Effective Data Sharing as a Conduit for Advancing Medical Product Development.

Introduction: Patient-level data sharing has the potential to significantly impact the lives of patients by optimizing and improving the medical product development process. In the product development setting, successful data sharing is defined as data sharing that is actionable and facilitates decision making during the development and review of medical products. This often occurs through the creation of new product development tools or methodologies, such as novel clinical trial design and enrichment strategies, predictive pre-clinical and clinical models, clinical trial simulation tools, biomarkers, and clinical outcomes assessments, and more.

Standardized Data Structures in Rare Diseases: CDISC User Guides for Duchenne Muscular Dystrophy and Huntington's Disease.

Interest in drug development for rare diseases has expanded dramatically since the Orphan Drug Act was passed in 1983, with 40% of new drug approvals in 2019 targeting orphan indications. However, limited quantitative understanding of natural history and disease progression hinders progress and increases the risks associated with rare disease drug development. Use of international data standards can assist in data harmonization and enable data exchange, integration into larger datasets, and a quantitative understanding of disease natural history.

Evaluation of multiple sclerosis disability outcome measures using pooled clinical trial data.

Objective: We report analyses of a pooled database by the Multiple Sclerosis Outcome Assessments Consortium to evaluate 4 proposed components of a multidimensional test battery.

Methods: Standardized data on 12,776 participants, comprising demographics, multiple sclerosis disease characteristics, Expanded Disability Status Scale (EDSS) score, performance measures, and Short Form-36 Physical Component Summary (SF-36 PCS), were pooled from control and treatment arms of 14 clinical trials. Analyses of Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), Low Contrast Letter Acuity (LCLA), and Symbol Digit Modalities Test (SDMT) included measurement properties; construct, convergent, and known group validity; and longitudinal performance of the measures individually and when combined into a multidimensional test battery relative to the EDSS and SF-36 to determine sensitivity and clinical meaningfulness.

Symbol Digit Modalities Test: A valid clinical trial endpoint for measuring cognition in multiple sclerosis.

Background: The need for more robust outcomes in multiple sclerosis (MS) clinical trials has been a main priority of the field for decades. Dissatisfaction with existing measures has led to several consensus meetings and initiatives over the past few decades in hopes of defining and gaining acceptance of measures that are valid, reliable, sensitive to change and progression, and most importantly, relevant to those living with MS. The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed for this purpose.

Application of a Dynamic Map for Learning, Communicating, Navigating, and Improving Therapeutic Development.

Drug discovery and development is commonly schematized as a "pipeline," and, although appreciated by drug developers to be a useful oversimplification, this cartology may perpetuate inaccurate notions of straightforwardness and is of minimal utility for process engineering to improve efficiency. To create a more granular schema, a group of drug developers, researchers, patient advocates, and regulators developed a crowdsourced atlas of the steps involved in translating basic discoveries into health interventions, annotated with the steps that are particularly prone to difficulty or failure. This Drug Discovery, Development, and Deployment Map (4DM), provides a network view of the process, which will be useful for communication and education to those new to the field, orientation and navigation of individual projects, and prioritization of technology development and re-engineering endeavors to improve efficiency and effectiveness.

The MSOAC approach to developing performance outcomes to measure and monitor multiple sclerosis disability.

Background: The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed by the National MS Society to develop improved measures of multiple sclerosis (MS)-related disability.

Objectives: (1) To assess the current literature and available data on functional performance outcome measures (PerfOs) and (2) to determine suitability of using PerfOs to quantify MS disability in MS clinical trials.

Methods: (1) Identify disability dimensions common in MS; (2) conduct a comprehensive literature review of measures for those dimensions; (3) develop an MS Clinical Data Interchange Standards Consortium (CDISC) data standard; (4) create a database of standardized, pooled clinical trial data; (5) analyze the pooled data to assess psychometric properties of candidate measures; and (6) work with regulatory agencies to use the measures as primary or secondary outcomes in MS clinical trials.

Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis.

The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with multiple sclerosis (MS). One of the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful in MS. This article addresses the history, application, and psychometric properties of one such MSOAC metric of ambulation or walking namely, the timed 25-foot walk (T25FW).

Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis.

Cognitive and motor performance measures are commonly employed in multiple sclerosis (MS) research, particularly when the purpose is to determine the efficacy of treatment. The increasing focus of new therapies on slowing progression or reversing neurological disability makes the utilization of sensitive, reproducible, and valid measures essential. Processing speed is a basic elemental cognitive function that likely influences downstream processes such as memory.

The Nine-Hole Peg Test as a manual dexterity performance measure for multiple sclerosis.

Impaired manual dexterity is a frequently reported disability in people with multiple sclerosis (MS) and is increasingly prevalent with worsening disease. While various tests and patient-reported outcome measures are available, the Nine-Hole Peg Test (NHPT) is considered as a gold standard measure of manual dexterity and most frequently used in MS research and clinical practice. The MS Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS.

Multiple Sclerosis Outcome Assessments Consortium: Genesis and initial project plan.

