and predicted poor outcome in the most aggressive form. Therefore, the understanding of the molecular mechanisms driven by miR-877-3p provides useful tools for CC clinical management, currently lacking of molecular biomarkers and targeted therapies. No therapeutic targets and molecular biomarkers are available in cervical cancer (CC) management. In other cancer types, micro-RNA-877-3p (miR-877-3p) has been associated with events relevant for CC development. Thus, we aimed to determine miR-877-3p role in CC. miR-877-3p levels were examined by quantitative-PCR in 117 cervical lesions and tumors. Effects on CC cell proliferation, migration, and invasion were evaluated upon anti-miR-877-3p transfection. miR-877-3p dependent molecular mechanism was comprehensively explored by proteomics, dual-luciferase reporter assay, western blot, and immunohistochemistry. Cervical tumors expressed higher miR-877-3p levels than benign lesions. miR-877-3p promoted CC cell migration and invasion, at least partly by modulating cytoskeletal protein folding through the chaperonin-containing T-complex protein 1 complex. Notably, miR-877-3p silencing synergized with paclitaxel. Interestingly, miR-877-3p downregulated the levels of an in silico-predicted target, ZNF177, whose expression and subcellular location significantly distinguished high-grade squamous intraepithelial lesions (HSILs) and squamous cell carcinomas of the cervix (SCCCs). Cytoplasmic ZNF177 was significantly associated with worse progression-free survival in SCCC. Our results suggest that: (i) miR-877-3p is a potential therapeutic target whose inhibition improves paclitaxel effects; (ii) the expression and location of its target ZNF177 could be diagnostic biomarkers between HSIL and SCCC; and (iii) cytoplasmic ZNF177 is a poor-prognosis biomarker in SCCC.
  • Autores: García-Penas, J. J. (Autor de correspondencia); Nagel-Rein, A. G.; Sánchez-Carpintero Abad, Rocío; et al.
    Revista: REVISTA DE NEUROLOGIA
    ISSN: 0210-0010 Vol.73 N° S01 2021 págs. S1 - S8
    Resumen
    Introduction. Cannabidiol (CBD) is one of the main components of the cannabis plant that has demonstrated anti-epileptic seizure effect. Following its clinical development, in September 2019 the European Medicines Agency approved its indication for the adjunctive therapy of epileptic seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS), combined with clobazam (CLB), in patients of 2 years of age and older. Aim. To establish recommendations on the use of plant-derived highly purified CBD on which Spanish experts have reached consensus for the treatment of epilepsy in patients with DS and LGS based on their clinical experience and the scientific evidence. Development. Consensus meeting with the participation of four Spanish neurologists and neuropediatric who are experts in epilepsy secondary to DS and LGS and with clinical experience in the use and management of CBD. They discussed on several topics, including posology (starting dose, dose escalation schema), efficacy (assessment of outcomes and indications for treatment withdrawal), and safety (evaluation, drug-drug interactions, adverse events management). Conclusions. In order to optimise CBD treatment, a slow dose escalation (>= 4 weeks) is recommended until the maximum recommended dose or the desire effect is reached. It is also recommended that the concomitant antiseizure medications (ASMs) be reduced in case of adverse events due to interactions, and that the treatment continues for at least 6 months if it is well tolerated. The efficacy and safety of CBD must be assessed individually, considering the benefits and risks for individual patients.
  • Autores: Pelletier, F. ; Perrier, S. ; Cayami, F. K. ; et al.
    Revista: JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
    ISSN: 0021-972X Vol.106 N° 2 2021 págs. e660 - e674
    Resumen
    Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting: This was a multicenter retrospective study using information collected from 3 predominant centers. Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
  • Autores: Scheffer, I. E. (Autor de correspondencia); Halford, J. J.; Miller, I.; et al.
    Revista: EPILEPSIA
    ISSN: 0013-9580 Vol.62 N° 10 2021 págs. 2505 - 2517
    Resumen
    Objective: Add-on cannabidiol (CBD) reduced seizures associated with Dravet syndrome (DS) in two randomized, double-blind, placebo-controlled trials: GWPCARE1 Part B (NCT02091375) and GWPCARE2 (NCT02224703). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or GWPCARE2, were enrolled in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5. Methods: Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/ml), titrated from 2.5 to 20 mg/kg/day over a 2-week period, added to their existing medications. Based on response and tolerance, CBD could be reduced or increased to 30 mg/kg/day. Results: Of the 330 patients who completed the original randomized trials, 315 (95%) enrolled in this open-label extension. Median treatment duration was 444 days (range = 18-1535), with a mean modal dose of 22 mg/kg/day; patients received a median of three concomitant antiseizure medications. Adverse events (AEs) occurred in 97% patients (mild, 23%; moderate, 50%; severe, 25%). Commonly reported AEs were diarrhea (43%), pyrexia (39%), decreased appetite (31%), and somnolence (28%). Twenty-eight (9%) patients discontinued due to AEs. Sixty-nine (22%) patients had liver transaminase elevations >3 × upper limit of normal; 84% were on concomitant valproic acid. In patients from GWPCARE1 Part B and GWPCARE2, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to Week 156 was 45%-74% for convulsive seizures and 49%-84% for total seizures. Across all visit windows, ¿83% patients/caregivers completing a Subject/Caregiver Global Impression of Change scale reported improvement in overall condition. Significance: We show that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.
