Attacking Illness at its Roots
Biotherapeutic Strategies in Precision Medicine
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Current strategies for prevention and management of serious illnesses, are primarily reliant on small molecule drugs which interfere in pathological pro-inflammatory signaling cascades and may very effectively abate pain, allowing some restoration of function, but fail to halt progressive tissue destruction occurring as a core element of the disease. This is particularly true for cancer, autoimmunity, and some infectious diseases which feature severe dysregulation of normal physiologic over inflammation. Another significant problem with pharmacotherapy as it is currently practiced, is that long-term use of many drugs is undesirable due to expense and often debilitating toxic effects. A treatment strategy that departs from simple analgesia and inhibits disease-associated tissue degradation, uses agents called "biologics" or "biotherapeutics," which are superior to currently available treatments, since many act by augmenting natural adaptive mechanisms such as increased expression of immunoregulatory molecules rather than interference with inflammation-associated homeostasis or traumatic interventions such as surgery and radiation. Collateral interference with pro-inflammatory signaling processes is a major source of drug toxicity. The proposed book will explore how interventions that selectively strengthen the biological effects of critical cytoprotective enzymes such as heme oxygenase-1 (HO-1) and superoxide dismutase; along with stress response products such as heat shock proteins contribute to stabilization of healthy tissue and organ function to prevent or mitigate illness. This book will also compare strategies for neutralizing the potentially pathological effects of reactive oxygen and inflammatory cytokines by reducing their expression, quenching them with antioxidants, or blocking interaction with their cognate receptors. Finally, this book will analyze the current socioeconomic impact of adverse effects resulting from current approaches to healthcare in the context of improvements anticipated by use of biotherapeutic strategies.
Table of Contents
FORWARD This section will be a description for scientifically literate general audiences, of how rapid advances in drug discovery are enabling increasingly more effective strategies for prevention and treatment of previously incurable illnesses with economically sustainable approaches that avoid major adverse side effects. Emphasis will be placed on the transformative effect on healthcare and society that this trend has the potential to engender. CHAPTER 1 PALLIATIVE THERAPY: THE GOOD, THE BAD AND THE COSTLY 1.1 Evolution of mainstream medical strategies. An overview will be provided here of current strategies for management of serious chronic illness, with emphasis on how mechanisms of each intervention utilized may abate disease symptoms, but create collateral damage that degrades quality-of-life; and becomes lifetime financial and physical burdens on those afflicted. 1.2 Medical dogma versus innovation: Paradigm shifts in healthcare. The section will outline general strategies by which endogenous processes which have evolved to maintain healthy homeostasis may be amplified by means that avoid adverse side effects. The major theme will be on current efforts to transition healthcare practice into use of Precision Medicine . This is an emerging field, based on means of inhibiting fundamental processes resulting in major symptoms of disease, such as overexpression of particular inflammatory mediators; critical survival cues for cancer cells and persistence of certain microbial flora. 1.3 Optimizing clinical use of emerging trends in biomedical science. This section will compare precision/biotherapeutic techniques with currently available interventions which treat symptoms without affecting underlying disease processes; and explore how these transitions in medical practice may impact healthcare choices. CHAPTER 2 VACCINES: THE EARLIEST BIOTHERAPEUTIC AGENTS 2.1 Mastering immunoregulation: an ongoing success story This section in particular will be written for a broad readership of both scientific professionals and literate non-scientists. Ideally the message of this portion of the book will provide the general public with a clear vision of how vaccine technology evolved to provide enormous benefit to public health and should not be the subject of irrational fear. The narrative will briefly review the origins of vaccine technology at the time of Ibn Sina (Avicenna), Jenner and Pasteur. Current understanding of mechanisms of vaccine-mediated immunoregulation will be explained in concise, but simple detail. 