Showing papers in "Expert Opinion on Therapeutic Targets in 2007"

Targeting selectins and selectin ligands in inflammation and cancer

Abstract: Inflammation and cancer metastasis are associated with extravasation of leukocytes or tumor cells from blood into tissue. Such movement is believed to follow a coordinated and sequential molecular cascade initiated, in part, by the three members of the selectin family of carbohydrate-binding proteins: E-selectin (CD62E), L-selectin (CD62L) and P-selectin (CD62P). E-selectin is particularly noteworthy in disease by virtue of its expression on activated endothelium and on bone-skin microvascular linings and for its role in cell rolling, cell signaling and chemotaxis. E-selectin, along with L- or P-selectin, mediates cell tethering and rolling interactions through the recognition of sialo-fucosylated Lewis carbohydrates expressed on structurally diverse protein-lipid ligands on circulating leukocytes or tumor cells. Major advances in understanding the role of E-selectin in inflammation and cancer have been advanced by experiments assaying E-selectin-mediated rolling of leukocytes and tumor cells under hydrodynamic shear flow, by clinical models of E-selectin-dependent inflammation, by mice deficient in E-selectin and by mice deficient in glycosyltransferases that regulate the binding activity of E-selectin ligands. Here, the authors elaborate on how E-selectin and its ligands may facilitate leukocyte or tumor cell recruitment in inflammatory and metastatic settings. Antagonists that target cellular interactions with E-selectin and other members of the selectin family, including neutralizing monoclonal antibodies, competitive ligand inhibitors or metabolic carbohydrate mimetics, exemplify a growing arsenal of potentially effective therapeutics in controlling inflammation and the metastatic behavior of cancer.

The IL-6/sIL-6R complex as a novel target for therapeutic approaches.

Abstract: IL-6 plays a pivotal role in immune responses and certain oncologic conditions. The intense investigation of its biological activity and function led to the discovery of two different IL-6-driven signalling pathways. Binding to the membrane-bound IL-6 receptor (mIL-6R, CD126) causes the recruitment of two gp130 co-receptor molecules (CD130) and the activation of intracellular signalling cascades via gp130. Although this classical pathway is mainly limited to hepatocytes, neutrophils, monocytes/macrophages and certain other leukocyte populations, which express IL-6R on their surface, an alternative mechanism has also been described. Proteolytic cleavage of the mIL-6R protein or translation from alternatively spliced mRNA leads to the generation of a soluble form of the IL-6R (sIL-6R), which is likewise able to bind to IL-6. The resulting IL-6/sIL-6R complex is also capable of binding to gp130 and inducing intracellular signalling. Through this so-called 'trans-signalling' mechanism, IL-6 is able to stimulate cells that lack an endogenous mIL-6R. High levels of IL-6 and sIL-6R have been reported in several chronic inflammatory and autoimmune diseases as well as in cancer. Preclinical animal disease models have provided strong evidence that specific blockade of IL-6-regulated signalling pathways represents a promising approach for the therapy of these diseases. An optimised variant of the recently described fusion protein sgp30Fc is now heading towards its clinical evaluation.

The 5-HT3 receptor as a therapeutic target

Abstract: The 5-HT3 receptor is a neurotransmitter-gated ion channel. It is a member of the Cys-loop family of receptors, which also includes nicotinic acetylcholine, glycine and GABAA receptors. Each member of the family consists of an arrangement of five subunits surrounding a central ion-conducting pore. The 5-HT3 receptor binding site is composed of six loops from two adjacent subunits, and the critical ligand binding residues within these loops are well documented. There are a range of 5-HT3 receptor agonists and competitive antagonists, but it is the antagonists that dominate their clinical use. Studies have proposed a range of disease symptoms that might be amenable to 5-HT3 receptor selective compounds; however, so far only the treatment of emesis and irritable bowel syndrome have been fully realised. In this review, the authors look at the structure, function and distribution of 5-HT3 receptors and how this may influence their role in disease. The authors also describe the existing clinical applications of 5-HT3 antagonists and the future potential of these drugs.

Targeting acetylcholinesterase to treat neurodegeneration.

