Annual Review of Medicine - Volume 59, 2008

Societal expectations about drug safety and efficacy are rising while productivity in the pharmaceutical industry is falling. In 2004, the US Food and Drug Administration introduced the Critical Path Initiative with the intent of modernizing drug development by incorporating recent scientific advances, such as genomics and advanced imaging technologies, into the process. An important part of the initiative is the use of public-private partnerships and consortia to accomplish the needed research. This article explicates the reasoning behind the Critical Path Initiative and discusses examples of successful consortia.

Heart failure is a major cardiovascular disease, characterized by considerable morbidity and mortality. Despite major advances in the pharmacotherapy of heart failure, the options for patients with severe end-stage symptoms remain limited. However, recent developments in the identification of the molecular basis for the progressive nature of heart failure have identified a number of potentially important new therapeutic targets. In particular, key components of the cardiomyocyte calcium-handling pathway show characteristic changes in heart failure. A body of research examining the effect of restoration of these defects in experimental models of heart failure, whether in genetically engineered mouse models or by myocardial gene transfer, very strongly supports the calcium-handling pathway as a target for clinical intervention.

For hemophilia patients with inhibitors against FVIII or FIX, the development of recombinant factor VIIa (rFVIIa) raises the possibility of a therapeutic alternative whose availability and convenience of treatment are comparable to those of FVIII or FIX. In support of this new concept for the treatment of bleeding episodes, pharmacological doses of FVIIa have been shown to induce hemostasis. Pharmacological doses of rFVIIa enhance thrombin generation on thrombin-activated platelets, thereby facilitating the formation of strong, well-structured fibrin plugs resistant to premature proteolysis. Modified rFVIIa molecules with a stronger hemostatic potential have been produced. Inhibition of the FVII-TF-dependent pathway (TFPI and rFVIIai) has been tried in attempts to prevent thrombosis, with promising results in animal models so far not confirmed in clinical trials.

Marfan syndrome is a common inherited disorder of connective tissue caused by deficiency of the matrix protein fibrillin-1. Effective surgical therapy for the most life-threatening manifestation, aortic root aneurysm, has led to a nearly normal lifespan for affected individuals who are appropriately recognized and treated. Traditional medical therapies, such as beta-adrenergic receptor blockade, are used to slow pathologic aortic growth and decrease the risk of aortic dissection by decreasing hemodynamic stress. New insights regarding the pathogenesis of Marfan syndrome have developed from investigation of murine models of this disorder. Fibrillin-1 deficiency is associated with excess signaling by transforming growth factor beta (TGFβ). TGFβ antagonists have shown great success in improving or preventing several manifestations of Marfan syndrome in these mice, including aortic aneurysm. These results highlight the potential for development of targeted therapies based on discovery of disease genes and interrogation of pathogenesis in murine models.

Preeclampsia is a systemic syndrome of pregnancy that originates in the placenta and is characterized by widespread maternal endothelial dysfunction. Until recently, the molecular pathogenesis of preeclampsia was largely unknown, but recent work suggests a key role for altered expression of placental antiangiogenic factors. Soluble Flt1 and soluble endoglin, secreted by the placenta, are increased in the maternal circulation weeks before the onset of preeclampsia. These antiangiogenic factors produce systemic endothelial dysfunction, resulting in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown, and the role of angiogenic proteins in early placental vascular development is just beginning to be explored. These discoveries have exciting clinical implications and are likely to transform the detection and treatment of preeclampsia in the future.