The need for improved clinical outcome measures in multiple sclerosis trials has been recognized for two decades, but only recently has the Food and Drug Administration (FDA) created a pathway for qualification of new clinician-reported outcome (ClinRO) assessments. Additionally, drug development in multiple sclerosis (MS) has been extraordinarily active, with numerous disease-modifying drugs now on the market. This shifting therapeutic landscape, along with the unmet need for drugs to treat the progressive forms of MS and the changing expectations of clinicians, patients, and payers, have led to the call for more sensitive and meaningful disability progression measures.

Thermodynamics of Zn2+ binding to Cys2His2 and Cys2HisCys zinc fingers and a Cys4 transcription factor site.

The thermodynamics of Zn(2+) binding to three peptides corresponding to naturally occurring Zn-binding sequences in transcription factors have been quantified with isothermal titration calorimetry (ITC). These peptides, the third zinc finger of Sp1 (Sp1-3), the second zinc finger of myelin transcription factor 1 (MyT1-2), and the second Zn-binding sequence of the DNA-binding domain of glucocorticoid receptor (GR-2), bind Zn(2+) with Cys(2)His(2), Cys(2)HisCys, and Cys(4) coordination, respectively. Circular dichroism confirms that Sp1-3 and MyT1-2 have considerable and negligible Zn-stabilized secondary structure, respectively, and indicate only a small amount for GR-2.

The genetic signature of perineuronal oligodendrocytes reveals their unique phenotype.

Oligodendrocytes--best known for assembling central nervous system myelin--can be categorized as precursors, myelin-forming cells and non-myelinating perineuronal cells. Perineuronal oligodendrocytes have been well characterized morphologically and ultrastructurally, but knowledge about their function remains scanty. It has been proposed that perineuronal oligodendrocytes support neurons and, following injury, transform into myelin-synthesizing cells.

A tool for examining the role of the zinc finger myelin transcription factor 1 (Myt1) in neural development: Myt1 knock-in mice.

The Myt1 family of transcription factors is unique among the many classes of zinc finger proteins in how the zinc-stabilized fingers contact the DNA helix. To examine the function of Myt1 in the developing nervous system, we generated mice in which Myt1 expression was replaced by an enhanced Green Fluorescent Protein fused to a Codon-improved Cre recombinase as a protein reporter. Myt1 knock-in mice die at birth, apparently due to improper innervation of their lungs.

MicroRNAs in neural cell differentiation.

The architecture and functioning of the mammalian nervous system are partly based on the complexity of combinatorial gene expression in the developing brain that results in a tremendous diversity of neural cells. MicroRNAs are small non-coding RNAs that are particularly abundant in the brain and are emerging as influential regulators of neural gene expression. This review summarizes the recently discovered role of microRNAs in the development and maintenance of the nervous system.

Integrating microRNA and mRNA expression profiles of neuronal progenitors to identify regulatory networks underlying the onset of cortical neurogenesis.

Background: Cortical development is a complex process that includes sequential generation of neuronal progenitors, which proliferate and migrate to form the stratified layers of the developing cortex. To identify the individual microRNAs (miRNAs) and mRNAs that may regulate the genetic network guiding the earliest phase of cortical development, the expression profiles of rat neuronal progenitors obtained at embryonic day 11 (E11), E12 and E13 were analyzed.

Results: Neuronal progenitors were purified from telencephalic dissociates by a positive-selection strategy featuring surface labeling with tetanus-toxin and cholera-toxin followed by fluorescence-activated cell sorting.

Tubulin polymerization-promoting protein (TPPP/p25) is critical for oligodendrocyte differentiation.

TPPP/p25, a recently identified tubulin polymerization-promoting protein (TPPP), is expressed mainly in myelinating oligodendrocytes of the CNS. Here, we show that TPPP/p25 is strongly upregulated during the differentiation of primary oligodendrocyte cells as well as the CG-4 cell line. The microRNA expression profile of CG-4 cells before and after induction of differentiation was established and revealed differential regulation of a limited subset of microRNAs.

Identification of dynamically regulated microRNA and mRNA networks in developing oligodendrocytes.

MicroRNAs (miRNAs) play important roles in modulating gene expression at the posttranscriptional level. In postnatal oligodendrocyte lineage cells, the miRNA expression profile ("microRNAome") contains 43 miRNAs whose expression dynamically changes during the transition from A2B5(+) oligodendrocyte progenitor cells to premyelinating GalC(+) cells. The combination of microRNAome profiling with analyses of the oligodendrocyte transcriptome reveals a target bias for a class of miRNAs which includes miR-9.

Identification of a novel oligodendrocyte cell adhesion protein using gene expression profiling.

Oligodendrocytes undergo extensive changes as they differentiate from progenitors into myelinating cells. To better understand the molecular mechanisms underlying this transformation, we performed a comparative analysis using gene expression profiling of A2B5+ oligodendrocyte progenitors and O4+ oligodendrocytes. Cells were sort-purified ex vivo from postnatal rat brain using flow cytometry.