Modern neuroscience must translate findings of basic science into useful therapies for those who suffer the devastating effects of neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and other related CNS diseases. Of all the therapeutic areas, these diseases of the CNS provide the biggest challenges to translational research in this era of increased productivity and novel targets. In fact, for CNS diseases the success rate is particularly low considering that only about 8% of drug candidates that have made it into clinical studies will enter the market as new medicines. Thus, there is a tremendous need for improvement and innovation for the benefit of patients suffering from such devastating diseases. Considering the gap between clinical and basic neuroscience, there is an unprecedented need to train investigators who are capable of bridging the basic-clinical neuroscience divide in the growing field of translational neuroscience.
The aim of this course is to provide an overview and up-to-date examples of how basic science and clinical observations lead to translational research. In this Course the basics of CNS drug discovery and development and relevant translational research aspects will be discussed, employing examples taken from pharmaceutical R&D. Translational neuroscience aims at the integration of molecular and cellular approaches, behavioral analysis and clinical applications in the study of CNS. Translational research, in the more general sense, is defined as (a) the process of turning an interesting idea into a real drug target, or (b) turning an interesting compound into a real drug.
This course seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions AD, PD disease. to translate what is learned at the bench into bedside applications.
Major CNS diseases like AD, PD, Levy body dementia (LBD) and schizophrenia will be discussed with a focus on overlaps among these diseases and challenges of developing efficacious therapies. Emphasis will be placed on aspects related to the selection of the most appropriate disease targets. In this regard, different types of therapeutic modalities with emphasis on AD and PD such as small organic molecules will be compared in order to highlight the advantages and disadvantages associated with each different approach. The extra challenge for CNS disease therapies caused by the blood-brain barrier will also be a key topic. The importance of animal models and the need for more predictive ones will be examined in detail.
The Course will address the following main topics:
A) CNS neuropsychiatric and neurodegenerative diseases; minimal cognitive impairment, AD, PD; Cerebral amyloid angiopathy, LBD, schizophrenia; pathologies, risk factors, statistics and costs to society. These mental and neurodegenerative diseases are biologically heterogeneous entities. This biological heterogeneity contributes to the well-established phenomenon of suboptimal response to treatment.
B) Enigmatic etiologies: Despite intensive research, underlying pathophysiological mechanisms in these disease states remain insufficiently documented for purposeful target discovery.
C) The complex world of drug discovery and development:
1 Where and how are CNS drug discovered?
2 What are the requirements for a drug?
3 What are the criteria for a potential CNS drug?
4 Regulatory requirements for drug developments; Preclinical and clinical phases.
5 Medicinal chemistry and structure-activity relationships.
6 Rational drug design or serendipity?
7 CNS penetration: the blood-CNS barrier.
8 Pharmacokinetic and pharmacodynamic considerations.
9 Lead Hypotheses in CNS diseases such as AD, PD
10 Target identification (e.g. receptors, enzymes, ion channels, kinases; protein aggregation, neuroinflammation and more).
11 Target identification based on risk factor, etiological aspects and genetics
12 Target validation: what is the "right" target? Is the drug development process in AD, for example, on the wrong track? Why so many drugs have failed in AD clinical trials?
13 IP considerations; Patents; Ethical vs. Generic Drugs
14 Biomarkers and Imaging
15 Progress in developing effective AD and dementia therapeutics has been hampered by a lack of short-term, sensitive biomarkers that correlate closely to clinical outcomes. Do we have reliable and validated markers?
16 Preclinical animal model systems:
Translational research, based on animal models, has been very useful in documenting the possible pathological mechanisms in many CNS diseases, yet they are not very predictive in the area of drug development. Critical evaluation of animal and translational models is needed to improve transition from drug discovery and clinical development. How can this be achieved?
Validated Models:
An important approach to reducing attrition rates in the clinical development of treatments for CNS disorders such as AD and schizophrenia is to improve the validity of preclinical models used to advance drug candidates. Measuring CNS function (e.g., learning and memory, mood) is inherently complicated in a preclinical setting.
• In vitro models (organoids)
• AD models have failed to meet disease state.
• Are PD models more successful?
• Cognition and other symptoms? Can we mimic them in animals?
• Will transgenic and induced models ever be true predictors for neurodegenerative drug discovery?
17 Examples for possible treatment strategies (Pros and Cons):
• Approved treatments and prescribed drugs
• Symptomatic treatments vs. Disease modification
• Small organic molecules with special emphasis on AD treatment [cholinergic drugs (e.g. cholinesterase inhibitors, muscarinic and nicotinic agonists), metabotropic and other GPCRs, allosteric and orthosteric ligands, ligands for molecular chaperones (sigma-1 receptor), anti-inflammatory drugs, alpha-secretase activators, beta-secretase or gamma-secretase inhibitors; kinase inhibitors or activators; amyloid, tau or alpha-synuclein anti-aggregation agents; antioxidants; monoamine oxidase-inhibitors and many more].
• Therapeutic Strategies for disease modifications
• Monotherapies vs. Polypharmaceuticals
• Immunotherapies
• Drug repurposing
Why did so many drugs fail in AD? Are the current hypotheses valid? What was done wrongly? Did we hit the right targets? What can we learn from successes and failures in recent CNS development programs? This course will address these major questions.
18 Clinical trials in AD and PD.
Major clinical studies were published recently and a few are due to be finalized and their outcome to be published by 2019; Other are still ongoing. The outcome of such studies may have a major impact on future treatment trends and various hypotheses implied in the etiology of AD and some related diseases such as MCI, LBD or PD. Emphasis will be given in this course to most up-dated information regarding such studies.
This course will attempt to bring perspective to the research, investment and translational impact of recent drug discovery, primarily for those outside biotech firms and large pharma attempting to advance novel AD, PD approaches towards the clinic.