  • Autores: Moscoso-Barrera, W. D.; Agudelo-Otalora, L. M.; Moreno-Giraldo, A. M.; et al.
    Revista: F1000RESEARCH
    ISSN: 2046-1402 Vol.10 2021 págs. 197
    Resumen
    Obstructive sleep apnoea-hypopnoea syndrome (OSA) is a respiratory disorder characterised by repetitive obstruction of the upper airway, leading to several interruptions during sleep. It is currently one of the main public health problems worldwide and one of the main cardiovascular risk factors in developed and intermediate developing countries, whose populations are increasing in rates of obesity and age. One of the common treatments for OSA is a continuous positive airway pressure (CPAP) device, which pumps air through a hose, reaches a mask that the patient has over his or her nose and travels the airway, keeping the upper airway open during sleep and avoiding episodes of airway collapse. The problem is that CPAP is not accepted by some patients due to a lack of adaptation, so alternative treatments may be needed. For some years, there have been explorations of treatments related to electrical stimulation of the muscles of the upper airway as therapy to reduce the number of episodes of apnoea (measured through the apnoea¿hypopnoea index) during the night, strengthening these muscles through stimulation. This is the protocol of the first clinical study of a rehabilitation device for home use that not only provides functional stimulation of the upper-airway dilator muscles but also provides sensory stimulation. This device works by strengthening the dilating muscles of the upper respiratory tract and improving the sensory capacity of the laryngo-pharyngeal tract and is based on existing publications on the effectiveness of functional and somatosensory neurostimulation through neuroplasticity in the recovery of neurological deficits.
  • Autores: Ricobaraza Abarquero, Ana
    Revista: MOLECULAR THERAPY
    ISSN: 1525-0016 Vol.29 N° 4 2021 págs. 285
  • Autores: Sánchez-Carpintero Abad, Rocío; Cock, H.; Wu, J. Y.; et al.
    Revista: EPILEPSIA
    ISSN: 0013-9580 Vol.62 N° S3 2021 págs. 32 - 32
  • Autores: Tordera Baviera, Rosa María; Cortés Erice, María; Díaz Perdigón, Teresa; et al.
    Revista: EUROPEAN NEUROPSYCHOPHARMACOLOGY
    ISSN: 0924-977X Vol.53 2021 págs. S46 - S46
  • Autores: Besné Villanueva, Guillermo Miguel; Alegre Esteban, Manuel; Podhorski, Adam; et al.
    Revista: ACTA OPHTHALMOLOGICA
    ISSN: 1755-375X Vol.98 N° 3 2020 págs. e397 - e399
  • Autores: Dautan, D. (Autor de correspondencia); Huerta-Ocampo, I. ; Gut, N. K.; et al.
    Revista: NATURE COMMUNICATIONS
    ISSN: 2041-1723 Vol.11 N° 1 2020
    Resumen
    Assimilation of novel strategies into a consolidated action repertoire is a crucial function for behavioral adaptation and cognitive flexibility. Acetylcholine in the striatum plays a pivotal role in such adaptation, and its release has been causally associated with the activity of cholinergic interneurons. Here we show that the midbrain, a previously unknown source of acetylcholine in the striatum, is a major contributor to cholinergic transmission in the striatal complex. Neurons of the pedunculopontine and laterodorsal tegmental nuclei synapse with striatal cholinergic interneurons and give rise to excitatory responses. Furthermore, they produce uniform inhibition of spiny projection neurons. Inhibition of acetylcholine release from midbrain terminals in the striatum impairs the association of contingencies and the formation of habits in an instrumental task, and mimics the effects observed following inhibition of acetylcholine release from striatal cholinergic interneurons. These results suggest the existence of two hierarchically-organized modes of cholinergic transmission in the striatum, where cholinergic interneurons are modulated by cholinergic neurons of the midbrain. Acetylcholine (ACh) in the striatum is involved in mediating action flexibility. Here the authors show that midbrain cholinergic nuclei provide a new source of Ach in the striatum, form excitatory synapses with striatal cholinergic interneurons (CIN) and contribute to instrumental learning.
  • Autores: Arzimanoglou, A. (Autor de correspondencia); Brandl, U.; Cross, J. H.; et al.
    Revista: EPILEPTIC DISORDERS
    ISSN: 1294-9361 Vol.22 N° 1 2020 págs. 1 - 14
    Resumen
    The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in legislation in some countries. Although there has been much speculation about the therapeutic value of cannabis-based products as an anti-seizure treatment for some time, it is only within the last two years that Class I evidence has been available for a pure form of CBD, based on placebo-controlled RCTs for patients with Lennox-Gastaut syndrome and Dravet syndrome. However, just as we are beginning to understand the significance of CBD as a treatment for epilepsy, in recent years, a broad spectrum of products advertised to contain CBD has emerged on the market. The effects of these products are fundamentally dependent on the purity, preparation, and concentration of CBD and other components, and consensus and standardisation are severely lacking regarding their preparation, composition, usage and effectiveness. This review aims to provide information to neurologists and epileptologists on the therapeutic value of CBD products, principally a purified form, in routine practice for patients with intractable epilepsy.
