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MD Biosciences Blog

Increase Validity of Preclinical Pain Research

Posted by MD Biosciences on Jan 20, 2015 11:12:09 AM

If you work in drug discovery and development, you are well aware of the failure rate at clinical trials. Industry estimates are that clinical candidates have a 85-90% chance of failure during clinical trials, the most costly stage of evaluation. A report in Nature Biotechnology 32, 40–51  breaks this success/failure rate down between phases as well as the likelihood of approval from the start of clinical trials. For candidates that are suspended during clinical stages, 83% of these reported efficacy or safety as the reason for suspension. 

This is costly and time consuming for drug developers. So is there a way to increase the predictability from preclinical phases to clinical phases?  We have been evaluating this question for a number of years in our Research Group at MD Biosciences. Animal models used in preclinical development phases are pivotal for understanding mechanisms that contribute to human disease conditions and effective therapies. Rodent models are commonly employed due to their reproducibility and simplicity, however the predictability to the clinic is often times lacking.

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Topics: Pain, Neuro/CNS, in vivo pain models

Preclinical Pig Models for Therapeutic Studies

Posted by MD Biosciences on Nov 7, 2013 11:08:00 AM

Historically, rodent models have been used for the discovery of various biological mechanisms within disease states as well as preclinical development of therapeutics. Unfortunately there are many ways that the biology of rodents fails to accurately predict the clinical conditions of humans - this is particularly the case in pain therapeutics. This can be evidenced by the estimates that as many as 80% of all drug candidates across therapeutic areas fail in the most expensive stages of development - clinical trials. While the failures can be attributed to various reasons such as insufficient efficacy, unacceptable safety profiles or PK properties. With the high cost of developing new therapeutics, there is certainly the need to validate biological and pharmacological findings in models using larger species, which can also address some of the known differences between rodents and human. The pig is one species which may provide more translatable data to the human condition, particularly in therapeutic areas such as cardiovascular, skin or wound healing conditions, metabolic and pain.

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Topics: Dermal, Pain, CRO/outsourcing, Cardiovascular, metabolic

Preclinical Models for Diabetic Neuropathy

Posted by MD Biosciences on Sep 5, 2013 9:12:00 AM

Diabetic neuropathies include a range of dysfunctions of the peripheral nerves that can be broadly categorized into generalized symmetric polyneuropathies and focal/multifocal neuropathies. Diabetic neuropathy (DN) is the most common long-term complication suffered by individuals afflicted with either type 1 diabetes (T1D) or type 2 diabetes (T2D). It is the leading cause of non-traumatic amputations and results in significant morbidity, mortality, and economic burden. Of patients suffering from DN, approximately 30% experience pain that is severe, debilitating, largely unresponsive to current pharmacotherapies, and persistent for several years. DN pain is often localized to the feet, described as “burning” or “sharp,” and worsens at night or during periods of fatigue or stress. DN pain can be spontaneous and/or can be in the form of either allodynia (pain caused by a normally benign stimulus) or hyperalgesia (exaggerated pain caused by a normally mildly painful stimulus) or both. [1-3] 

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Topics: metabolic

Cell Types Involved in ischemic Neuroinflammation

Posted by MD Biosciences on Sep 4, 2013 11:10:00 AM

Post-stroke neuroinflammation is a very complex phenomenon involving multiple resident and invading cell types at varying degrees of differentiation or activation each expressing specific subsets of diffusible factors, receptors, cellular adhesion molecules, and other markers, all of which is changing as time passes to create an initially neurotoxic and then finally neuroprotective environment. This inflammatory process in the penumbra offers a broad array of potential cellular and molecular targets with much wider therapeutic windows. At the cellular level, neurons, microglia, astrocytes, and cerebrovascular endothelial cells are the first affected by the ischemic conditions and their responses to massive cell death in neighboring tissue initiates the precisely timed arrival of successive subsets of leukocytes – first neutrophils, followed by monocytes and macrophages, and finally T cells. Targeting these cells via manipulation of their phenotypes or activation states or their movements into lesion sites or their release of harmful mediators represents a major investigative pathway toward potential therapeutics for ischemic stroke sufferers. [1-4]

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Topics: Neuro/CNS

Cognitive Impairment Neurodegenerative Disease Models

Posted by MD Biosciences on Jul 31, 2013 7:36:00 AM

Diseases of the central nervous system are extremely debilitating, increasingly common, and affect millions of people worldwide. Neurodegenerative diseases often result in a combination of cognitive and motor deficits that affect an individual’s ability to perform daily tasks. Affected patients become dependent on medical services and family support as their disease progresses. Improvements in health have lengthened lifespan; however, this has resulted in a higher incidence of neurodegenerative conditions that affect the aging population. Genetics often has a major role in the development of neurodegenerative diseases and disease severity sometimes increases with each generation. However, environmental factors may be equally important in contributing to the severity, progression, and outcome of patients with other types of neurodegenerative disorders. Exposure to environmental toxins, metals, industrial chemicals, and certain dietary or lifestyle factors, may result in damage to the nervous system. Acute brain injuries, such as head trauma or oxygen deprivation, can also result in cognitive impairments.