2.2 Vaccine-related hazards and countermeasures Here, the enormous benefit of vaccine technology will be examined in the context of hazards associated with use of these agents. A description of adverse effects known to result from use of vaccines will be provided, along with descriptions of the underlying molecular biological pathomechanisms of such problems where such information is available. Current controversy regarding linkage of vaccinations to occurrence of autism and other disorders will be examined by industry experts. CHAPTER 3 CANCER: WARS OF ATTRITION, VERSUS SMART WEAPONS 3.1 Current cancer treatment: successes and failures 3.1a Chemotherapy 3.1b Surgery 3.1c Radiotherapy 3.1d Immunotherapy This chapter will describe contemporary orthodoxy in cancer treatment, with emphasis on cellular-molecular mechanisms of the major triad of treatments cancer patients typically undergo: specifically, chemotherapy, radiation treatment and surgery. State-of-the-art applications of each of these approaches will be discussed in the context of ongoing efforts to improve their effectiveness and minimize adverse side effects. A major quandary faced by oncologists in treatment of their patients will be discussed. This is the problem of which arises as a result of targeting cancer cells for deletion based on features such as rapid division, specialized microtubule organization and high expression levels of certain kinds of molecules such as PSA (in prostate tumors). The extent to which such features are shared with normal cells typically determines the extent of collateral damage to the individual undergoing treatment regimens that target these tumor cell characteristics. 3.2 Alternative cancer treatments: Magic bullets, miracles and disappointments. 3.2a Dietary strategies for cancer prevention and treatment 3.2b Supplements and related natural products 3.2c Cancer vaccines and novel immunotherapeutic strategies. Biotherapeutic/precision approaches will be considered, that avoid massive attrition of cancer cells based on attributed that are often common to healthy tissue. These include consideration of how various materials in the diet and supplements are being developed as prevention and adjuvant therapy for cancers. Three major precision approaches to fighting cancer will be explored in detail: The first, are regimens that kill tumor cells using antibodies to tumor-specific antigens, which upon binding to a tumor cell, destroy via a linked toxin; or paint the cell for destruction by the immune system. A second approach that will be discussed in this chapter are cancer-specific vaccines that may sometimes be tailored to a specific individual and specific tumor clone. A third strategy that has shown enormous promise in late-stage metastatic cancer treatment that will be covered in this chapter, is restoration and/or enhancement of tumor suppressive mechanisms by blockade of their physiologic inhibitors. An example that will be considered in detail, is the PNC-27 is a peptide identified by Matt Pincus and their collegues (who are invited authors for this chapter). This peptide binds to the HDM2 oncogene protein, which is prevalently over-expressed in the cell membranes of many, if not all cancers, especially in those which are aggressive or advanced and reducing the activity of this protein has been shown to result in tumor suppression. This protein is largely localized in the plasma cell membranes of cancer cells, whereas only minimal amounts of HDM2 are found in the cell membranes of normal cells. Blockade of HDM2 with PNC-27 allows the p53 protein to function with greater effectiveness in driving a nascent tumor cell into apoptosis and treatment of patients with this peptide has produced some very encouraging preliminary results. This, and related strategies which enhance naturally occurring anti-tumor processes will be covered in this chapter. CHAPTER 4 HEAT SHOCK PROTEINS: BIOTHERAPEUTIC BLOCKBUSTERS 4.1 Physiological responses to stress: Mechanisms and molecules This chapter will focus on therapeutic application of stress response gene products including, but not limited to heat shock proteins (HSP). The narrative will describe the conditions under which HSP expression is upregulated by cells and their function as chaperones, ensuring proper configuration of cellular proteins. 4.2 Pharmacological enhancement of stress responses: dietary inducers of heat shock proteins The cytoprotective role of HSP will be discussed in this section, with special emphasis on HSP-32, also known as heme oxygenase-1 (HO-1), inducers of which, such as sour cherry seed flavonoids, are increasingly finding therapeutic use in a wide range of clinical venues. 4.3 Tolerogenic heat shock protein vaccines: Induced immunoregulation for autoimmunity A significant portion of this chapter will examine the ability of the component peptides of HSP to interact with immune system in ways that have engendered powerful countermeasures to a wide range of inflammatory pathologies, in particular , autoimmune diseases A therapy based on this phenomenon called MAM-14 Immunotherapy (USPTO # 20090232834) vaccinates a patient with HSP harvested from peripheral blood leukocytes. The injected HSP are degraded into component peptides, that then interact with some fraction of the patient s pathogenic T cell subpopulation, converting many into regulatory forms. These cells migrate to the same tissue that activated, pathogenic T cells are attacking and downregulate activity of the remaining autoreactive T cells within a tissue under attack, via bystander effect . A related strategy for therapeutic use of stress response gene products, called TOLDC/B29, uses autologous dendritic cells in vitro loaded with antigens and made tolerogenic (tolDC) prior to re-administering into the patient. This therapy is aimed to abate autoimmune tissue destruction long-term with a brief intervention. The mechanisms contributing to these processes will be discussed in this chapter. CHAPTER 5 CARDIOVASCULAR DISEASE: HEARTBREAK AND HOPE 5.1 Current strategies in cardiovascular medicine: successes and failures 5.1a Prevention and health maintenance 5.1b Pharmacotherapy 5.1c Surgery Current approaches to prevention of and treatment for cardiovascular disease will be discussed in this chapter, with emphasis on mechanisms by which drugs and surgery may improve heart function. As in other chapters, therapeutic mechanisms of each intervention currently approved for mainstream medical use will be analyzed in the context of adverse side effects that occur as expected consequences of the interventions applied. Descriptions of orthodox therapies will include analyses of how they might be refined so as to reduce corollary tissue damage. 