  • Autores: Martín-Suárez, S.; Abiega, O.; Ricobaraza Abarquero, Ana; et al.
    Revista: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
    ISSN: 2296-634X Vol.8 N° 654 2020
    Resumen
    Hippocampal neurogenesis, the process by which neural stem cells (NSCs) continuously generate new neurons in the dentate gyrus (DG) of most mammals including humans, is chiefly regulated by neuronal activity. Thus, severe alterations have been found in samples from epilepsy patients and in the hippocampal neurogenic niche in mouse models of epilepsy. Reactive-like and gliogenic NSCs plus aberrant newborn neurons with altered migration, morphology, and functional properties are induced by seizures in experimental models of temporal lobe epilepsy. Hippocampal neurogenesis participates in memory and learning and in the control of anxiety and stress. It has been therefore hypothesized that part of the cognitive symptoms associated with epilepsy could be promoted by impaired hippocampal neurogenesis. We here analyze for the first time the alterations of the neurogenic niche in a novel mouse model of Dravet syndrome (DS), a genetic encephalopathy with severe epilepsy in infancy and multiple neurological comorbidities. Scn1a(WT/A1783V)mice, hereafter referred to as DS, carrying a heterozygous and clinically relevant SCN1A mutation (A1783V) recapitulate the disease at the genetic and phenotypic levels. We demonstrate that in the neurogenic niche of young adult DS mice there are fewer NSCs, they have impaired cell division and bear reactive-like morphology. In addition, there is significant aberrant neurogenesis. Newborn immature neurons migrate abnormally, and several morphological features are drastically changed. Thus, this study shows for the first time important modifications in hippocampal neurogenesis in DS and opens venues for further research on this topic.
  • Autores: Sánchez-Carpintero Abad, Rocío (Autor de correspondencia); Urrestarazu Bolumburu, Elena; Cieza Ortiz, Sofía Isabel; et al.
    Revista: EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY
    ISSN: 1090-3798 Vol.24 2020 págs. 134 - 141
    Resumen
    Objective: To evaluate the capability of children with Dravet syndrome to generate brain gamma-oscillatory activity in response to auditory steady-state stimulation. Methods: Fifty-one subjects were included: 13 with Dravet syndrome with SCN1A gene alterations, 26 with non-Dravet epilepsies and 12 healthy controls. Responses to auditory steady-state stimulation elicited with a chirp-modulated tone between 1 and 120 Hz were collected in subjects and compared across groups. Results: Subjects with Dravet syndrome showed weak or no responses in the 1-120 Hz frequency range. Healthy controls showed oscillatory responses following the frequency of the modulation that were maximal in the low (30-70 Hz) and high (80-120) gamma-ranges both, in the power and inter-trial coherence estimates. Non-Dravet epileptic children showed differences in the auditory responses when compared with the healthy controls but were able to generate oscillatory evoked activities following the frequency-varying stimulation. Conclusions: The ability to generate brain gamma-oscillatory activity of children with Dravet in response to a chirp-modulated auditory stimulus is highly impaired, is not due to epilepsy and is consistent with the Nav1.1 channel dysfunction affecting interneuron activity seen in Dravet mouse models. Significance: The reported deficits in the brain oscillatory activity evoked by chirp modulated tones in children with Dravet is compatible with Dravet syndrome disease mechanisms and constitutes a potential biomarker for future disease-modifying interventions. (C) 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
  • Autores: Vélez-Galarraga, M. D. ; Coronel, M.; Vaca, R.; et al.
    Revista: JOURNAL OF PEDIATRIC EPILEPSY
    ISSN: 2146-457X Vol.9 N° 1 2020 págs. 13 - 17
    Resumen
    Early infantile epileptic encephalopathies (EIEEs) constitute a group of severe early onset epilepsies. Although still classified under syndromic clusters of clinical features, the genetic basis of several EIEEs leads to the definition of new types of epilepsies. We report a newborn male with seizures since his second day of life. The results of the first line diagnostic tests did not identify the cause of the seizures, which prompted a genetic study. A de novo KCNQ2 genomic variant that may explain the neonatal epileptic encephalopathy was found and led to more appropriate treatment. Genetic testing allows more specific treatment and more accurate prognosis, and also adds to the database of the phenotypes associated with the genomic variants.
  • Autores: Nabbout, R.; Mistry, A. ; Zuberi, S.; et al.
    Revista: JAMA NEUROLOGY
    ISSN: 2168-6149 Vol.77 N° 3 2020 págs. 300 - 308
    Resumen
    Importance Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. Objective To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens. Design, Setting, and Participants This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. Interventions Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients' assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. Main Outcomes and Measures The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. Results A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (>= 50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension. Conclusions and Relevance Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome.
  • Autores: Miller, I.; Scheffer, I. E.; Gunning, B.; et al.