Abstract: Neurodegenerative disorders, such as Alzheimer's disease, are often characterised by the degeneration of the cholinergic system. Thus, the aim of many treatment regimens is to support this system either by means of muscarinic agonists or by inhibitors of acetylcholinesterase (AChE), the latter being able to increase the concentration of acetylcholine. However, both pharmacological groups of drugs can only help in the beginning of the progressive disease. The finding that the occupation of the peripheral anionic site of AChE is able to stop the formation of the amyloid plaque led to the development of bivalent ligands that occupy both the active and the peripheral site. This dual action might be more beneficial for treatment of Alzheimer s disease than simple inhibition of the acetylcholine hydrolysis. Thus, the new bivalent ligands are the focus of this review.

Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery

Abstract: Nicotinamide adenine dinucleotide (NAD+) has crucial roles in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Enzymes involved in NAD+...

TRAIL in cancer therapy: present and future challenges

Abstract: Since its identification in 1995, TNF-related apoptosis-inducing ligand (TRAIL) has sparked growing interest in oncology due to its reported ability to selectively trigger cancer cell death. In contrast to other members of the TNF superfamily, TRAIL administration in vivo is safe. The relative absence of toxic side effects of this naturally occurring cytokine, in addition to its antitumoural properties, has led to its preclinical evaluation. However, despite intensive investigations, little is known in regards to the mechanisms underlying TRAIL selectivity or efficiency. An appropriate understanding of its physiological relevance, and of the mechanisms controlling cancer cells escape from TRAIL-induced cell death, will be required to optimally use the cytokine in clinics. The present review focuses on recent advances in the understanding of TRAIL signal transduction and discusses the existing and future challenges of TRAIL-based cancer therapy development.

NF-kappa B as a therapeutic target in neurodegenerative diseases.

Abstract: NF-κB is a transcription factor that regulates numerous physiological functions, and that is involved in the pathogenesis of various diseases. In the nervous system there is evidence supporting a dual role of NF-κB in neurodegenerative diseases; activation of NF-κB in neurons promotes their survival, whereas activation in glial and immune cells mediates pathological inflammatory processes. The reason for such a dichotomy lies in the complexity of the NF-κB system. Emerging research has begun to dissect the pathways leading to the activation of the different NF-κB proteins, and the gene targets of NF-κB, in cells of the nervous system. In this article the authors discuss recent findings concerning the roles of NF-κB in the pathogenesis of several neurodegenerative disorders, and its potential as a pharmaceutical target for these disorders.

FOXP1: a potential therapeutic target in cancer

Abstract: Forkhead Box P1 (FOXP1) is a member of the FOX family of transcription factors which have a broad range of functions. Foxp1 is widely expressed and has been shown to have a role in cardiac, lung and lymphocyte development. FOXP1 is targeted by recurrent chromosome translocations and its overexpression confers a poor prognosis in a number of types of lymphomas, suggesting it may function as an oncogene. In contrast, FOXP1 localises to a tumour suppressor locus at 3p14.1 and loss of FOXP1 expression in breast cancer is associated with a worse outcome, suggesting FOXP1 may function as a tumour suppressor in other tissue types. These data suggest that FOXP1 may not only be useful in prognosis but also may be used to develop FOXP1-directed therapeutic strategies.

Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved

Abstract: Accumulating preclinical and clinical data suggest that the cardiac drug digitoxin might be used in cancer therapy. Recent reports have shown that digitoxin can inhibit the growth and induce apoptosis in cancer cells at concentrations commonly found in the plasma of cardiac patients treated with this drug. Several mechanisms have been associated with the anticancer activity of digitoxin, yet at present it is unknown why malignant cells are more susceptible to this cardiac glycoside than non-malignant cells. This report analyses the possible anticancer mechanisms of digitoxin and proposes that the inhibition of glycolysis may be a key mechanism by which this natural product selectively targets cancer cells. Finally, whether or not there is enough evidence to support the clinical evaluation of digitoxin in patients with cancer is discussed.