5.2 Phytotherapy, specialized exercise and hyperbaric oxygen. A very exciting biotherapeutic/precision approach in this subject venue, is the use of terpene lactones to inhibit calcium influx to stretch/pressure receptor stimulation of cardiomyocytes, allowing much lower dosages of antiarrhythmic drugs to achieve desired clinical effects. This effect was demonstrated by a team led by the primary author of this book (Haines, et al., J. Cardiovasc. Pharmacol. (2000), 35: 37-44.) and follow-on drug discovery based on these findings continues. These methods may be combined with specialized types of exercise and exposure to elevated oxygen levels (including, but not limited to hyperbaric therapy). The anticipated clinical outcomes include restoration and long-term maintenance of healthy cardiac function. Particular focus in this section will be given to prevention of and treatment for ischemia- reperfusion injury and resulting ventricular arrhythmias. 5.3 Stem cell therapy for heart disease: role of telocyte networks. This section will cover possible clinical uses of telocytes, discovered recently by Prof. Lauren iu M. Popescu, at Victor Babes National Institute of Pathology in Bucharest. These filamentatious cells, which are at the limit of resolution for light microscopy, form networks within a tissue that coordinate activity of component cells and stabilize the stem cell niche. This last function is of particular importance since stem cell therapies for cardiovascular conditions are recognized as having potential to catalyze revolutionary advances in cardiovascular medicine. The fundamental challenge remaining to clinical application of these technologies is stable engraftment of stem cells administered to a patient. Currently,engraftment success is very poor, but with better understanding of how telocyte function within a tissue may be manipulated to favor engraftment, the efficacy of stem cell-based cardiovascular therapies will greatly improve. The final portion of the chapter will deal with how telocyte networks and autophagy levels in myocardial cells interact to affect stem cell engraftment. ARTHRITIS AND TYPE 2 DIABETES: DEFUSING INFLAMMATORY TIME BOMBS 6.1 Etiology and pathogenesis of metabolic syndrome and rheumatoid arthritis: current prevention and treatment strategies Rheumatoid arthritis, along with certain variants of type 2 diabetes, both occur as co- morbidities of cardiovascular disease. Accordingly approaches to prevention and treatment of arthritic syndromes as well as diabetes, may be described as an extension of dysregulated cellular signaling underlying heart disease and related disorders. 6.2 Biotherapeutic approaches to treatment of rheumatoid and osteoarthritis. Successes and failures This section will examine evolving attempts to apply biotherapeutic approaches to osteoarthritis, that have worked very well in treatment of rheumatoid arthritis and discuss the possible reasons that these attempts have mostly failed. A model for biotherapeutic strategies designed to inhibit activity of inflammatory cytokines is Amgen s highly successful product, Enbrel, the trade name for Etanercept, which is an expression product of a synthetic genetic element, constructed of DNA containing a portion of the gene for TNF, spliced to the Fc (constant) portion of the Immunoglobin G1 (IgG1) antibody. The resulting fusion protein binds strongly to TNF-a under physiologic conditions, preventing interaction with its cognate receptor and reducing physiologically available free TNF, thus blocking pro-inflammatory effects of this cytokine. The product very effectively remediates symptoms of rheumatoid arthritis, along with a diverse range of other chronic inflammatory syndromes. Unexpectedly, this approach failed to remediate osteoarthritis, despite the critical role of TNF-a in OA pathogenesis. Nevertheless, biotherapeutic amelioration of OA was achieved by Mahmoud at al (CSAC, Nov. 2014 http://link.springer.com/article/10.1007/s12192-014-0553-0/fulltext.html ), who blocked expression of TNF-a by activated T cells in human patients, rather than attempting to neutralize the molecule after production. 