    Revista: JAMA NEUROLOGY
    ISSN: 2168-6149 Vol.77 N° 5 2020 págs. 613 - 621
    Resumen
    mportance: Clinical evidence supports effectiveness of cannabidiol for treatment-resistant seizures in Dravet syndrome, but this trial is the first to evaluate the 10-mg/kg/d dose. Objective: To evaluate the efficacy and safety of a pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo for adjunctive treatment of convulsive seizures in patients with Dravet syndrome. Design, setting, and participants: This double-blind, placebo-controlled, randomized clinical trial (GWPCARE2) recruited patients from April 13, 2015, to November 10, 2017, with follow-up completed on April 9, 2018. Of 285 patients screened from 38 centers in the United States, Spain, Poland, the Netherlands, Australia, and Israel, 86 were excluded, and 199 were randomized. Patients were aged 2 to 18 years with a confirmed diagnosis of Dravet syndrome and at least 4 convulsive seizures during the 4-week baseline period while receiving at least 1 antiepileptic drug. Data were analyzed from November 16 (date of unblinding) to December 13 (date of final outputs), 2018, based on intention to treat and per protocol. Interventions: Patients received cannabidiol oral solution at a dose of 10 or 20 mg/kg per day (CBD10 and CBD20 groups, respectively) or matched placebo in 2 equally divided doses for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were blinded to group assignment. Main outcomes and measures: The primary outcome was change from baseline in convulsive seizure frequency during the treatment period. Secondary outcomes included change in all seizure frequency, proportion with at least a 50% reduction in convulsive seizure activity, and change in Caregiver Global Impression of Change score. Results: Of 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomized to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI, 8.4%-46.2%; P = .01) for CBD10 group and 25.7% (95% CI, 2.9%-43.2%; P = .03) for the CBD20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium. Conclusions and relevance: Adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome. Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety. Trial registration: ClinicalTrials.gov Identifier: NCT02224703.
  • Autores: Nabbout, R.; Sánchez-Carpintero Abad, Rocío; Halford, J. J.; et al.
    Revista: EUROPEAN JOURNAL OF NEUROLOGY
    ISSN: 1351-5101 Vol.27 N° Supl. 1 2020 págs. 435
  • Autores: Halford, J. J. ; Scheffer, I.; Nabbout, R. ; et al.
    Revista: NEUROLOGY
    ISSN: 0028-3878 Vol.94 N° 15 2020
  • Autores: Wu, J.; Cock, H. ; Devinsky, O.; et al.
    Revista: NEUROLOGY
    ISSN: 0028-3878 Vol.94 N° 15 2020
  • Autores: Cocho Archiles, Borja; Manzanilla Zapata, Oscar; Horrillo Maysonnial, Alejandro; et al.
    Revista: JOURNAL OF SLEEP RESEARCH
    ISSN: 0962-1105 Vol.29 2020 págs. 339 - 340
  • Autores: Malaga, I. (Autor de correspondencia); Sánchez-Carpintero Abad, Rocío; Roldan, S.; et al.
    Revista: ANALES DE PEDIATRIA
    ISSN: 1695-4033 Vol.91 N° 6 2019 págs. 415.e1 - 415.e10
    Resumen
    It is estimated that about 70 million people all over the world suffer from epilepsy, half of which are children, in whom the prevalence is around 0.5 to 0.8%. Although there are several therapies, the treatment of epilepsy is based mainly on drugs, which, depending on the year of coming onto the market are classified as first, second, or third generation. In this article, a description is presented on the main characteristics of the latest generation of anti-epileptic drugs (lacosamide, eslicarbazepine acetate, brivaracetam, perampanel, retigabine, everolimus and cannabidiol). These, with the exception of retigabine (is not yet on the market), are considered safe and effective in the paediatric population. Everolimus and cannabidiol have very specific indications (tuberous sclerosis, Dravet syndrome, and Lennox Gastaut syndrome), while the rest are indicated in the management of seizures of focal origin in children from 4 years-old. These new molecules have been developed in order to provide a pharmaceutical profile and tolerance superior to the previously available drugs, and it is forecast that as their use increases, their true potential and profile will widen. Furthermore, for the first time in Paediatric Epileptology, the extrapolation of the efficacy data in adults have been used (together with specific safety and pharmacokinetic studies in the paediatric population), in order to speed up their approval for use in the child population.
  • Autores: Ricobaraza Abarquero, Ana (Autor de correspondencia); Mora Jiménez, Lucía; Puerta Ruiz de Azua, Elena; et al.
