Healthy aging and preclinical dementia: the United States-Israel Longitudinal Database project.

This article proposes the establishment of a United States-Israel Longitudinal Database for Healthy Aging and Preclinical Dementia as a prototype model for the eventual creation of an international database. It is envisioned that such a comprehensive international database, as a shared research resource, will provide the foundation for a systems approach to solve the dual public health problems of: (1) Early detection of individuals at an elevated risk of developing Alzheimer's disease, and (2) Developing interventions to delay onset of, or prevent, chronic brain disorders later in life.

Pipeline pharmacogenetics: a novel approach to integrating pharmaco-genetics into drug development.

There has been a decline in the number of new drugs registered over the past decade and regulatory concerns for safety as well as payer concerns for efficacy have focused attention on stratified medicine. Integration of pharmacogenetics into the drug development pipeline will contribute to the development of new stratified drugs. We describe here the concept of pipeline pharmacogenetics and its application throughout the phases of drug discovery. Pipeline pharmacogenetics enables the evaluation of the genetic contribution to safety potentially lowering barriers to registration as well as providing rationale for efficacy and enabling co-development of genetic in vitro diagnostics.

A roadmap for the prevention of dementia II: Leon Thal Symposium 2008.

This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

The medical and economic roles of pipeline pharmacogenetics: Alzheimer's disease as a model of efficacy and HLA-B(*)5701 as a model of safety.

Pharmacogenetics (PGX) is the study of drug response as a function of an individual's DNA. PGX is often viewed as an extension of disease association genetics, and although this information may be related, it is not the study of drug response. Although medicines are used to treat diseases, the value of strategies that identify and incorporate DNA biomarkers associated with clinical efficacy, or DNA biomarkers for untoward clinical responses, can be applied directly to pharmaceutical pipelines. The growth of adverse event PGX studies involving marketed medicines generally uses relatively large numbers of affected patients, but has been productive. However, the two critical strategies for pipeline genetics must make use of fewer patients: (1) the early identification of efficacy signals so that they can be applied early in development for targeted therapies and (2) identification of safety signals that can subsequently be validated prospectively during development using the least number of patients with adverse responses. Assumptions are often made that large numbers of patients are necessary to recognize PGX hypotheses and to validate DNA biomarkers. In some ways, pipeline pharmacogenetics may be viewed as the opposite of current genome-wide scanning designs. The goal is to obtain PGX signals in as few patients as possible, and then validate PGX hypotheses for specificity and sensitivity as development trials go forward--not using hundreds of thousand of markers to detect strong linkage disequilibrium signals in thousands of patients and their controls. Drug development takes 5-7 years for a drug candidate to traverse to registration--and this is similar to the timeframe for validating genetic biomarkers using sequential clinical trials. Two important examples are discussed, the association of APOE genotypes to the demonstration of actionable efficacy signals for the use of rosiglitazone for Alzheimer's disease; and the identification of HLA-B(*)5701 as a highly sensitive and specific predictive marker for abacavir treated patients who will develop hypersensitivity syndrome (HSS). The rosiglitazone study prevented pipeline attrition by changing the interpretation of a critical Phase IIB proof of concept study (2005) from a failed study, to a positive efficacy response in a genetically predictable proportion of patients. Now, three years later, a Phase III program of clinical trials using pharmacogenetic designs is months away from completion (late08). If successfully registered (early09), millions of patients could benefit, and efficacy PGX would have achieved its first prospective block-buster. The use of safety candidate gene association genetics in patients who received abacavir therapy and developed HSS starting in 1998 culminated in a double blind clinical trial that determined sensitivity > 97% and specificity >99% in 2007. Clinical consensus panels rapidly recommended abacavir as the preferred therapy along with HLA-B(*)5701 pre-testing, immediately increasing the market share of abacavir with respect to other reverse transcriptases that are associated with there own adverse events. Targeting of medicines during drug development is now possible, practical, and profitable.

The knockout mouse project.

Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.

Pharmacogenetics and pharmacogenomics: recent developments, their clinical relevance and some ethical, social, and legal implications.

In recent debates on novel procedures of molecular medicine pharmacogenomics is attracting more and more attention as a genotype-based approach for improving safety and efficacy of the use of therapeutic substances. Promoted by basic knowledge generated in the field of medical genomics, facilitated by novel technological tools for mapping genetic variation in individuals, and supported by results of initial clinical studies linking specific genotypes to metabolic characteristics of individuals important for assessing drug response, procedures of pharmacogenetics and pharmacogenomics now are starting to impact significantly on clinical research and development and medical practice. In this situation assessing the goals, risk, and benefits of pharmacogenetics and pharmacogenomics is essential for the medically successful, ethically justifiable, and socially acceptable implementation of genotype-based diagnosis and pharmacotherapy. We discuss the current state of the art in pharmacogenetics and pharmacogenomics and introduce a model for evidence based assessment of its goals, risk, and benefits. We differentiate here between pragmatic and normative issues in the development of pharmacogenomics in order to contrast prevailing, insufficiently interest-based modes of public technology assessment with the evidence-based mode that can be established as part of clinical study design. Finally, we provide a framework for the analysis of social accountability that can be used for technology development and technology assessment with regard to pharmacogenomics in particular and molecular medicine in general.

Genome-based pharmacogenetics and the pharmaceutical industry.

Pharmacogenetic capabilities have changed markedly since The SNP Consortium made a dense single-nucleotide polymorphism (SNP) map freely available in 2001. For more than 40 years, pharmacokinetics and pharmacodynamics of drug-metabolizing molecules were the focus of practical applications. Today, it is possible to use SNP-mapping technologies to create a genetic profile of each individual that can be used to identify patterns of susceptibility genes for common diseases as well as genetic risk/efficacy factors that are related to the effects of drugs.