Inflammatory mediators modulating the transient receptor potential vanilloid 1 receptor: therapeutic targets to treat inflammatory and neuropathic pain

Abstract: The transient receptor potential vanilloid 1 receptor (TRPV1) plays an important role in inflammatory heat hyperalgesia. TRPV1 is a non-selective cation channel gated by noxious heat, protons and capsaicin, thus being regarded as a polymodal molecular integrator in nociception. Abundant evidence has demonstrated that TRPV1 is also modulated by numerous inflammatory mediators, including growth factors, neurotransmitters, peptides or small proteins, lipids, chemokines and cytokines. By activating multiple protein kinases to increase the phosphorylation of TRPV1, pronociceptive inflammatory mediators sensitise the TRPV1 response to noxious heat, protons and capsaicin, thus augmenting thermal hyperalgesia. In contrast, by inhibiting protein kinases or other mechanisms, antinociceptive inflammatory mediators suppress the response of TRPV1 to these stimuli, thus damping thermal hyperalgesia. The positive modulation of TRPV1 by inflammatory mediators may constitute a novel mechanism underlying sustained inflamma...

Cathelicidins and functional analogues as antisepsis molecules

Abstract: The emergence of antibiotic-resistant bacteria together with the limited success of sepsis therapeutics has lead to an urgent need for the development of alternative strategies for the treatment of systemic inflammatory response syndrome and related disorders. Immunomodulatory compounds that do not target the pathogen directly (therefore limiting the development of pathogen resistance), and target multiple inflammatory mediators, are attractive candidates as novel therapeutics. Cationic host defence peptides such as cathelicidins have been demonstrated to be selectively immunomodulatory in that they can confer anti-infective immunity and modulate the inflammatory cascade through multiple points of intervention. The human cathelicidin LL-37, for example, has modest direct antimicrobial activity under physiological conditions, but has been demonstrated to have potent antiendotoxin activity in animal models, as well as the ability to resolve certain bacterial infections. A novel synthetic immunomodulatory peptide, IDR-1, built on this same theme has no direct antimicrobial activity, but is effective in restricting many types of infection, while limiting pro-inflammatory responses. The ability of these peptides to selectively suppress harmful pro-inflammatory responses, while maintaining beneficial infection-fighting components of host innate defences makes them a good model for antisepsis therapies that merit further investigation.

Fatty acid receptors as new therapeutic targets for diabetes.

Abstract: G-protein-coupled receptors (GPCRs) are key regulators of several physiological functions. Their roles in cellular signal transduction have made them the target for majority of all currently prescribed drugs. Additionally, there are many orphan GPCRs that provide potential novel therapeutic targets. Several GPCRs are involved in metabolic regulation and glucose homeostasis such as GLP-1 receptor, glucagon receptor, adiponectin receptor and so on. Recently, free fatty acids (FFAs) have been demonstrated as ligands for orphan GPCRs and have been proposed to play a critical role in physiological glucose homeostasis. GPR40 and GPR120 are activated by medium and long-chain FFAs, whereas GPR41 and GPR43 can be activated by short-chain FFAs. GPR40, which is preferentially expressed in pancreatic beta-cells, mediates the majority of the effects of FFAs on insulin secretion. In this review, these findings and also critical analysis of these GPCRs as novel targets for diabetes are discussed.

Targeting Nur77 translocation

Abstract: The ultimate growth of a tumour depends on not only the rate of tumour cell proliferation, but also the rate of tumour cell death (apoptosis). Nur77 (also known as TR3 or NGFI-B), an orphan member of the nuclear receptor superfamily, controls both survival and death of cancer cells. A wealth of recent experimental data demonstrates that the Nur77 activities are regulated through its subcellular localisation. In the nucleus, Nur77 functions as an oncogenic survival factor, promoting cancer cell growth. In contrast, it is a potent killer when migrating to mitochondria, where it binds to Bcl-2 and converts its survival phenotype, triggering cytochrome c release and apoptosis. Agents, such as 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437), which induce Nur77 migration from the nucleus to mitochondria, effectively induce apoptosis of cancer cells. Moreover, Nur77 translocation is highly controlled by retinoid X receptor (RXR), suggesting a role of RXR ligands in regulating the p...

Suppressing renal NADPH oxidase to treat diabetic nephropathy.

Abstract: Renal nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase is an important source of oxidative stress and its expression is enhanced in the glomerulus and distal tubules of diabetic nephropathy. High glucose-induced protein kinase C signalling or renal angiotensin II signalling increases the membrane translocation of cytosolic component p47phox. NADPH oxidase-derived reactive oxygen species (ROS) in the podocytes damage the glomerular basement membrane and the slit diaphragm causing proteinuria, and mesangial and glomerular endothelial NADPH oxidase increase TGF-β and cause collagen and fibronectin accumulation. Tubular NADPH oxidase stimulated by angiotensin II or aldosterone contributes to sodium retention and to tubulointerstitial damage. Thus, inhibition of the renal renin–angiotensin II–aldosterone system with angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blocker or selective aldosterone inhibitor indirectly suppresses NADPH oxidase reducing renal ROS, pr...

IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases

Abstract: IL-19 and IL-20 are two cytokines that were discovered in 2000 and 2001, respectively. Based on the structure and location of their genes, their primary and secondary protein structures and the used receptor complexes, they were classified with IL-10, IL-22, IL-24, IL-26, IL-28 and IL-29 in the IL-10 family of cytokines, and form a subgroup with IL-24 within this family. IL-19 and IL-20 are produced by monocytes as well as non-immune tissue cells under inflammatory conditions. IL-19 and IL-20 act via a receptor complex that consists of the IL-20R1 and IL-20R2 chains. IL-20 is additionally able to signal via a second receptor complex (IL-22R1/IL-20R2). It is controversial whether or not IL-19 and IL-20 regulate the function of immune cells. However, the expression of their receptors aliments the perception that the cells of the skin, lungs and reproductive organs as well as various glands are major targets of these mediators. Results from animal experiments and massively increased expression of these media...

P-selectin: a common therapeutic target for cardiovascular disorders, inflammation and tumour metastasis.

Abstract: P-selectin belongs to the family of selectin adhesion molecules, and is expressed by platelets and endothelial cells on stimulation. This pattern of expression may indicate an involvement of this molecule in inflammation and coagulation. Data from mice lacking P-selectin expression confirmed this assumption. In addition, a key role of P-selectin in the formation of tumour metastases has been established. Apparently unrelated, clinical experience has pointed towards a detrimental interaction of inflammation and cancer with thromboembolic diseases and vice versa. Therefore, targeting molecules such as P-selectin contributing to coagulation, inflammation and metastasis may offer novel therapeutic strategies to treat chronic inflammatory diseases and metastatic cancer. The authors aim to critically evaluate the contribution of P-selectin in these diseases, and discuss the value of therapeutic inhibition of P-selectin functions in coagulation, inflammation and metastasis.

Targeting enzyme inhibitors in drug discovery.

Abstract: Drugs that function as enzyme inhibitors constitute a significant portion of the orally bioavailable therapeutic agents that are in clinical use today. Likewise, much of drug discovery and development efforts at present are focused on identifying and optimizing drug candidates that act through inhibition of specific enzyme targets. The attractiveness of enzymes as targets for drug discovery stems from the high levels of disease association (target validation) and druggability (target tractability) that typically characterize this class of proteins. In this expert opinion the authors describe the existing practices and future directions in drug discovery enzymology, with emphasis on how a detailed understanding of the catalytic mechanism of specific targets can be used to identify and optimize small-molecule compounds that interact with conformationally distinct forms of the enzyme, thus resulting in high potency, high selectivity inhibitors.

NF-κB as a target for cancer therapy

Abstract: NF-kappaB transcription factors and the signaling pathways that activate them play a critical role in cancer development, progression and therapy, and recently have become a focal point for intense drug discovery and development efforts. This article presents a critical review on the different types of inhibitors targeting the NF-kappaB pathway at several stages.

Glutamate excitotoxicity and therapeutic targets for amyotrophic lateral sclerosis.

Abstract: Two forms of amyotrophic lateral sclerosis (ALS) are known, the familial (FALS), due in part to mutations in superoxide dismutase 1 (SOD1), and the sporadic (SALS), which accounts for > 90% of all cases. The cause of SALS is not known, but excitotoxicity due to overactivation of glutamate receptors may mediate the motor neuron degeneration in the spinal cord, which is the hallmark of this disease. Overactivation of calcium-permeable alpha-amino-3-hydroxy-5-isoxazole propionate receptors lacking the subunit glutamate receptor 2, leading to an increase in calcium cytoplasmic concentration, seems to play an important role in the mechanism of neuronal death. The knowledge of this mechanism, in addition to other factors, provides several possible targets for therapeutic strategies that are reviewed in this article. Some of these strategies have proven to be partially effective in both human mutant superoxide dismutase 1 transgenic rodents (FALS model) and the few existing in vivo models of spinal motor neurodegeneration induced by excitotoxicity (SALS models), although observable benefits are still to be shown in clinical trials.