    Revista: SCIENTIFIC REPORTS
    ISSN: 2045-2322 Vol.9 2019 págs. 14172
    Resumen
    Dravet Syndrome (DS) is an encephalopathy with epilepsy associated with multiple neuropsychiatric comorbidities. In up to 90% of cases, it is caused by functional happloinsufficiency of the SCN1A gene, which encodes the alpha subunit of a voltage-dependent sodium channel (Nav1.1). Preclinical development of new targeted therapies requires accessible animal models which recapitulate the disease at the genetic and clinical levels. Here we describe that a C57BL/6 J knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V) presents a full spectrum of DS manifestations. This includes 70% mortality rate during the first 8 weeks of age, reduced threshold for heat-induced seizures (4.7 degrees C lower compared with control littermates), cognitive impairment, motor disturbances, anxiety, hyperactive behavior and defects in the interaction with the environment. In contrast, sociability was relatively preserved. Electrophysiological studies showed spontaneous interictal epileptiform discharges, which increased in a temperature-dependent manner. Seizures were multifocal, with different origins within and across individuals. They showed intra/inter-hemispheric propagation and often resulted in generalized tonic-clonic seizures. F-18-labelled flourodeoxyglucose positron emission tomography (FDG-PET) revealed a global increase in glucose uptake in the brain of Scn1a(WT/A1783V) mice. We conclude that the Scn1a(WT/A1783V) model is a robust research platform for the evaluation of new therapies against DS.
  • Autores: Gil-Nagel, A.; Sánchez-Carpintero Abad, Rocío; San Antonio, V. ; et al.
    Revista: REVISTA DE NEUROLOGIA
    ISSN: 0210-0010 Vol.68 N° 2 2019 págs. 75 - 81
    Resumen
    Introduction. Dravet syndrome (DS) is a rare, drug resistant epilepsy that starts very early in life with febrile seizures followed by cognitive impairment and diverse seizure types. Aim. To generate evidence on the epidemiology of DS, its diagnosis, patient-flow, treatment and unmet needs from the perspective of Spanish experts. Development. A two-round Delphi study involving 19 physicians was conducted. Questionnaires were based on literature review and validated by clinical experts. Consensus was reached when topics were subject to routine clinical practice and individual experience, or the coefficient of variation among answers was <= 0.3. The estimated number of new DS patients is 73 per year. Prevalence is estimated to be between 348-540 patients. DS is mostly diagnosed in children. Survival varies from 5 to 60 years. There is no standardised follow-up of patients beyond the age of 18 and mortality rates are uncertain. No standard guidelines exist for diagnosing or treating DS. It takes 9 to 15 months to confirm the diagnosis and genetic testing is unevenly available. Valproic acid, clobazam, stiripentol and topiramate are commonly used. Poor efficacy and safety are the main reasons for treatment switch. Conclusions. The epidemiology of DS in Spain is not well known and several areas of unmet needs still exist. Experts' views offer a starting point for further research into the reality of DS in Spain. Epidemiological studies, consensus criteria, easy access to genetic testing, treatment options, training and research into quality of life aspects are highly needed.
  • Autores: Halford, J.; Scheffer, I. ; Nabbout, R. ; et al.
    Revista: NEUROLOGY
    ISSN: 0028-3878 Vol.92 N° 15 2019
  • Autores: Miller, I.; Scheffer, I. ; Gunning, B. ; et al.
    Revista: EPILEPSIA
    ISSN: 0013-9580 Vol.60 N° Supl. 2 2019 págs. 23 - 23
  • Autores: Romero-Duque, P.; Sanchez-Mejias, A.; Gonzalez-Aparicio, M.; et al.
    Revista: HUMAN GENE THERAPY
    ISSN: 1043-0342 Vol.30 N° 11 2019 págs. A163 - A163
  • Autores: Nabbout, R. ; Halford, J. ; Scheffer, I. E.; et al.
    Revista: EPILEPSIA
    ISSN: 0013-9580 Vol.60 N° Supl. 2 2019 págs. 63 - 63
  • Autores: Mora Jiménez, Lucía; Lumbreras Roche, Sara; Valencia Ustárroz, Miguel; et al.
    Revista: HUMAN GENE THERAPY
    ISSN: 1043-0342 Vol.30 N° 11 2019 págs. A97 - A97
  • Autores: Baptista Jardín, Peter Michael (Autor de correspondencia); Garaycochea Mendoza del Solar, Octavio; Álvarez Gómez, Laura; et al.
    Revista: ACTA OTORRINOLARINGOLOGICA ESPAÑOLA
    ISSN: 0001-6519 Vol.69 N° 1 2018 págs. 42 - 47
    Resumen
    The objective of this communication is to describe our preliminary results in upper airway stimulation surgery via hypoglossal nerve stimulation implantation for obstructive sleep apnoea. We describe 4 cases and the outcomes of the surgery were analysed using the Epworth scale, apnoea-hypopnoea index, minimal 02 Sat, average 02 Sat and snoring intensity. In all cases a significant reduction in Epworth scale values and apnoea-hypopnoea index were obtained (P<.05). The minimum and average oxygen saturation had better values after the surgery, however, there was no statistically significant difference. The snoring severity measured subjectively changed from "intense" to "absent", in all cases. The preliminary results obtained with the upper airway stimulation surgery via hypoglossal nerve stimulation showed objective and subjective improvement after the implant activation. (C) 2017 Elsevier Espana, S.L.U. and Sociedad Espanola de Otorrinolaringologia y Cirugia de Cabeza y Cuello. All rights reserved.
  • Autores: Baptista Jardín, Peter Michael; Garaycochea Mendoza del Solar, Octavio; Álvarez Gómez, Laura; et al.
