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BACKGROUND: Mitochondrial diseases are difficult to diagnose and treat. Recent advances in genetic diagnostics and more effective treatment options can improve patient diagnosis and prognosis, but patients with mitochondrial disease typically experience delays in diagnosis and treatment. Here, we describe a unique collaborative practice model among physicians and scientists in Spain focused on identifying TK2 deficiency (TK2d), an ultra-rare mitochondrial DNA depletion and deletions syndrome. MAIN BODY: This collaboration spans research and clinical care, including laboratory scientists, adult and pediatric neuromuscular clinicians, geneticists, and pathologists, and has resulted in diagnosis and consolidation of care for patients with TK2d. The incidence of TK2d is not known; however, the first clinical cases of TK2d were reported in 2001, and only ~ 107 unique cases had been reported as of 2018. This unique collaboration in Spain has led to the diagnosis of more than 30 patients with genetically confirmed TK2d across different regions of the country. Research affiliate centers have led investigative treatment with nucleosides based on understanding of TK2d clinical manifestations and disease mechanisms, which resulted in successful treatment of a TK2d mouse model with nucleotide therapy in 2010. Only 1 year later, this collaboration enabled rapid adoption of treatment with pyrimidine nucleotides (and later, nucleosides) under compassionate use. Success in TK2d diagnosis and treatment in Spain is attributable to two important factors: Spain's fully public national healthcare system, and the designation in 2015 of major National Reference Centers for Neuromuscular Disorders (CSURs). CSUR networking and dissemination facilitated development of a collaborative care network for TK2d disease, wherein participants share information and protocols to request approval from the Ministry of Health to initiate nucleoside therapy. Data have recently been collected in a retrospective study conducted under a Good Clinical Practice-compliant protocol to support development of a new therapeutic approach for TK2d, a progressive disease with no approved therapies. CONCLUSIONS: The Spanish experience in diagnosis and treatment of TK2d is a model for the diagnosis and development of new treatments for very rare diseases within an existing healthcare system.
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Modelos Animales de Enfermedad , Enfermedades Raras , Timidina Quinasa/deficiencia , Animales , Humanos , Ratones , Enfermedades Raras/diagnóstico , Estudios Retrospectivos , EspañaRESUMEN
In type 1 diabetes (T1D), there is an intense inflammatory response that destroys the ß cells in the pancreatic islets of Langerhans, the site where insulin is produced and released. A therapy for T1D that targets the specific autoimmune response in this disease while leaving the remainder of the immune system intact, has long been sought. Proinsulin is a major target of the adaptive immune response in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserve ß cell function in T1D patients through reduction of insulin-specific CD8⺠T cells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within the past 5 years. Subjects were randomized 2:1 to receive intramuscular injections of BHT-3021 or BHT-placebo, weekly for 12 weeks, and then monitored for safety and immune responses in a blinded fashion. Four dose levels of BHT-3021 were evaluated: 0.3, 1.0, 3.0, and 6.0 mg. C-peptide was used both as an exploratory efficacy measure and as a safety measure. Islet-specific CD8⺠T cell frequencies were assessed with multimers of monomeric human leukocyte antigen class I molecules loaded with peptides from pancreatic and unrelated antigens. No serious adverse events related to BHT-3021 were observed. C-peptide levels improved relative to placebo at all doses, at 1 mg at the 15-week time point (+19.5% BHT-3021 versus -8.8% BHT-placebo, P < 0.026). Proinsulin-reactive CD8⺠T cells, but not T cells against unrelated islet or foreign molecules, declined in the BHT-3021 arm (P < 0.006). No significant changes were noted in interferon-γ, interleukin-4 (IL-4), or IL-10 production in CD4 T cells. Thus, we demonstrate that a plasmid encoding proinsulin reduces the frequency of CD8⺠T cells reactive to proinsulin while preserving C-peptide over the course of dosing.
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Péptido C/metabolismo , Linfocitos T CD8-positivos/microbiología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/terapia , Plásmidos/genética , Proinsulina/metabolismo , Adulto , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Proinsulina/genéticaRESUMEN
The recommendations for clinical research standards published in 2000 by a task force of the Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis Foundation of America (MGFA) were largely successful in introducing greater uniformity in the recording and reporting of MG clinical trials. Recognizing that changes in clinical trial design and implementation may increase the likelihood that new therapies are developed for MG, the MGFA MSAB Task Force here presents updated recommendations for the design and implementation of clinical trials in MG, including (a) the use of a quantitative measure, such as the MG-Composite, that is weighted for clinical significance and incorporates patient reported outcomes; (b) consideration of nontrial strategies; and (c) development of biomarkers that support mechanistic studies of pharmacotherapies. The hope is that these updated task force recommendations will expedite the development and acceptance of more effective and less noxious therapies for MG.