The hERG potassium channel as a therapeutic target

Abstract: The hERG (human ether-a-go-go-related gene) potassium channel has elicited intense scientific interest due to its counter-intuitive kinetics and its association with arrhythmia and sudden death. hERG blockade is involved in both antiarrhythmic pharmacotherapy and the pathogenesis of familial and acquired long QT syndrome (LQTS). Short QT syndrome (SQTS), muscular atrophy and many forms of cancer have also been associated with hERG as a target. Molecular models of both the channel and its blocker pharmacophores exist, revealing methods to design hERG liability out of potential drug molecules. Future developments will synthesise preclinical data on hERG with other criteria to determine net arrhythmogenic risk. Also, the molecular actions of hERG and its genetics will be elucidated in detail to allow clinical risk reduction.

Antimalarial drug discovery: targeting protein kinases

Abstract: Protein kinases (PKs) are prime targets for drug discovery in a variety of diseases, including cancer and neurodegenerative pathologies The characterisation of the kinome of the human malaria parasite Plasmodium falciparum has revealed profound divergences, at several levels, between PKs of the parasite and those of its host Here, the authors review the major issues and recent advances regarding the development of Plasmodium-selective PK inhibitors, with emphasis on target identification and validation, and on structure-based design The authors also discuss the possibility of interfering with: i) Plasmodium PKs regulating transmission to the mosquito vector; and ii) host PKs that may be required for parasite survival

The potential for phospholipase D as a new therapeutic target.

Abstract: Mammalian phospholipase D (PLD), a signal transduction-activated enzyme, hydrolyzes phosphatidylcholine to generate the lipid second messenger phosphatidic acid (PA) and choline Genetic and pharmacological methods have implicated PLD and its product PA in a wide variety of cellular processes including vesicle trafficking, receptor signaling, cell proliferation and survival Dysregulation of these cell biologic processes occurs in a diverse range of illnesses including cancer This review summarizes PLD regulation and function and highlights its potential as a therapeutic target in disease settings

STAT3 and suppressor of cytokine signaling 3: potential targets in lung inflammatory responses

Abstract: The expanding knowledge involving the cytokine transcription factor network has provided new insights into the acute lung inflammatory response. There are numerous lung inflammatory diseases that at present lack effective treatment (adult respiratory distress syndrome, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma and so on). Although cytokines themselves and their receptors comprise a communication system that is crucial to detect the presence of pathogens and the injured lung, the cytokine signals and the milieu that surrounds these signals can clearly determine the nature of the lung responses that are elicited. Functioning as a transcription factor, STAT3 participates in the signaling pathways for many cytokines in various cells and organs that are regulated by the suppressor of cytokine signaling (SOCS) family, including SOCS3. Recently, data on the activation and function of STAT3 and SOCS3 in the lung during the acute inflammatory response are emerging, suggesting that these molecules can be potential targets for regulating pulmonary inflammatory responses. The authors review the progress in understanding how STAT3 and SOCS3 regulate the lung inflammatory response.

Selective Raf inhibition in cancer therapy.

Abstract: Over the past 5 years, the Raf kinase family has emerged as a promising target for protein-directed cancer therapy development. The goal of this review is to first provide a concise summary of the data validating Raf proteins as high-interest therapeutic targets. The authors then outline the mode of action of Raf kinases, emphasizing how Raf activities and protein interactions suggest specific approaches to inhibiting Raf. The authors then summarize the set of drugs, antisense reagents and antibodies available or in development for therapeutically targeting Raf or Raf-related proteins, as well as existing strategies combining these and other therapeutic agents. Finally, the authors discuss recent results from systems biology analyses that have the potential to increasingly guide the intelligent selection of combination therapies involving Raf-targeting agents and other therapeutics.

Tumour targeting by microtubule-depolymerizing vascular disrupting agents.

Abstract: Low molecular weight vascular disrupting agents of the microtubule depolymerizing family cause marked and selective disruption of the established tumour blood vessel network, resulting in tumour cell necrosis. The combretastatins are members of this family and these, together with several other related compounds, have undergone extensive preclinical testing and are now in clinical trials for cancer. Potentially, vascular disrupting agents can also interfere with angiogenesis and constitute a very promising group of novel cancer drugs. In vitro analysis of their signalling activities points to the endothelial cytoskeleton as being their major target and a key player in the events that culminate in vascular collapse. As more of these agents progress into the clinical setting, more research in this area is warranted in order to decipher exact mechanisms responsible for vascular disruption and to understand the reasons for drug selectivity for the tumour vasculature. This information is essential in order to identify new targets within the tumour vasculature and to improve present therapies.