    Revista: ACTA OTORRINOLARINGOLOGICA ESPAÑOLA
    ISSN: 0001-6519 Vol.69 N° 1 2018 págs. 42 - 47
    Resumen
    The objective of this communication is to describe our preliminary results in upper airway stimulation surgery via hypoglossal nerve stimulation implantation for obstructive sleep apnoea. We describe 4 cases and the outcomes of the surgery were analysed using the Epworth scale, apnoea-hypopnoea index, minimal O2 Sat, average O2 Sat and snoring intensity. In all cases a significant reduction in Epworth scale values and apnoea-hypopnoea index were obtained (P<.05). The minimum and average oxygen saturation had better values after the surgery, however, there was no statistically significant difference. The snoring severity measured subjectively changed from «intense» to «absent» in all cases. The preliminary results obtained with the upper airway stimulation surgery via hypoglossal nerve stimulation showed objective and subjective improvement after the implant activation.
  • Autores: Marrugal-Lorenzo, J. A. ; Serna-Gallego, A.; Gonzalez-Gonzalez, L.; et al.
    Revista: ANTIVIRAL RESEARCH
    ISSN: 0166-3542 Vol.159 2018 págs. 77 - 83
    Resumen
    The repurposing of drugs approved by the regulatory agencies for other indications is emerging as a valuable alternative for the development of new antimicrobial therapies, involving lower risks and costs than the de novo development of novel antimicrobial drugs. Adenovirus infections have showed a steady increment in recent years, with a high clinical impact in both immunosuppressed and immunocompetent patients. In this context, the lack of a specific drug to treat these infections supports the search for new therapeutic alternatives. In this study, we examined the anti-HAdV properties of mifepristone, a commercially available synthetic steroid drug. Mifepristone showed significant in vitro anti-HAdV activity at low micromolar concentrations with little cytotoxicity. Our mechanistic assays suggest that this drug could affect the microtubule transport, interfering with the entry of the virus into the nucleus and therefore inhibiting HAdV infection.
  • Autores: Devinsky, O.; Patel, A.D.; Cross, J.H.; et al.
    Revista: NEW ENGLAND JOURNAL OF MEDICINE
    ISSN: 0028-4793 Vol.378 N° 20 2018 págs. 1888 - 1897
    Resumen
    BACKGROUND: Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy. METHODS: In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period. RESULTS: A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations. CONCLUSIONS: Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations.
  • Autores: Aguilera Albesa, Sergio; Crespo Eguilaz, Nerea; del Pozo León, José Luis; et al.
    Revista: JOURNAL OF ATTENTION DISORDERS
    ISSN: 1087-0547 Vol.22 N° 9 2018 págs. 864 - 871
  • Autores: Cordon Medrano, Ivan; Nicolás Apesteguía, María Jesús; Arrieta Eguren, Sandra; et al.
    Revista: BRAIN STIMULATION
    ISSN: 1935-861X Vol.11 N° 1 2018 págs. 231 - 238
    Resumen
    Background: High-frequency deep brain stimulation (DBS) has become a widespread therapy used in the treatment of Parkinson's Disease (PD) and other diseases. Although it has proved beneficial, much recent attention has been centered around the potential of new closed-loop DBS implementations. Objective: Here we present a new closed-loop DBS scheme based on the phase of the theta activity recorded from the motor cortex. By testing the implementation on freely moving 6-OHDA lesioned and control rats, we assessed the behavioral and neurophysiologic effects of this implementation and compared it against the classical high-frequency DBS. Results: Results show that both stimulation modalities produce significant and opposite changes on the movement and neurophysiological activity. Close-loop stimulation, far from improving the animals' behavior, exert contrary effects to those of high-frequency DBS which reverts the parkinsonian symptoms. Motor improvement during open-loop, high-frequency DBS was accompanied by a reduction in the amount of cortical beta oscillations while akinetic and disturbed behavior during close-loop stimulation coincided with an increase in the amplitude of beta activity. Conclusion: Cortical-phase-dependent close-loop stimulation of the STN exerts significant behavioral and oscillatory changes in the rat model of PD. Open-loop and close-loop stimulation outcomes differed dramatically, thus suggesting that the scheme of stimulation determines the output of the modulation even if the target structure is maintained. The current framework could be extended in future studies to identify the correct parameters that would provide a suitable control signal to the system. It may well be that with other stimulation parameters, this sort of DBS could be beneficial. (C) 2017 Elsevier Inc. All rights reserved.
  • Autores: Jiang, L. ; Berraondo López, Pedro; Jerico, D.; et al.
    Revista: NATURE MEDICINE
    ISSN: 1078-8956 Vol.24 N° 12 2018 págs. 1899 - 1909
    Resumen
    Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks. Furthermore, hPBGD mRNA protected against mitochondrial dysfunction, hypertension, pain and motor impairment. Repeat dosing in AIP mice showed sustained efficacy and therapeutic improvement without evidence of hepatotoxicity. Finally, multiple administrations to nonhuman primates confirmed safety and translatability. These data provide proof-of-concept for systemic hPBGD mRNA as a potential therapy for AIP.
