Neuroprotection: Translation of Mechanism and Model into Therapy
ASENT 5th Annual Meeting
Thursday, March 13 - Saturday, March 15, 2003
Capital Hilton Hotel, Washington, DC
Speaker Abstracts: Neuroprotection: Translation of Mechanism and Model into Therapy
Which Way Did They Go? Neural Cell Death Pathways
Dale Bredesen, MD
A large number of the disease states dealt with by neurologists and neurosurgeons—and against which neurotherapeutics will be directed—involve the dysfunction and ultimately death of neural cells. Examples of such diseases include stroke, Alzheimer’s disease and other neurodegenerative diseases, and neurotrauma. In addition, CNS neoplasms also display abnormalities of cell death, but in contrast to the preceding examples, feature a decrease rather than an increase in cell death. It has become increasingly clear that cells may take more than one pathway to death, and that, in contrast to previous beliefs, cells may play an active role in their own demise. Until recently, a major focus of research was on extrinsic factors that contribute to cell loss—e.g., hypoxia, ischemia, and glucose deprivation. However, it has become clear that intrinsic factors also play crucial roles in the outcomes of neural insults, and that cells can effectively set their own probabilities of death over a relatively wide range. Therefore, it is of interest to examine the biochemical pathways of neural cell death and the modulation thereof. Broadly speaking, cells may die passively or actively; when the cell’s role is passive, this is referred to as necrosis. When the cell undergoes active, “suicidal” death, this is referred to as programmed cell death (pcd). Over 50,000 research papers have been published to date on one form of pcd, apoptosis, which is characterized by the activation of a set of cell death cysteine proteases, dubbed caspases. These cleave specific substrates (over 100 have been identified, and the total number may turn out to be closer to 1000) at specific aspartate residues, leading to the apoptotic phenotype, which includes nuclear fragmentation, chromatin condensation, internucleosomal DNA fragmentation, membrane blebbing, the budding of cellular fragments (apoptotic bodies), and phagocytosis of the apoptotic cell. However, recent work has reinforced the notion that alternative, non-apoptotic forms of pcd also occur, and may play important roles in disease states. Much less is known about these alternative forms, which include autophagic cell death, paraptosis, and oncosis, among others. In some cases, blocking one form of cell death has been shown to push the cell toward an alternative pathway, and therefore it will be important to develop both markers and modulators for these alternative programmatic cell deaths.
Mechanisms of Cell Injury: Implications for Treating Neurological Disorders
Alan Faden, MD
Injuries to the central nervous system cause biochemical changes, which include neurotoxic as well as neuroprotective components. The balance between these two types of delayed reactions, which are remarkably stereotypic across categories of insult, substantially determines the ultimate extent of tissue damage and associated neurological dysfunction. Secondary injury factors are induced from seconds to weeks or months after trauma or ischemia, and may lead to either necrotic or apoptotic neural cell death. Blocking these delayed neurotoxic reactions or enhancing endogenous neuroprotective responses provide the theoretical basis for development of neuroprotective treatment strategies. Because various injury pathways may occur in parallel, and blockade of one type of cell death pathway may shunt to another, the most effective neuroprotection approaches may require multi-drug treatment or use of single agents with multipotential actions. Examples of promising multipotential drug treatment are discussed.
Translational Challenges: From Animal to Human Experimentation
Justin Zivin, MD PhD
At present, only thrombolysis with tissue plasminogen activator has been approved by regulatory agencies in several countries, including the FDA, for treatment of acute stroke. Numerous neuroprotective agents have been tested in poorly and well designed clinical trials, but so far, all have failed to provide convincing evidence of safety and efficacy. A large number of drugs, and some devices, have been shown to reduce neurological injury and histological damage to the brain in a variety of animal stroke models, but these encouraging experimental findings have not resulted in successful treatments for human stroke victims. Although it is commonly thought that the animal models do not predict the results of human clinical trials, I would contend that some animal models are actually reasonably accurate predictors of human responses to cerebral ischemia and the effects of some types of therapies. There are numerous possible reasons for the trial failures, and we have encountered obstacles at virtually every step in the process of translating theory into clinically practical therapies. I will discuss the reasons for many of the past difficulties and possible ways to achieve better results in the future.
Application of Imaging Approaches in Neuroprotection
Alan Koretsky, MD
Abstract not received in time for printing.
Strategic Challenges in Neuroprotective Drug Development
Christopher Gallen, MD PhD
Much of the power of modern medicine results from a core of important pharmaceuticals, biologicals and vaccines developed by the combined efforts of academicians, the pharmaceutical industry, government, clinical investigators and research subjects over the decades. The proliferation of potential therapeutic targets opened up by genomic and proteomic technologies, the ability of combinatorial chemistry to generate myriad test molecules and the development of high-throughput technologies to rapidly screen new molecules against new targets promises even more powerful therapies. Yet massive increases in Research and Development expenditures have not produced a proportional increase in new therapeutics developed. The relative dearth of new chemical entity introductions has raised significant concerns about the robustness of the pharmaceutical, biotech and vaccines industries. Despite intensive focus in recent years, CNS diseases - particularly neurodegenerative diseases - have been particularly prominent as a source for recurrent failures of new therapies – often late in development with great expense and potential risk to patients. Three key issues must be addressed to reduce costs and risks while enhancing speed and success rates:
Future development of neuroprotective compounds must incorporate the fact of high rates of failures into the strategy of CNS development by using technologies to aggressively test key sources of potential failure very early in development. Does the compound penetrate to the target organ? Does it mechanistically do what it is supposed to do? Does it produce biological activity? We should reject inadequate compounds early, without full clinical testing.
While approaches based on narrow therapeutic mechanisms are intellectually attractive, many effective compounds affect multiple mechanisms. Approaches using compounds with multi-mechanistic targets, possibly designed using inferences from disease models, may produce more robust therapies.
Technology and more effective management are a better source for time-savings in research than relying on guesswork on dose selection by skipping phase II.