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Ensayos Clínicos como Asunto/normas , Miastenia Gravis/terapia , Proyectos de Investigación/normas , Comités Consultivos , Biomarcadores , Humanos , Evaluación de Resultado en la Atención de Salud , Sociedades Médicas , Estados UnidosRESUMEN
Persistent black holes (PBH) are associated with axonal loss and disability progression in multiple sclerosis (MS). The objective of this work was to determine if BHT-3009, a DNA plasmid-encoding myelin basic protein (MBP), reduces the risk of new lesions becoming PBH, compared to placebo, and to test if pre-treatment serum anti-MBP antibody levels impact on the effect of BHT-3009 treatment. In this retrospective, blinded MRI study, we reviewed MRI scans of 155 MS patients from a double-blind, randomized, phase II trial with three treatment arms (placebo, 0.5 and 1.5 mg BHT-3009). New lesions at weeks 8 and 16 were tracked at week 48 and those appearing as T1-hypointense were classified as PBH. A subset of 46 patients with available pre-treatment serum anti-MBP IgM levels were analyzed separately. Overall, there was no impact of treatment on the risk for PBH. However, there was a significant interaction between anti-MBP antibodies and treatment effect: patients receiving 0.5 mg BHT-3009 showed a reduced risk of PBH with higher antibody levels compared to placebo (p < 0.01). Although we found no overall reduction of the risk for PBH in treated patients, there may be an effect of low-dose BHT-3009, depending on the patients' pre-treatment immune responses.
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Esclerosis Múltiple/inmunología , Esclerosis Múltiple/prevención & control , Vacunas de ADN/uso terapéutico , Adolescente , Adulto , Análisis de Varianza , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina M/sangre , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/patología , Proteína Básica de Mielina/inmunología , Oportunidad Relativa , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Systemic inflammation, typically attributed to sepsis, has been repeatedly linked to adverse long-term outcomes in infants born prematurely. However, it is unclear whether other factors can contribute to potentially harmful systemic inflammatory responses. OBJECTIVE: To determine the timing and extent of systemic inflammation occurring in absence of infection in preterm infants exposed to intensive care. METHODS: First, we screened for inflammation biomarkers most strongly linked to infection in a large prospective cohort of 425 newborns (gestational age 24-42 weeks). Second, we longitudinally measured levels of infection-related inflammation biomarkers up to 42 days of post-natal life in a series of 58 infants born ≤30 weeks of gestation exposed to intensive care. Ante- or post-natal infections were excluded using stringent definitions including rigorous histological placental examination. Spearman correlations were used to identify putative clinical factors potentially linked to inflammation. RESULTS: Three biomarkers were most strongly associated with neonatal sepsis (IL-6, IL-8 and G-CSF) in the first cohort. Using these markers, we found a predominant early high intensity systemic inflammation period within the first 72 h of preterm infants' extra-uterine life. Remarkably, this systemic inflammatory response was of magnitude comparable to that observed during sepsis in absence of ante- or post-natal signs of infection, and correlated with the amount of supplemental oxygen exposure (r=0.51-0.60). CONCLUSIONS: Non-infectious sources of systemic inflammation are significant in preterm infants exposed to intensive care and may contribute to intensive care-related organ injury.