Lipid-modifying therapy has been proven to significantly reduce cardiovascular events and total mortality. Most of the data have come from statin trials. Statin therapy is generally well-tolerated and safe, and for patients who are at higher than average risk of cardiovascular disease, the benefit of lipid-modifying therapy far exceeds the risk. Careful risk assessment is a critical component of effective lipid-modifying therapy. In the foreseeable future, low-density lipoprotein cholesterol (LDL-C) will remain the primary therapeutic target, and combination therapy is likely to become the norm. The major questions are how low to treat and how to achieve increasingly aggressive targets in lipid-lowering therapy. Many patients on LDL-lowering therapy continue to have abnormalities of the triglyceride–high-density lipoprotein (TG-HDL) axis, so additional drug therapy is often considered for such patients. In this review, we briefly discuss new developments in cardiovascular risk assessment, then discuss recent developments in treatment to reduce LDL, and finally discuss current concepts regarding therapy targeting the TG-HDL axis.

Despite major advances in our knowledge of glycemic pathophysiology and the availability of multiple therapeutic options to confront type 2 diabetes, unraveling the complex link between genetic risk and environmental factors in this burgeoning epidemic has proven difficult. Linkage approaches have clarified the etiology of monogenic diabetic syndromes and congenital lipodystrophies, and candidate gene association studies have identified a number of common variants implicated in type 2 diabetes. This year we have witnessed the advent of genome-wide association scanning: As many as nine genetic loci have now been reproducibly associated with type 2 diabetes in five genome-wide scans. Of particular interest are preliminary explorations of the connections between genetic risk and pharmacologic response. An improved understanding of genetic mechanisms should allow us to test whether behavioral or pharmacologic therapies can be tailored and thus the tremendous disease burden inflicted by type 2 diabetes alleviated.

Advances in the fabrication of DNA microarrays as well as transformations in detection chemistries have vastly increased the throughput for genotyping, DNA sequencing, and array-based copy number analysis (ABCNA). Rapid changes in technology are not only affecting research but also revolutionizing DNA diagnostics. Here we focus on the application of high-throughput ABCNA and genotyping. Targeted and genome-wide ABCNA has led to the discovery of extensive DNA copy number variation in the population and the delineation of many previously unrecognized submicroscopic chromosomal aberrations (genomic disorders). High-throughput single-nucleotide polymorphism (SNP) genotyping is being widely applied in genome-wide association studies (GWASs) with recent successes in identification of common variants that confer risk for common adult diseases. Future applications of high-throughput genotyping and array-based DNA sequencing technology will undoubtedly involve research and diagnostic analyses of rare mutations and perhaps ultimately enable full individual genome sequencing.

Mitochondrial genetic diseases can result from defects in mitochondrial DNA (mtDNA) in the form of deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These mutations may be spontaneous, maternally inherited, or a result of inherited nuclear defects in genes that maintain mtDNA. This review focuses on our current understanding of nuclear gene mutations that produce mtDNA alterations and cause mitochondrial depletion syndrome (MDS), progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). To date, all of these etiologic nuclear genes fall into one of two categories: genes whose products function directly at the mtDNA replication fork, such as POLG, POLG2, and TWINKLE, or genes whose products supply the mitochondria with deoxynucleotide triphosphate pools needed for DNA replication, such as TK2, DGUOK, TP, SUCLA2, ANT1, and possibly the newly identified MPV17.

The prevalence and severity of childhood obesity have increased steadily over the past three decades. The human species evolved to rigorously defend its lower limit for weight and adiposity but is tolerant of the upper limit, which, until recent times, was rarely approached. Neuroendocrine mechanisms within the limbic core of the brain prevent starvation (ventromedial hypothalamus), heighten reward (ventral tegmental area and nucleus accumbens), and attenuate stress (amygdala), in order to promote food-seeking and ingestive behavior and to conserve energy output. In a stressful modern environment with ready access to calorie-dense, highly palatable foods and limited venues for activity, normal, reflexive responsiveness to these three drives makes weight gain all but inevitable. The obesity that ensues often engenders insulin resistance, which undermines the ability of normal hunger and satiety signals to accurately modulate energy intake versus expenditure. Obesity interventions that rely on cognitive information alone cannot free children from this “limbic triangle.” Integrated multidisciplinary family- and community-based education, effective stress reduction, and a societal commitment to alter the food and built environments are all necessary components to battle the global obesity epidemic.