6.3 Biotherapeutic management of type 2 diabetes: reversing the damage The discussion of biotherapeutric approaches to prevetion and treatment of type 2 diabetes will draw on recent animal studies atUC Davis and the University of Barcelona which demonstrate that modulation of soluble epoxide hydrolase (sEH) activity may prevent and reverse the effects of diabetes in obese mice along with renal failure, hypertension, diabetic pain, hardening of the arteries and heart failure. Related findings show this approach to stabilize metabolites of DHA, an omega-3 fatty acid. Approaches to clinical utilization of these observations will be discussed in this chapter. HEMP: RECREATIONAL AND BIOTHERAPEUTIC USES 7.1 Medical marijuana: hazards and advantages The first portion of this chapter examines the hazards of marijuana use at the level of adverse consequences of sustained exposure to hemp cannabinoids on metabolic functions affecting major organ systems. In particular, neuroendocrine and immune effects will be examined at the level of signaling pathways and cell and organ function. These adverse effects will be discussed in the context of an acknowledgement that recreational marijuana use occurs on a large scale and is unlikely to decrease in coming years, particularly as use of the plant is legalized in the USA. 7.2 Non-psychoactive canabinoids: advantages and drawbacks in healthcare A significant portion of the chapter will be devoted to consideration of how adverse effects of hemp use may be mitigated by configuring recreational hemp usage as biotherapeutic approaches to disease prevention and in some limited venues, as augmentation for existent therapeutic regimens. It will be mentioned in the chapter that dual use of a recreational biochemical as a health aid is not without precedent red wine being a prime example. CHAPTER 8 PERIODONTITIS, A PARADIGM OF CHRONIC BACTERIAL INFLAMMATION: BIOTHERAPEUTIC COUNTERMEASURES 8.1 Periodontal disease: an incurable chronic inflammatory syndrome This chapter describes a biotherapeutic approach for treatment of a bacterial infection and thus departs somewhat from other descriptions of biotherapeutic strategies in this book, which describe targeting of some fairly specific cellular process, to result in a cascade of downstream effects that result in prevention or abatement of disease symptoms. 8.2 A biotherapeutic approach to curing periodontitis: nanoparticle-mediated delivery of microbicidal agents This section describes a countermeasure to periodontal disease that involves precision-guided delivery of nanoparticle-encapsulated antibacterial drugs to specified anatomical locations. The methodology may be considered biotherapeutic based on the high specificity of physical delivery of a therapeutic agent, rather than specificity of action on a particular cellular process. The chapter will describe a preparation containing biodegradable NPs loaded with agent known to inhibit growth, viability and tooth adherence of periopathic bacteria. 8.3 General use of nanoparticle-delivered antimicrobial agents This section will consider other microbial syndromes in which biotherapeutic treatment approaches would be advantageous. Of particular concern in both veterinary and human medicine are MERSA and other superbugs, which often penetrate into anatomical spaces that do not build up or sustain sufficient levels or oral or injected antimicrobials. Nanoparticle-based drug delivery systems such as those described in this chapter offer the potential for definitive treatment of highly virulent bacterial strains that are not currently available. CHAPTER 9 CHEMICAL SENSITIVITY: IDENTIFYING AND REMOVING THREATS 9.1 Living in a toxic soup: global toxicant exposure levels and related disease A chapter that focuses on the consequences of and countermeasures for chemical sensitivity (CS) is appropriate for a book on biotherapeutic/precision healthcare strategies, because clinical application of CS principles may be conceptually viewed as a kind of inverse biotherapeutic strategy. Specifically, rather than intervening in physiological processes by altering a particular critical activity, precision-medical approaches undertaken based on CS-related analyses, benefit a patient by simply avoiding consumption or contact with a particular substance. For example, many cosmetics contain formaldehyde precursors which cause joint pain in people who use them. 9.2 Acquired toxicant sensitivities and countermeasures This section explores strategies for selective elimination of exposures to specific environmental toxicants in the context of lifestyle changes that may be required and desired health-related outcome. For example, a very effective countermeasure against disease of unknown etiology, for which toxicant exposure is suspected, is to evaluate a patient for sensitivity to a panel of potentially immunogenic substances and if one or more are identified, then take steps to remove it as a hazard. This may be often be simply accomplished by discontinuing use of products that contain it. This chapter will discuss examples of this kind of preventive medicine and provide strategies for making this a general preventive measure that all people might use routinely. CHAPTER 10 SUPERFOODS AND BIOTHERAPEUTIC DIETARY STRATEGIES 10.1 Modern dietary habits and their consequences This chapter will describe lifestyle choices, including diet, that are acknowledged to trigger or exacerbate disease. Particular focus will be given to cellular and molecular mechanisms whereby certain dietary components such as pro-inflammatory lipids (and others), initiate cascades of cell signaling that disrupt healthy tissue homeostasis and lead to dysregulated inflammatory processes and disease. 