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Background: The current road to developing treatments for rare diseases is often slow, expensive, and riddled with risk. Change is needed to improve the process, both in how we think about rare disease treatment development and the infrastructure we build to support ongoing science. The National Institutes of Health (NIH)-supported Rare Diseases Clinical Research Network (RDCRN) was established to advance the diagnosis, management, and treatment of rare diseases and to promote highly collaborative, multi-site, patient-centric, translational, and clinical research. The current iteration of the RDCRN intends to build upon and enhance successful approaches within the network while identifying innovative methods to fill gaps and address needs in the approach to the rare disease treatment development process through innovation, collaboration, and clinical trial readiness. Objective: The objective of this paper is to provide an overview of the productivity and influence of the RDCRN since it was first established 20 years ago. Design and methods: Using a suite of tools available to NIH staff that provides access to a comprehensive, curated, extensively linked data set of global grants, patents, publications, clinical trials, and FDA-approved drugs, a series of queries were executed that conducted bibliometric, co-author, and co-occurrence analysis. Results: The results demonstrate that the entire RDCRN consortia and network has been highly productive since its inception. They have produced 2763 high-quality publications that have been cited more than 100,000 times, expanded international networks, and contributed scientifically to eight FDA-approved treatments for rare diseases. Conclusion: The RDCRN program has successfully addressed some significant challenges while developing treatments for rare diseases. However, looking to the future and being agile in facing new challenges that arise as science progresses is important.
A National Institute of Health-funded research network working toward better treatments for people with rare diseases The Rare Diseases Clinical Research Network (RDCRN) is a Federally directed research network that targets research to help investigators move closer to treatments for rare diseases. The network supports 20 different groups that study rare diseases. Each group focuses on three or more rare diseases and the research is conducted at multiple sites. Each group works closely with both the National Institutes of Health (NIH) and patient advocacy groups. The primary focus of the network is clinical trials readiness, which simply means knowing who to treat, when to treat, and how to treat, thus taking some of the risk out of clinical trials. This knowledge is gained through natural history studies. The network, supported by grants, holds a competition every five years to select groups to participate in the network. The RDCRN is supported by ten different institutes at the NIH. To date the RDCRN has published numerous manuscripts in topics ranging from findings from natural history studies and case reports to practice guidelines and clinical trials. To date the RDCRN has been involved in work that has led to eight treatments being approved by the Food and Drug Administration (FDA).
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Gene-targeted therapies (GTTs) are therapeutic platforms that are in principle applicable to large numbers of monogenic diseases. The rapid development and implementation of GTTs have profound implications for rare monogenic disease therapy development. This article provides a brief summary of the primary types of GTTs and a brief overview of the current state of the science. It also serves as a primer for the articles in this special issue.
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Terapia Genética , HumanosRESUMEN
This paper focuses on the question of, "When is the best time to identify an individual at risk for a treatable genetic condition?" In this review, we describe a framework for considering the optimal timing for pursuing genetic and genomic screening for treatable genetic conditions incorporating a lifespan approach. Utilizing the concept of a carousel that represents the four broad time periods when critical decisions might be made around genetic diagnoses during a person's lifetime, we describe genetic testing during the prenatal period, the newborn period, childhood, and adulthood. For each of these periods, we describe the objectives of genetic testing, the current status of screening or testing, the near-term vision for the future of genomic testing, the advantages and disadvantages of each approach, and the feasibility and ethical considerations of testing and treating. The notion of a "Genomics Passbook" is one where an early genomic screening evaluation could be performed on each individual through a public health program, with that data ultimately serving as a "living document" that could be queried and/or reanalyzed at prescribed times during the lifetime of that person, or in response to concerns about symptoms of a genetic disorder in that individual.
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Pruebas Genéticas , Longevidad , Recién Nacido , Humanos , NiñoRESUMEN
The cost and time needed to conduct whole-genome sequencing (WGS) have decreased significantly in the last 20 years. At the same time, the number of conditions with a known molecular basis has steadily increased, as has the number of investigational new drug applications for novel gene-based therapeutics. The prospect of precision gene-targeted therapy for all seems in reach or is it? Here we consider practical and strategic considerations that need to be addressed to establish a foundation for the early, effective, and equitable delivery of these treatments.