Newborn screening (NBS) represents the largest volume of genetic testing. The 45-year history of NBS has demonstrated its benefits, as well as the importance of an evidence base. The recent addition of tandem mass spectrometry (MS/MS) resulted in a fivefold increase in the number of tests. Experience with MS/MS also showed that laboratory tests are just one part of the NBS system. The lessons learned from NBS will provide important insights as we move into the predictive, preventive, and personalized era of genomic medicine.

The induction of hypometabolism in cells and organs to reduce ischemia damage holds enormous clinical promise in diverse fields, including treatment of stroke and heart attack. However, the thought that humans can undergo a severe hypometabolic state analogous to hibernation borders on science fiction. Some mammals can enter a severe hypothermic state during hibernation in which metabolic activity is extremely low, and yet full viability is restored when the animal arouses from such a state. To date, the underlying mechanism for hibernation or similar behaviors remains an enigma. The beneficial effect of hypothermia, which reduces cellular metabolic demands, has many well-established clinical applications. However, severe hypothermia induced by clinical drugs is extremely difficult and is associated with dramatically increased rates of cardiac arrest for nonhibernators. The recent discovery of a biomolecule, 5′-AMP, which allows nonhibernating mammals to rapidly and safely enter severe hypothermia could remove this impediment and enable the wide adoption of hypothermia as a routine clinical tool.

Most patients want some control over their medical care, including—or even especially—when they are too sick to participate in decisions. Clinicians who have to make decisions for patients who are unable to participate often would appreciate guidance from patients’ wishes. Advance care planning responds to these needs. The process provides for discussions about goals in different scenarios and allows inclusion of the family and physician as well as the patient. It helps to have the patient and family complete validated worksheets that walk them through the various considerations and result in expressions of preference that are clinically meaningful. For the clinician, scenario-based goals for care and personal thresholds for when desired care shifts from primarily cure-oriented to primarily palliative are the most useful features to know about. The patient and family should do most of the discussing on their own time; the physician and team should coordinate to screen for problems and ensure agreement. Ideally, this should occur over the course of regular clinical encounters, with some dedicated time for the topic at suitable intervals.

The development and spread of breast and other human cancers are caused by the overexpression, mutation, and/or deletion of specific genes that drive these events. Finding genetic and molecular differences between cancerous and healthy cells can reveal the genetic determinants of cancer. This knowledge results in a better understanding of the carcinogenic process and improved predictive power, with implications for identifying new drug targets, designing novel therapies, and improving preclinical and clinical studies. We review the concepts of biomarker, genetic marker, and genetic determinant in cancer, with particular focus on the most aggressive and lethal form of breast cancer, termed inflammatory breast cancer (IBC). Using IBC as an example, we describe in detail the approaches to identify the genes that are responsible for—and not merely associated with—this disease.

Myeloproliferative disorders (MPDs) are characterized by a clonal expansion of myeloid cells. Over the past two years, the identification of the JAK2V617F mutation in most cases of polycythemia vera (PV) as well as ∼50% of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF) has greatly advanced our understanding of MPDs. The JAK2V617F mutation alters the JAK2 tyrosine kinase to confer constitutive activation and affect downstream signaling pathways. Data from mouse models demonstrate that the mutation is sufficient for development of PV, but additional work is needed to better understand how this allele functions in ET and IMF. Regardless of the various pathologies, the JAK2V617F discovery highlights the importance of JAK-STAT signaling in myeloid differentiation and focuses effort on developing a clinically relevant JAK2 inhibitor.