  • Autores: Hernández Alcoceba, Rubén; Buñuales Aramendía, María; Gonzalez-Aparicio, M.; et al.
    Revista: MOLECULAR THERAPY
    ISSN: 1525-0016 Vol.26 N° 5 2018 págs. 195 - 195
  • Autores: Bonkovsky, H. L.; Bissell, D. M. ; Ventura, P.; et al.
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.68 N° Supl. 1 2018 págs. 723A - 724A

Proyectos desde 2018

  • Título: DISEÑO Y DESARROLLO DE UN DISPOSITIVO DE MONITORIZACIÓN DE PARÁMETROS BIOMÉDICOS MEDIANTE IMPRESIÓN FUNCIONAL E HIDROGELES (Skin Sensor- SKS)
    Código de expediente: 0011-1365-2023-000131
    Investigador principal: MIGUEL VALENCIA USTARROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2023 GN I+D EMPRESAS (Transferencia del conocimiento 2020)
    Fecha de inicio: 01-09-2023
    Fecha fin: 31-07-2025
    Importe concedido: 53.578,87€
    Otros fondos: Fondos FEDER
  • Título: Suplementación de SCN1A para la Reversión de Encefalopatías Genéticas
    Código de expediente: PID2021-128587OB-I00
    Investigador principal: RUBEN HERNANDEZ ALCOCEBA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2021 MCIU AEI GENERACION CONOCIMIENTO
    Fecha de inicio: 01-09-2022
    Fecha fin: 31-08-2025
    Importe concedido: 162.140,00€
    Otros fondos: -
  • Título: Nuevas terapias genéticas basadas en inteínas para el síndrome de Dravet
    Código de expediente: CPP2021-008999
    Investigador principal: RUBEN HERNANDEZ ALCOCEBA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2021 MCI - AEI PROYECTOS DE COLABORACIÓN PUBLICO-PRIVADAS
    Fecha de inicio: 10-02-2022
    Fecha fin: 09-02-2025
    Importe concedido: 747.542,60€
    Otros fondos: Fondos MRR
  • Título: Estudio del mecanismo y potencial terapéutico del procesamiento y traducción de mARNs en respuesta estrés en la Esclerosis Lateral Amiotrófica. RNAreg2CureALS.
    Código de expediente: PID2020-120497RB-I00
    Investigador principal: MONTSERRAT ARRASATE IRAGUI, TOMAS ARAGON AMONARRIZ.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2020 MCIU - AEI PROYECTOS DE I+D RETOS INVESTIGACION
    Fecha de inicio: 01-09-2021
    Fecha fin: 31-08-2024
    Importe concedido: 205.700,00€
    Otros fondos: -
  • Título: GNE 2020 PREDOC IRENE GONZALEZ M.VALENCIA
    Código de expediente: 0011-0537-2020-000041
    Investigador principal: IRENE GONZALEZ BURGOS.
    Financiador: GOBIERNO DE NAVARRA / DPTO. EDUCACIÓN CULTURA Y TURISMO
    Convocatoria: FIMA GNE 2020 BECAS PREDOCTORALES
    Fecha de inicio: 10-06-2021
    Fecha fin: 09-06-2024
    Importe concedido: 68.718,00€
    Otros fondos: -
  • Título: GNE 2020 PREDOC JOSE ANGEL OCHOA M. VALENCIA
    Código de expediente: 0011-0537-2020-000089
    Investigador principal: JOSE ANGEL OCHOA MARTINEZ.
    Financiador: GOBIERNO DE NAVARRA / DPTO. EDUCACIÓN CULTURA Y TURISMO
    Convocatoria: FIMA GNE 2020 BECAS PREDOCTORALES
    Fecha de inicio: 10-06-2021
    Fecha fin: 24-11-2023
    Importe concedido: 56.582,00€
    Otros fondos: -
  • Título: Utilización de datos genómicos para generar una vacuna contra el cáncer (BLANCA: Breast Long non coding ANti-Cancer Antigens)
    Código de expediente: 0011-1411-2021-000070
    Investigador principal: MARIA PURIFICACION FORTES ALONSO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2021 GN PROYECTOS ESTRATEGICOS DE I+D 2021-2024
    Fecha de inicio: 15-04-2021
    Fecha fin: 31-12-2023
    Importe concedido: 831.819,75€
    Otros fondos: -
  • Título: Optimización de vectores de terapia génica para el tratamiento del síndrome de Dravet
    Código de expediente: 0011-1307-2020-000049
    Investigador principal: RUBEN HERNANDEZ ALCOCEBA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2020 -GN DOCTORANDOS INDUSTRIALES 2020- 2021
    Fecha de inicio: 24-09-2020
    Fecha fin: 30-09-2021
    Importe concedido: 14.000,00€
    Otros fondos: -
  • Título: INNOLFACT: Implementación de Medicina de Precisión Olfatoria y Desarrollo de terapias nasales
    Código de expediente: 0011-1411-2020-000036
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022
    Fecha de inicio: 01-07-2020
    Fecha fin: 30-11-2022
    Importe concedido: 601.228,00€
    Otros fondos: -
  • Título: Neurodegeneración en epilepsia: ¿Una nueva Taupatía no descrita? Estudio in-vivo del depósito de proteina Tau en epilepsia temporal
    Código de expediente: PI19/00610
    Investigador principal: MARIA CENTENO SOLADANA, ASIER GOMEZ IBAÑEZ, ASIER GOMEZ IBAÑEZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2019 AES Proyectos de investigación
    Fecha de inicio: 01-01-2020
    Fecha fin: 30-06-2024
    Importe concedido: 75.020,00€
    Otros fondos: Fondos FEDER
  • Título: Expresión generalizada de transgenes en interneuronas inhibitorias del cerebro mediante vectores adenovirales de alta capacidad: aplicación al Síndrome de Dravet (TweAds)
    Código de expediente: RTI2018-097730-B-I00
    Investigador principal: RUBEN HERNANDEZ ALCOCEBA, ANA LOURDES Ricobaraza Abarquero.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2018 - PROYECTOS DE I+D RETOS INVESTIGACION
    Fecha de inicio: 01-01-2019
    Fecha fin: 30-04-2022
    Importe concedido: 121.000,00€
    Otros fondos: Fondos FEDER
  • Título: Plataforma para la captación de constantes vitales en entornos no clínicos.