10.2 Functional foods This section will provide an overview on the general topic of functional foods , which are defined as foodstuffs that affect physiologic functions in ways that significantly mitigate a particular disease. The chapter will first provide a summary of dietary substances that have been shown through nutritional studies to achieve statistically valid amelioration of symptoms of various diseases. In each case, whatever information is provided on specific cellular mechanisms responsible for the outcomes reported, wilconsidered. Also within the chapter, foods capable of mediating biotherapeutic effects will be considered. An example of a particular food component that fits this description is curcumin. This component of the commonly-used spice, turmeric, has many health-enhancing properties, including induction of heme oxygenase-1 (HO-1). As described previously in this outline, Mahmoud et al demonstrated that HO-1 induction by sour cherry seed flavonoids preferentially blocked activation of CD3+T cells to express TNF-a. an inflammatory cytokine necessary for progression of osteoarthritis (CSAC, Nov. 2014 http://link.springer.com/article/10.1007/s12192- 014-0553-0/fulltext.html ). Given these results, it is likely that consumption of foods containing curcumin may also provide health benefits related to HO-1 induction although likely not as intense as reported by Mahmoud et al., due to the high level of HO-1 expression achieved using the flavonoid topical preparation. CHAPTER 11 SENESCENT CELLS, AGING AND LIFE EXTENSION STRATEGIES The main focus of this chapter is an examination of how senescent cellular phenotypyes contribute to physical aging: Progressively sophisticated understanding of cellular and molecular processes that contribute to age-related physical deterioration is being gained from ongoing research into cancer, chronic inflammatory syndromes and other serious disorders that increase with age. Particularly valuable insight has resulted from characterization of how senescent cells affect the tissues in which they form in ways that decrease an organism s overall viability. Increasingly, the underlying pathophysiology of aging is recognized as a consequence of oxidative damage. This leads to hyperactivity of cell growth pathways, prominently including mTOR (mammalian target of rapamycin), that contribute to a build-up in cells of toxic aggregates such as progerin (a mutant nuclear cytoskeletal protein), lipofuscin and other cellular debris, triggering formation of senescent cellular phenotypes, which interact destructively with surrounding tissue by high expression of inflammatory cytokines. Indeed, senescent cell ablation dramatically inhibits physical deterioration in progeroid (age-accelerated) mice (Haines et al., 2013). Here, strategies for reducing the adverse impact of senescent cells within a tissue will be examind, including , prominently, methods of promoting their apoptotic deletion, along with approaches to replacement with mesenchymal stem cells. CHAPTER 12 ENDGAME: BIOTHERAPEUTICS AND QUALITY-OF LIFE The final chapter in this book will be fairly short, but is potentially the most important portion of the book s main message. This chapter will be configured as a commentary on the highly positive shift in the moral and ethical climate under which healthcare is administered. Currently, extremely costly processes for development of novel therapies, combined with simple avarice on the part of some of its practitioners have resulted in healthcare policy and practice becoming an enormous burden on the infrastructures of most of the World s nations. Precision Medicine offers a countermeasure to this trend. Increasing efficiency of prevention and treatment for serious illnesses meet three fundamental sustainability goals in public health: First, these methods embody the concept of affordable healthcare , by streamlining of expense for medical treatment paid by individuals and insurance providers; Secondly, such streamlining promotes social equity. Adoption of Precision medical techniques will allow a broader scope of the population to meet the financial obligations of medical treatment, thus reducing perceived and actual inequities in access to effective healthcare by all strata of society. Finally, widespread use of this technology will reduce the level of stress and anxiety almost everyone is subjected to in an environment of uncertainty regarding personal health status. Here the term environment is particularly important. The concept to be emphasized in the chapter is the socioeconomic milieu of a nation as it is influenced by standard of healthcare available to most of the population. For this reason, the impact that the message of this final chapter may have on fundamental attitudes toward the way healthcare is practiced is highly positive. Indeed, it is to be hoped that this narrative may influence public health policy in ways that promote adoption of Precision Medicine as core operating principle of good governance and global prosperity. In order to optimize this impact, it would be ideally articulated by clerics with scientific backgrounds. By inviting representatives of the 3 major Abrahamic faiths to make this commentary, the chapter will contain a moral and ethical dimension that, all other issues aside, promote tolerance and cooperation, running counter to cynical attempts to fracture societies along lines of religion, ethnicity and economic status. Indeed, a major outcome of this book will be to encourage development of healthcare and biomedical science as a venue for harmonized diversity rather than discord.
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