Gene-targeted therapies: Overview and implications.

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.

When is the best time to screen and evaluate for treatable genetic disorders?: A lifespan perspective.

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.

Are we prepared to deliver gene-targeted therapies for rare diseases?

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.

Newborn Screening: Beyond the Spot.

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.

The Rare Diseases Clinical Research Network: a model for clinical trial readiness.

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).

Acute management of propionic acidemia.

Propionic acidemia or aciduria is an intoxication-type disorder of organic metabolism. Patients deteriorate in times of increased metabolic demand and subsequent catabolism. Metabolic decompensation can manifest with lethargy, vomiting, coma and death if not appropriately treated. On January 28-30, 2011 in Washington, D.C., Children's National Medical Center hosted a group of clinicians, scientists and parental group representatives to design recommendations for acute management of individuals with propionic acidemia. Although many of the recommendations are geared toward the previously undiagnosed neonate, the recommendations for a severely metabolically decompensated individual are applicable to any known patient as well. Initial management is critical for prevention of morbidity and mortality. The following manuscript provides recommendations for initial treatment and evaluation, a discussion of issues concerning transport to a metabolic center (if patient presents to a non-metabolic center), acceleration of management and preparation for discharge.

Natural history of propionic acidemia.

Propionic acidemia is an organic acidemia that can lead to metabolic acidosis, coma and death, if not treated appropriately in the acute setting. Recent advancements in treatment have allowed patients with propionic acidemia to live beyond the neonatal period and acute presentation. The natural history of the disease is just beginning to be elucidated as individuals reach older ages. Recent studies have identified the genomic mutations in the genes PCCA and PCCB. However, as of yet no clear genotype-phenotype correlations are known. As patients age, the natural progression of propionic acidemia illuminates intellectual difficulties, increased risk for neurological complications, including stroke-like episodes, cardiac complications, and gastrointestinal difficulties, as well as a number of other complications. This article reviews the available literature for the natural history of propionic acidemia.

Neurologic considerations in propionic acidemia.

Propionic acidemia (PA) is an organic acidemia which has a broad range of neurological complications, including developmental delay, intellectual disability, structural abnormalities, metabolic stroke-like episodes, seizures, optic neuropathy, and cranial nerve abnormalities. As the PA consensus conference hosted by Children's National Medical Center progressed from January 28 to 30, 2011, it became evident that neurological complications were common and a major component of morbidity, but the role of imaging and the basis for brain pathophysiology were unclear. This paper reviews the hypothesized pathophysiology, presentation and uses the best available evidence to suggest programs for treatment, imaging, and monitoring the neurological complications of PA.

Carrier testing for spinal muscular atrophy.

Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care. This leaves health care providers without clear guidance. In fall 2009, a meeting was held by National Institutes of Health to examine the scientific basis for spinal muscular atrophy carrier screening and to consider the issues that accompany such screening. In this article, the meeting participants summarize the discussions and conclude that pan-ethnic carrier screening for spinal muscular atrophy is technically feasible and that the specific study of implementing a spinal muscular atrophy carrier screening program raises broader issues about determining the scope and specifics of carrier screening in general.

Stanford-Binet & WAIS IQ Differences and Their Implications for Adults with Intellectual Disability (aka Mental Retardation).

Stanford-Binet and Wechsler Adult Intelligence Scale (WAIS) IQs were compared for a group of 74 adults with intellectual disability (ID). In every case, WAIS Full Scale IQ was higher than the Stanford-Binet Composite IQ, with a mean difference of 16.7 points. These differences did not appear to be due to the lower minimum possible score for the Stanford-Binet. Additional comparisons with other measures suggested that the WAIS might systematically underestimate severity of intellectual impairment. Implications of these findings are discussed regarding determination of disability status, estimating prevalence of ID, assessing dementia and aging-related cognitive declines, and diagnosis of ID in forensic cases involving a possible death penalty.

Maladaptive behaviors related to dementia status in adults with Down syndrome.

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.

Cholesterol level, statin use and Alzheimer's disease in adults with Down syndrome.

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.

Outcome Measures for Clinical Trials in Down Syndrome.

Increasingly individuals with intellectual and developmental disabilities, including Down syndrome, are being targeted for clinical trials. However, a challenge exists in effectively evaluating the outcomes of these new pharmacological interventions. Few empirically evaluated, psychometrically sound outcome measures appropriate for use in clinical trials with individuals with Down syndrome have been identified. To address this challenge, the National Institutes of Health (NIH) assembled leading clinicians and scientists to review existing measures and identify those that currently are appropriate for trials; those that may be appropriate after expansion of age range addition of easier items, and/or downward extension of psychometric norms; and areas where new measures need to be developed. This article focuses on measures in the areas of cognition and behavior.

Newborn Sequencing in Genomic Medicine and Public Health.

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

Obesity in children with developmental and/or physical disabilities.

Children with developmental or physical disabilities, many of whom face serious health-related conditions, also are affected by the current obesity crisis. Although evidence indicates that children with disabilities have a higher prevalence of obesity than do children without disabilities, little is known of the actual magnitude of the problem in this population. To address this concern, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) held a conference on obesity in children with intellectual, developmental, or physical disabilities, bringing together scientists and practitioners in the fields of obesity and disability to foster collaboration, identify barriers to healthy weight status in populations with disabilities, propose avenues to solutions through research and practice, and develop a research agenda to address the problem. This article describes current knowledge about prevalence of obesity in this population, discusses factors influencing obesity risk, and summarizes recommendations for research presented at the conference.

Maladaptive behaviors related to adaptive decline in aging adults with mental retardation.

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.

Incidence and temporal patterns of adaptive behavior change in adults with mental retardation.

The age-associated incidence of significant decline in adaptive behavior and the temporal pattern of decline in specific functional skill domains were examined in 646 adults with mental retardation through 88 years of age. Cumulative incidence of significant decline for adults with Down syndrome increased from less than.04 at age 50 to.67 by age 72, whereas cumulative incidence of significant decline for adults with mental retardation without Down syndrome increased from less than.02 at age 50 to.52 at age 88. Among adults experiencing overall decline, four clusters of behaviors were identified based upon the sequence and magnitude of changes, suggesting a pattern of loss not unlike that noted in the population without mental retardation with dementia.

Incidence and prevalence of dementia in elderly adults with mental retardation without down syndrome.

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.