    Código de expediente: 0011-1383-2019-000006
    Investigador principal: MIGUEL VALENCIA USTARROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2019 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION
    Fecha de inicio: 01-12-2018
    Fecha fin: 30-11-2019
    Importe concedido: 52.862,01€
    Otros fondos: -
  • Título: Terapia génica para enfermedades metabólicas congénitas con afectación neurológica: Xantomatosis cerebrotendinosa.
    Código de expediente: 0011-1383-2019-000006
    Investigador principal: RUBEN HERNANDEZ ALCOCEBA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2019 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION
    Fecha de inicio: 01-12-2018
    Fecha fin: 30-11-2019
    Importe concedido: 116.861,88€
    Otros fondos: -
  • Título: Implantación del diagnóstico de la epilepsia y la migraña en Navarra (Geneurona)
    Código de expediente: 0011-1411-2018-000053
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2018 GN PROYECTOS ESTRATEGICOS DE I+D 2018-2020
    Fecha de inicio: 01-04-2018
    Fecha fin: 30-11-2020
    Importe concedido: 18.481,69€
    Otros fondos: -
  • Título: Terapia génica para enfermedades metabólicas congénitas con afectación neurológica: Xantomatosis cerebrotendinosa
    Código de expediente: 0011-1383-2018-000011
    Investigador principal: RUBEN HERNANDEZ ALCOCEBA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2018 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION
    Fecha de inicio: 01-02-2018
    Fecha fin: 30-11-2018
    Importe concedido: 155.406,00€
    Otros fondos: -
  • Título: Implantes Crónicos con aplicación en Neurociencias
    Código de expediente: 0011-1383-2018-000011
    Investigador principal: MIGUEL VALENCIA USTARROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2018 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION
    Fecha de inicio: 01-02-2018
    Fecha fin: 30-11-2018
    Importe concedido: 151.269,06€
    Otros fondos: -
  • Título: Combinación de terapia celular adoptiva y expresión intratumoral de genes inmunoestimuladores para el tratamiento del cáncer de páncreas
    Código de expediente: SAF2015-65157-R
    Investigador principal: RUBEN HERNANDEZ ALCOCEBA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN FUNDACIÓN INSTITUTO DE INVESTIGACIÓN SANITARIA DE NAVARRA
    Convocatoria: 2015 - PROYECTOS DE I+D RETOS
    Fecha de inicio: 01-01-2016
    Fecha fin: 31-12-2018
    Importe concedido: 128.480,00€
    Otros fondos: Fondos FEDER
  • Título: Curing Dravet Syndrome by Gene Therapy
    Código de expediente: AC17/00029
    Investigador principal: ROCIO SANCHEZ-CARPINTERO ABAD
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: E-RARE
    Fecha de inicio: 01-01-2018
    Fecha fin: 31-05-2021
    Importe concedido: 59.290,00€
    Otros fondos: Fondos FEDER
  • Título: Reduction of inflammatory responses against adenoviral vectors to improve safety and efficacy of gene therapy for Dravet syndrome (RIRADS)
    Investigador principal: RUBEN HERNANDEZ ALCOCEBA
    Financiador: Dravet Syndrome Foundation ¿ Delegación en España
    Convocatoria: 2020 FIMA AYUDAS FUNDACION DRAVET 2020
    Fecha de inicio: 01-06-2021
    Fecha fin: 31-10-2023
    Importe concedido: 58.073,00€
  • Título: Terapia Génica para el Síndrome de Dravet
    Investigador principal: MIGUEL VALENCIA USTARROZ
    Financiador: FUNDACION INOCENTE INOCENTE
    Convocatoria: FUNDACION INOCENTE INOCENTE 2017
    Fecha de inicio: 19-10-2017
    Fecha fin: 31-01-2019
    Importe concedido: 29.755,00€