Cannabinoid receptors as new targets of antifibrosing strategies during chronic liver diseases.

Abstract: Chronic liver injury exposes the patient to liver fibrosis and its end stage, cirrhosis, is a major public health problem worldwide. In western countries, prevailing causes of cirrhosis include chronic alcohol consumption, hepatitis C virus infection and non-alcoholic steatohepatitis. Current treatment of hepatic fibrosis is limited to withdrawal of the noxious agent. Nevertheless, suppression of the cause of hepatic injury is not always feasible and numerous efforts are directed at the development of liver-specific antifibrotic therapies. Along these lines, the authors recently demonstrated that the endocannabinoid system shows promise as a novel target for antifibrotic therapy during chronic liver injury. Indeed, cannabinoid receptors CB1 and CB2 promote dual pro- and antifibrogenic effects, respectively. Therefore, endocannabinoid-based therapies, combining CB2 agonists and CB1 antagonists may open novel therapeutic perspectives for the treatment of chronic liver diseases.

The Src signaling pathway: a potential target in melanoma and other malignancies.

Abstract: Although Src was the first oncogene to be discovered as the transforming protein of the Rous sarcoma virus almost three decades ago, the role of Src and the Src family kinases in human oncogenesis is still not completely understood. Recent studies have shown that Src regulates cell adhesion, invasiveness and motility in cancer cells and in tumor vasculature, rather than directly influencing cell replication. The role of the Src family kinases in human cancer is evolving and elevated levels of Src kinase activity have been reported in a number of human cancers in vitro and in vivo. Src expression and activity are increased in melanoma cell lines and in melanoma tumors in vivo. Src can activate STAT3, STAT5 and other downstream targets in melanoma. Src and STAT3 are expressed in their activated forms in both primary and metastatic melanoma in humans, although the expression level is variable. Cumulatively, these data mark Src signaling as attractive therapeutic targets in melanoma. Studies are currently underway with novel Src inhibitors in melanoma and in other tumor types.

FOXA1 as a therapeutic target for breast cancer.

Abstract: Gene expression profiling studies have classified breast cancer into five intrinsic subtypes with distinct prognostic significance: luminal type A, luminal type B, normal-like, HER-2-positive and b...

The epidermal growth factor receptor in malignant gliomas: pathogenesis and therapeutic implications.

Abstract: Activated epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target for a variety of solid tumors, particularly malignant gliomas. Mutation or amplification of EGFR is commonly observed in malignant gliomas and these modifications are associated with increased cell proliferation and radiation resistance. Small-molecule kinase inhibitors targeting the intracellular kinase domain of the EGFR and monoclonal antibodies against the extracellular domain of the EGFR have demonstrated in vitro efficacy and have spawned clinical trials incorporating EGFR inhibition into the management of malignant gliomas, for example, combining EGFR inhibitors with radiation therapy. This early clinical experience indicates that EGFR inhibitors are well tolerated; however, it remains unclear how best to integrate EGFR inhibition into the management of malignant gliomas. As signaling pathways become better defined, patients may be treated with EGFR inhibitors based on the molecular features of their tumors and treatment efficacy may be improved by combining EGFR inhibition with other small kinase inhibitors and radiation therapy.

New therapeutic targets in atrophic age-related macular degeneration.

Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. There is no effective treatment for the most prevalent atrophic (dry) form of AMD. Atrophic AMD is triggered by abnormalities in the retinal pigment epithelium (RPE) that lies beneath the photoreceptor cells and normally provides critical metabolic support to these light-sensing cells. Secondary to RPE dysfunction, macular rods and cones degenerate leading to the irreversible loss of vision. Oxidative stress, formation of drusen, accumulation of lipofuscin, local inflammation and reactive gliosis represent the pathologic processes implicated in pathogenesis of atrophic AMD. This review discusses potential target areas for small-molecule and biologic intervention, which may lead to development of new therapeutic treatments for atrophic AMD.