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Terapia Genética , Enfermedades Raras , Humanos , Enfermedades Raras/genética , Enfermedades Raras/terapiaRESUMEN
The newborn screening paradigm of testing all newborns in the United States for treatable conditions within the first few hours of birth has proven to be a remarkable success story in the realm of public health by reducing neonatal and childhood morbidity and mortality. The Newborn Screening Saves Lives Act of 2007 and its successor, the Reauthorization Act of 2014, legislated the establishment of a Department of Health and Human Services Advisory Committee to make recommendations around newborn screening and a methodology to establish and add new conditions to a Recommended Uniform Screening Panel (RUSP) which currently includes 34 core conditions. In spite of the absence of a federal mandate that requires each of the states in the U.S. to screen for the disorders on the RUSP, most state public health laboratories have adopted the conditions on this panel. Moreover, the evolution of the evidence-based review process for adding new conditions to the RUSP has led to improvements in incorporating the public health impact and feasibility and implementation considerations. The cooperation between the federal partners who support implementation and rollout of state-based screening programs, develop technical standards and proficiency materials for laboratories, review and approve new technology platforms, and promote research to develop new assays and treatments for screenable disorders, points to the success of the newborn screening enterprise nationwide. As new technologic advances are made in the realm of genomic sequencing, the potential for incorporating these technologies holds great promise for newborn screening, but the ethical ramifications must be carefully considered to avoid harming the existing trust in the program.
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Pruebas con Sangre Seca , Tamizaje Neonatal/métodos , Enfermedades Raras/diagnóstico , Pruebas con Sangre Seca/normas , Diagnóstico Precoz , Humanos , Recién Nacido , Tamizaje Neonatal/efectos adversos , Tamizaje Neonatal/normas , Guías de Práctica Clínica como Asunto , Valor Predictivo de las Pruebas , Pronóstico , Enfermedades Raras/sangre , Enfermedades Raras/terapia , Medición de Riesgo , Factores de RiesgoRESUMEN
OBJECTIVE: Progress in basic neuroscience has led to identification of molecular targets for treatment in fragile X syndrome (FXS) and other neurodevelopmental disorders; however, there is a gap in translation to targeted therapies in humans. One major obstacle to the demonstration of efficacy in human trials has been the lack of generally accepted endpoints to assess improvement in function in individuals with FXS. To address this problem, the National Institutes of Health convened a meeting of leading scientists and clinicians with the goal of identifying and standardizing outcome measures for use as potential endpoints in clinical trials in FXS. METHODS: Participants in the meeting included FXS experts, experts in the design and implementation of clinical trials and measure development, and representatives from advocacy groups, industry, and federal agencies. RESULTS: The group generated recommendations for optimal outcome measures in cognitive, behavioral, and biomarker/medical domains, including additional testing and validation of existing measures and development of new measures in areas of need. Although no one endpoint or set of endpoints could be identified that met all criteria as an optimal measure, recommendations are presented in this report. CONCLUSION: The report is expected to guide the selection of measures in clinical trials and lead to the use of a more consistent battery of measures across trials. Furthermore, this will help to direct research toward gaps in the development of validated FXS-specific outcome measures and to assist with interpretation of clinical trial data by creating templates for measurement of treatment efficacy.
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Ensayos Clínicos como Asunto/métodos , Síndrome del Cromosoma X Frágil/terapia , Niño , Ensayos Clínicos como Asunto/normas , Cognición , Educación , Escolaridad , Función Ejecutiva , Humanos , Lenguaje , Pruebas del Lenguaje , Aprendizaje , Memoria , Pruebas Neuropsicológicas , Resultado del TratamientoRESUMEN
Changes in psychiatric symptoms related to specific stages of dementia were investigated in 224 adults 45 years of age or older with Down syndrome. Findings indicate that psychiatric symptoms are a prevalent feature of dementia in the population with Down syndrome and that clinical presentation is qualitatively similar to that seen in Alzheimer's disease within the general population. Psychiatric symptoms related to Alzheimer's disease vary by the type of behavior and stage of dementia, but do not seem to be influenced by sex or level of premorbid intellectual impairment. Some psychiatric symptoms may be early indicators of Alzheimer's disease and may appear prior to substantial changes in daily functioning. Improvements in understanding the progression of dementia in individuals with Down syndrome may lead to improved diagnosis and treatment.
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Enfermedad de Alzheimer/epidemiología , Síndrome de Down/epidemiología , Trastornos Mentales/epidemiología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Comorbilidad , Estudios Transversales , Deluciones/diagnóstico , Deluciones/epidemiología , Deluciones/psicología , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/epidemiología , Trastorno Depresivo/psicología , Progresión de la Enfermedad , Síndrome de Down/diagnóstico , Síndrome de Down/psicología , Femenino , Alucinaciones/diagnóstico , Alucinaciones/epidemiología , Alucinaciones/psicología , Humanos , Estudios Longitudinales , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/psicología , Persona de Mediana Edad , New York , Determinación de la PersonalidadRESUMEN
The authors present a case study of a 70-year-old man with Down syndrome ("Mr. C.") who they followed for 16 years and who does not exhibit declines in cognitive or functional capacities indicative of dementia, despite having well-documented, complete trisomy 21. The authors describe the age-associated changes that occurred over 16 years as well as provide detailed information regarding Mr. C.'s health and genetic status. To further emphasize Mr. C.'s successful aging, the authors compared his longitudinal performance profile with that of 2 peers of comparable level of intellectual functioning: 1 similar-aged man with clinical Alzheimer's disease and a younger man who was healthy. The authors present potential explanations for the phenotypic variability observed in individuals with Down syndrome.