Human papillomavirus (HPV) is a necessary, though not sufficient, cause of cervical cancer. Two vaccines have been developed that prevent two HPV types associated with 70% of cervical cancers. One of the vaccines (a quadrivalent vaccine) also prevents two HPV types associated with 90% of genital warts. Both HPV vaccines have shown very good efficacy and safety. This review summarizes the guidelines for use of the quadrivalent vaccine published by the Advisory Committee on Immunization Practices, presents data on vaccine efficacy and safety, and gives an overview of the findings of cost-effectiveness studies. In addition, we summarize the research on the attitudes of parents and health care providers toward HPV vaccine and critically evaluate controversial and challenging issues surrounding HPV vaccination, including concerns about sexual disinhibition and potential obstacles to vaccine distribution and uptake.

The anti-CD20 monoclonal antibody rituximab, first approved for clinical use in 1997, has changed the standard of care for many patients with non-Hodgkin's lymphoma (NHL). Recent data from large randomized clinical trials confirm that the addition of rituximab to standard chemotherapy regimens (chemoimmunotherapy) improves both response rates and survival outcomes in patients with follicular NHL and diffuse large B cell lymphoma (DLBCL), the two most common subtypes of NHL. Population-based analyses have found substantial improvements in NHL survival over the past decade; studies indicate that rituximab has favorably altered the long-term prognosis of follicular NHL and DLBCL patients. This review discusses the clinical development of rituximab-based therapies for patients with low-grade or follicular NHL and newly diagnosed DLBCL, highlighting recent key randomized trials with a focus on survival outcomes.

The biological picture of cancer is rapidly advancing from models built from phenomenological descriptions to network models derived from systems biology, which can capture the evolving pathophysiology of the disease at the molecular level. The translation of this (still academic) picture into a clinically relevant framework can be enabling for the war on cancer, but it is a scientific and technological challenge. In this review, we discuss emerging in vitro diagnostic technologies and therapeutic approaches that are being developed to handle this challenge. Our discussion of in vitro diagnostics is guided by the theme of making large numbers of measurements accurately, sensitively, and at very low cost. We discuss diagnostic approaches based on microfluidics and nanotechnology. We then review the current state of the art of nanoparticle-based therapeutics that have reached the clinic. The goal of the presentation is to identify nanotherapeutic strategies that are designed to increase efficacy while simultaneously minimizing the toxic side effects commonly associated with cancer chemotherapies.

Deregulation of gene expression is a hallmark of cancer. Although genetic lesions have been the focus of cancer research for many years, it has become increasingly recognized that aberrant epigenetic modifications also play major roles in the tumorigenic process. These modifications are imposed on chromatin, do not change the nucleotide sequence of DNA, and are manifested by specific patterns of gene expression that are heritable through many cell divisions. We review these modifications in normal and cancer cells and the evolving approaches used to study them. Additionally, we outline advances in their potential use for cancer diagnostics and targeted epigenetic therapy.

Asthma is an immunological disease with multiple inflammatory and clinical phenotypes, characterized by symptoms of wheezing, shortness of breath, and coughing due to airway hyperreactivity (AHR) and reversible airway obstruction. In allergic asthma, the most common form of asthma, airway inflammation is mediated by adaptive immune recognition of protein allergens by Th2 cells, resulting in airway eosinophilia. However, in other forms of asthma, inflammation is associated with immune responses to respiratory infections and airway neutrophilia. A central feature common to all forms of asthma is AHR, the heightened responsiveness of the airways to nonspecific stimuli. AHR has been shown recently in animal models of asthma to require the presence of CD1d-restricted, invariant T cell receptor-positive, natural killer T (iNKT) cells. Although allergen-specific Th2 cells and iNKT cells have many phenotypic similarities (e.g., expression of CD4 and production of Th2 cytokines), they have complementary activities, such as production of Th2 cytokines under different conditions, differential sensitivity to corticosteroids, and responsiveness to different classes of antigen (proteins versus glycolipids). We hypothesize that Th2 cells and iNKT cells interact synergistically to induce asthma but that different forms of asthma result from distinct roles of CD4⁺iNKT cells versus Th2 cells.