Although there are a variety of pathways leading to neurodegenerative disease, the end result is the same: loss of function in the central nervous system and resulting impairments. Many neurodegenerative disorders are progressive in nature, resulting in a decline in function that may occur over several years or several decades. While there are some treatments available for neurodegenerative disorders, there are no cures. Therefore, there is great interest in researching neurodegenerative diseases and a need to halt or slow the process of cognitive decline. Understanding the basic biological mechanism of disease and cognitive impairment is pertinent for the development of therapeutics. 

The outcome in oxygen stress and neurodegenerative diseases

Homeostasis is critical for cell viability and cell maintenance. In cases of oxygen deprivation, autoimmune disease, or expression of disease factors, the cell is no longer able to maintain homeostasis and perform its necessary functions. Affected cells may die by necrosis or by apoptosis. When dead cells accumulate, reactive glial cells migrate to the site of injury and begin clearing the debris, but they also form scars that hinder axon regeneration and remylination [1]. Immune activation of glia may cause bystander effect and result in damage to the surrounding tissues. While it was once thought that cells of the central nervous system were unable to regenerate, we now know that restrictive microenvironmental factors are mostly responsible for preventing repair [2]. Strategies such as stem cell therapy, nanoparticle drug delivery, and gene therapy are being studied to determine if modulating the cellular microenvironment can lead to repair in the central nervous system [3-5].

Patients with cell death as a result of prolonged oxygen deprivation or disease have functional deficits. Although the young brain does display a high degree of plasticity, the adult brain is not easily able to regain lost function. After a stroke, the adult brain must undergo extensive changes in the motor cortical network in order to overcome resulting motor deficits. In patients with autoimmune disorders or neurodegeneration, the disease is typically progressive and patients are less likely to show any improvement in cognitive or motor function. Both cognitive function and motor function are typically affected by these progressive and acute brain injuries. Distinguishing between loss of motor function and loss of cognitive function is important for accurately studying these diseases and injuries in animal models. 

Distinguishing between motor function and cognition

Differentiating between motor function and cognitive deficits can sometimes be a difficult task. For example, slow and slurred speech may lead a listener to suspect a patient has problems with language processing. However, difficulty with speech could be caused by damage to the hypoglossal nerve that controls movement of the tongue. Different areas of the central nervous system are responsible for voluntary (cognitive) and involuntary (reflexive) muscle movements. Deficits in purely motor function are often seen as problems in coordination, balance, and strength. A majority of involuntary motor function is controlled by the spinal cord. Even processes like walking are regulated by a feedback loop within the spinal cord and individuals do not consciously consider how to lift and place each leg. The cerebellum coordinates movement fluidity through feedback prediction. Patients with degeneration of the cells of the cerebellum have difficulty reaching for an intended target. Other motor deficits may lead patients to experience tremors, which are common in Parkinson’s disease. While lost motor functions are extremely problematic in performing daily tasks, some functions may be regained under certain conditions. In one study, 76% of patients regained motor functions six months after suffering a stroke [6]. Motor function was also regained in monkey models of brain lesions [7].

Cognitive regulation of motor function (motor planning) is controlled by the cerebral cortex. When an individual makes a decision to move, the cerebral cortex sends signals to the spinal cord where information is streamlined and relayed to muscles. Defects in cognitive planning may hijack successful completion of the motor task at hand. One of the paradoxes of Parkinson’s disease is that patients lose the cognitive decision to move, however the motor function needed to perform the action is maintained. Cognitive impairments do not appear to resolve as easily as motor impairments. The probability of long-term cognitive improvement after a stroke was only 54% for patients with damage to the left hemisphere of the brain [8]. When oxygen deprivation or neurodegenerative processes occur, patients often experience varying de- grees of loss of motor function combined with cognitive deficits. A stroke patient usually has muscle weakness on the contralateral side of the body and cognitive impairments related to the area of the brain that was damaged.

Because disease patients often experience varying degrees of motor and cognitive impairments, it is difficult to study neurodegenerative disease and cognition in humans. Similar biological processes control loss of cognitive function in humans and animals; therefore mouse models recapitulate the cell biology resulting in cognitive decline.