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Enfermedades Transmisibles/complicaciones , Enfermedades Transmisibles/patología , Cuidados Críticos , Recien Nacido Prematuro/inmunología , Inflamación/complicaciones , Inflamación/patología , Biomarcadores/metabolismo , Femenino , Humanos , Recién Nacido , Estudios Longitudinales , Masculino , Sepsis/complicaciones , Sepsis/patología , Factores de TiempoRESUMEN
RATIONALE: High-resolution computed tomography (HRCT) has been suggested as a potential outcome surrogate for cystic fibrosis (CF) lung disease. An important attribute of a valid outcome surrogate is that the surrogate reflects true clinical outcomes. OBJECTIVES: We performed this study to validate HRCT, a proposed surrogate outcome measure for CF lung disease, against a true clinical outcome, the number of respiratory tract exacerbations occurring in 2 yr, and to assess the correlation of CT scores and pulmonary function tests (PFTs) with this clinical outcome. METHODS: CTs and PFTs were performed on 6- to 10-yr-old children at the beginning and end of a 2-yr study during which the number of exacerbations were recorded. Spearman correlations and Poisson models were used to assess the correlation of the number of exacerbations with baseline values and changes in PFTs and CT scores. MEASUREMENTS AND MAIN RESULTS: Nine of 61 subjects had a total of 22 respiratory tract exacerbations. At baseline, PFTs and four CT scores showed significant correlation with number of exacerbations, but no variable by itself predicted exacerbations with high accuracy. For change over the 2-yr period, three CT scores showed significant correlation with exacerbations, whereas no PFTs showed significant correlation. CONCLUSION: This is the first study showing correlation between CT and a true clinical outcome. Change in CT scores correlates moderately well with the number of exacerbation. Poor correlation between change in FEV1 and exacerbations suggests that HRCT may be a more appropriate outcome surrogate for longitudinal studies of young children.
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Fibrosis Quística/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Trastornos Respiratorios/etiología , Antibacterianos/administración & dosificación , Niño , Fibrosis Quística/complicaciones , Fibrosis Quística/tratamiento farmacológico , Desoxirribonucleasa I/uso terapéutico , Femenino , Hospitalización , Humanos , Infusiones Intravenosas , Masculino , Reproducibilidad de los Resultados , Pruebas de Función Respiratoria , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
OBJECTIVE: To assess pulmonary abnormalities detected by high-resolution computed tomography (HRCT) in young children with cystic fibrosis (CF) and mild to moderate lung disease. STUDY DESIGN: High-resolution computed tomography was performed in 60 children, 6 to 10 years old, with mild to moderate lung disease (forced expiratory volume in 1 minute [FEV(1)], 52-137; mean, 102; SD, 15% predicted). HRCTs were scored by using a system that evaluates each lobe for severity and extent of CF lung disease. Findings of CF lung disease were tabulated in all subjects and in a subgroup with normal pulmonary function tests. HRCT scores were correlated with FEV(1), forced vital capacity (FVC), and forced expiratory flow between 25% and 75% of expired vital capacity (FEF(25-75)) in 57 patients. RESULTS: Bronchiectasis was present in 35% of subjects, mucous plugging in 15%, and air trapping in 63%. No abnormality was detected in 25%. In 37 subjects with FEV(1), FVC, and FEF(25-75) >85% predicted, bronchiectasis was present in 30%. In 17% of these subjects, bronchiectasis was seen in > or =4 lobes. Correlations between HRCT scores and FEV(1) were significant and showed fair to moderate correlation (r=0.36-0.46). CONCLUSIONS: High-resolution computed tomography demonstrated a broad range of pulmonary abnormalities in young patients with CF with mild to moderate lung disease. In this study, abnormalities, including bronchiectasis, were common in young children with CF and normal pulmonary function tests.
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Fibrosis Quística/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Bronquiectasia/diagnóstico por imagen , Niño , Fibrosis Quística/fisiopatología , Flujo Espiratorio Forzado/fisiología , Volumen Espiratorio Forzado/fisiología , Humanos , Volumen Residual/fisiología , Mucosa Respiratoria/patología , Espirometría , Capacidad Vital/fisiologíaRESUMEN
Inhaled recombinant human deoxyribonuclease (rhDNase) delivered by nebulizer improves pulmonary function and reduces the rate of pulmonary exacerbations in cystic fibrosis subjects. Standard jet nebulizers are relatively inefficient and require a delivery time of 10-20 min. We conducted an open-label, proof-of-concept study to evaluate whether bolus inhalation of rhDNase with a more efficient delivery system was safe and effective in cystic fibrosis subjects. The AERx system used for this study aerosolized 1.35 mg of rhDNase in three inhalations at a single sitting. The predicted AERx lung dose was approximately 0.68 mg, a dose consistent with lung doses of rhDNase given by jet nebulizer. In our 16 subjects with cystic fibrosis, a mean relative increase in FEV(1) of 7.8% (p < or = 0.001) was observed after 15 days of bolus delivery of rhDNase with the AERx system. The safety profile of rhDNase given as a bolus was similar to that observed with traditional nebulizer delivery. This study demonstrated that bolus inhalation of rhDNase was feasible, reasonably well-tolerated, and associated with improvement in pulmonary function in this small group of cystic fibrosis subjects.