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Logro , Envejecimiento , Cognición , Síndrome de Down/psicología , Anciano , Citogenética/métodos , Síndrome de Down/genética , Humanos , MasculinoRESUMEN
Changes in maladaptive behaviors related to specific stages of dementia were investigated in 251 adults 45 years of age and older with Down syndrome. Findings indicate clear differences in maladaptive behaviors at various stages of dementia. Generally, individuals with no signs or symptoms of dementia displayed fewer and less severe maladaptive behaviors than individuals in the early and mid-stages of dementia. Individuals transitioning into the early stages of dementia from no dementia displayed increased aggression, fearfulness, sadness, sleep problems, social inadequacy, stealing, and general regressive behavior. Thus, new concerns regarding these types of behaviors could be particularly useful in clarifying the dementia status of adults with Down syndrome and developing individualized plans for support.
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Enfermedad de Alzheimer/diagnóstico , Síndrome de Down/diagnóstico , Trastornos Mentales/diagnóstico , Anciano , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/psicología , Estudios Transversales , Progresión de la Enfermedad , Síndrome de Down/epidemiología , Síndrome de Down/psicología , Femenino , Estudios de Seguimiento , Humanos , Inteligencia , Masculino , Trastornos Mentales/epidemiología , Trastornos Mentales/psicología , Determinación de la Personalidad/estadística & datos numéricos , Psicometría/estadística & datos numéricos , Reproducibilidad de los ResultadosRESUMEN
Adults with Down syndrome (DS) are at significantly higher risk of Alzheimer's disease (AD) than the general population, but there is considerable variability in age at onset. This study tested the hypothesis that total cholesterol (TC) levels are related to vulnerability, and that the use of statins may decrease risk. The relation of TC level and statin use to risk of AD was investigated in 123 Caucasian adults with DS. Evaluations included serial assessments of cognitive, adaptive and maladaptive behavior, medical records, and neurological examinations. Mean length of follow-up was 5.5 years [1.2-7.1] for the entire sample, 5.1 years [1.2-7.1] for subjects who developed dementia, and 5.6 years [1.5-7.1] for those who did not develop dementia. Controlling for covariates, participants with TC>or=200mg/dL were more than two times as likely to develop AD than subjects with lower TC [hazard rate (HR)=2.59, p=.029, 95% CI: 1.1, 6.1]. In contrast, participants with higher TC levels who used statins during the study, had less than half the risk of developing AD than participants with higher TC levels who did not use statins (HR=.402, p=.095, 95% CI: .138, 1.173). If the protective effects of statins can be further validated, these findings suggest that their use may delay or prevent AD onset in vulnerable populations.
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Enfermedad de Alzheimer , Colesterol/metabolismo , Síndrome de Down , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Adulto , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/prevención & control , Síndrome de Down/complicaciones , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , RiesgoRESUMEN
Rates of dementia in adults with mental retardation without Down syndrome were equivalent to or lower than would be expected compared to general population rates, whereas prevalence rates of other chronic health concerns varied as a function of condition. Given that individual differences in vulnerability to Alzheimer's disease have been hypothesized to be due to variation in cognitive reserve, adults with mental retardation, who have long-standing intellectual and cognitive impairments, should be at increased risk. This suggests that factors determining intelligence may have little or no direct relationship to risk for dementia and that dementia risk for individuals with mental retardation will be comparable to that of adults without mental retardation unless predisposing risk factors for dementia are also present.
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Demencia/epidemiología , Síndrome de Down/epidemiología , Discapacidad Intelectual/epidemiología , Anciano , Anciano de 80 o más Años , Demencia/diagnóstico , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Estado de Salud , Humanos , Masculino , Pruebas Neuropsicológicas , Factores de Riesgo , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
Changes in patterns of maladaptive behavior related to age-associated adaptive declines were investigated in 529 adults with mental retardation. Although individuals with no significant adaptive decline displayed stable patterns of maladaptive behavior over a 3-year period, those with declines in function showed more variable patterns. Certain maladaptive behaviors were related to the onset of adaptive declines, with some becoming of increasing concern even before adaptive declines were noted (e.g., lack of boundaries). Other behaviors increased as adaptive declines developed (e.g., withdrawal). In general, findings suggest similarities in the course of age-associated dementia of adults with and without mental retardation and indicate that increases in selected areas of maladaptive behavior may be early indicators of concern for individuals at risk.