Mouse models provide many advantages to the study of neurodegenerative disorders. Models such as EAE for neuroimmunological disorders, the 4VO and MCAo for oxygen deprivation and 6-OHDA for neurodegenerative disease can be used to study cognitive impairments related to human disease.

 

Download the rest of the article to continue reading about measuring cognitive impairment in preclinical models. 

 

References:

  1. Fawcett J.W., & Asher, R.A. The glial scar and central nervous system repair. Brain Research Bulletin. 49, 377-391 (1999)

  2. Horner, P.J., Gage, F.H. Regenerating the damaged central nervous system. Nature 407, 963-970 (2000)

  3. Berry, M., Barrett, L., Seymour, L., Baird, A., Logan, A. Gene therapy for central nervous system repair. Current Opinion in Molecular Therapies 3, 338-349 (2001)

  4. Aboody, K., Capela, A., Niazi, N., Stern, J.H., Temple, S. Translating stem cell studies to the clinic for CNS repair: current state of the art and the need for a Rosetta stone. Neuron 70, 597-613 (2011)

  5. Chen, B., Bohnert, D., Borgens, R.B., Cho, Y. Pushing the science forward: chitosan nanoparticles and functional repair of CNS tissue after spinal cord injury. Journal of Biological Engineering 7, 15 (2013) [Epub ahead of print]

  6. Bonita, R., Beaglehole, R. Recovery of motor func- tion after stroke. Stroke 19, 1497-500 (1988)

  7. Black, P., Markowitz, R.S., Cianci, S.N. Recovery of motor function after lesions in motor cortex of monkey. Ciba Foundation symposium 34, 65-83 (1975) 

 

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Topics: Neuro/CNS

IMQ-induced Psoriasis Model | Correlates with Human Psoriasis

Posted by MD Biosciences on Apr 29, 2013 4:28:00 PM

First let's start by talking about what makes a good preclinical model of psoriasis?

A good pre-clinical psoriasis model should obviously re-capitulate the key features of the clinical disease in humans. Therefore, a plausible model will exhibit the following criteria:

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Topics: Dermal, Psoriasis

Contributions of Preclinical 6OHDA Model to Understanding PD

Posted by MD Biosciences on Mar 4, 2013 10:23:00 AM

Background of the preclinical 6-OHDA model of PD 

The 6-hydroxydopamine (6-OHDA) model of Parkinson's Disease (PD) was the first model of PD generated, and has since been widely used to investigate parkinsonism in rodents. The model was originally developed following the discovery that injecting 6-OHDA into the substantia nigra pars compacta (SNpc) caused anterograde degeneration of the nigrostriatal dopaminergic system, producing a loss of dopaminergic neurons in the SNpc and loss of dopaminergic terminals in the striatum (to which the SNpc projects), similar to that observed in Parkinson’s disease. 6-OHDA is similar in structure to dopamine, but the presence of an additional hydroxyl group makes it toxic to dopaminergic neurons. Once in the cytosol, 6-OHDA auto-oxidizes to form reactive oxygen species, which are thought to cause neurodegeneration by reducing levels of anti-oxidant enzymes, elevating iron, and inhibiting mitochondrial respiration. The main features of this model that have made it popular are that it is relatively fast, inexpensive and simple to implement, and that the lesions it produces are reproducible and substantial.

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Topics: Neuro/CNS

Bioimaging in Preclinical Models of Rheumatoid Arthritis

Posted by MD Biosciences on Nov 5, 2012 11:12:00 AM

Rheumatoid arthritis is a chronic and progressive inflammatory condition estimated to affect between 0.5-1% of the world's population, with more women being affected than men. It is a systemic disease manifesting mainly as a disabiling destruction of the synovial joints of the hands and feet.

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Topics: Inflammation

Post-stroke Neuroinflammation | Astrocytes & Microglia

Posted by MD Biosciences on Jul 9, 2012 12:22:00 PM

Post-stroke neuroinflammation is a very complex phenomenon involving multiple resident and invading cell types at varying degrees of differentiation or activation - each expressing specific subsets of diffusable factors, receptors, cellular adhesion molecules and other markers - all of which is changing as time passes to create an initially neurotoxic and then finally neuroprotective environment. This inflammatory process in the penumbra offers a broad array of potential cellular and molecular targets with much wider therapeutic windows.

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Topics: Neuro/CNS

MMPs in ischemic conditions (stroke and myocardial infarct)

Posted by MD Biosciences on Jun 25, 2012 2:20:00 PM

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that function to degrade extracellular matrix. The turnover of ECM in organs is regulated by a balance by MMPs and their inhibitors (TIMPs) and the imbalance is implicated in a variety of diseases. Here we focus on the roles of MMPs in ischemia - particularly cerebral stroke and myocardial infarct.

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Topics: Neuro/CNS, Cardiovascular