Atrial fibrillation is the most common arrhythmia observed in the clinic, affecting 6 million patients in Europe and accounting for 30% of strokes. The prevalence of atrial fibrillation continues to grow due to an aging population and is expected to double over the next 50 years. Given the need to develop safer and more effective anti-arrhythmic therapeutics, considerable efforts have been made to understand the cellular mechanisms of the disease and translate this knowledge into innovative treatments.
Improving biological tools for disease modelling and drug discovery: human iPSC-derived Atrial Cardiomyocytes
The rapid development of induced pluripotent stem cell-derived cells (iPSCs) is set to revolutionise modern drug discovery through the increased utilisation of human cell reagents in research.
Until recently, despite being the most prominent cell type in the human brain, research on astrocytes has been overshadowed by neurons. Once thought to only provide structural support to neurons it has become clear that astrocytes are a vastly heterogenous population of cells with varied functions and roles to match.
Neuropathic pain is a debilitating side effect of many commonly-used chemotherapy drugs, and in severe cases can result in the discontinuation of a cancer treatment. By understanding the mechanisms through which chemotherapeutics induce neuropathic pain, researchers aim to develop effective treatments designed specifically to alleviate the condition. These will combat the dose-limitation imposed on chemotherapeutics, as well as offering utility for conditions including multiple sclerosis, diabetes and HIV.
Understanding the mechanisms of chemotherapy induced neuropathic pain using iPSC-derived sensory neurons
Many commonly used chemotherapy drugs cause unpleasant side effects and complications. Of these, neuropathic pain can be particularly debilitating. Most of the current treatments for neuropathic pain are medications that were originally approved for other health disorders, such as anti-depressants and anti-seizure drugs. These have their own accompanying problems, and since no single drug is effective against all forms of neuropathic pain, it is essential that new therapeutic agents are developed specifically for the treatment of this condition.
Through the previous blogs in this series, we have understood the challenges which somatic cells face when changing their career path to become induced pluripotent stem cells (iPSCs), the ways in which we can induce this change, and how we might assess whether this is the right career for the cells through pluripotency and differentiation assays.
In our previous blog we likened somatic cell reprogramming to a career change. Once a somatic cell has been converted to an induced pluripotent stem cell (iPSC), the next stage in the process can be thought of as an appraisal or performance review. This is essential to confirming that the reprogrammed cell is behaving as expected.
Cardiovascular diseases (CVD) include coronary heart disease, stroke, myocardial infarction and heart failure. They are the leading cause of mortality globally, with CVD accounting for 31% of deaths worldwide in 2015. Within the UK alone 27.4% of male deaths and 25.2% of female deaths in 2015 were due to CVD.
Traditionally, there have been difficulties in obtaining and culturing human cardiac cells of a high quality due to a scarcity of healthy donor material, culture issues associated with the non-dividing state of terminally differentiated cardiomyocytes. The development of human embryonic stem cell technology allowed major advancements to be made as protocols were developed to differentiate cardiomyocytes from a replenishable pluripotent source. A huge issue with the use of human embryonic stem cell-derived cells was the controversial ethical issues and strict regulations regarding their use. This meant that Yamanaka's breakthrough when his group produced the Nobel Prize winning technology in the form of induced pluripotent stem cells had a gargantuan impact on the study of human cardiac cells.
Drug toxicity is a significant cause of clinical failure, accounting for approximately one third of all pipeline attrition. This has driven huge interest across the pharmaceutical industry to understand drug toxicity early within the drug development pipeline. The aim of this is to de-risk drug candidates from a safety perspective before they enter the clinic, as well as reducing the substantial costs associated with drug development.
Characterized by their star-like shape astrocytes, also known as astroglia, represent the most abundant cell type in the brain. Closely linked to neurons with pivotal roles in synaptic activity and blood-brain barrier function, the study of astrocytes using in vitro co-culture models is becoming increasingly important in neuroscience research.
Somatic cells can be compared to human beings in that they grow up to perform a specific function in life. While a human being may develop into a world class athlete or a research scientist, a somatic cell can develop into any of the cell types that make up an organism except the germline cells.
Using hiPSC-Derived Renal Proximal Tubular Cells in vitro assays to advance disease research and drug development
The rising numbers of kidney patients and a shortage of transplantable organs is a global health issue with high economic costs. Previous disease research and drug development has traditionally used animal models, but these fail to recapitulate human renal cellular function and so limit our ability to elucidate disease mechanisms and therapeutic targets.
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All pharmaceutical development programs carry a certain amount of risk. However, when it comes to developing drugs that target the central nervous system, the odds of success narrow significantly.
Amyotrophic Lateral Sclerosis (ALS), a Motor Neuron Disease (MND) subtype, is a debilitating neurodegenerative disorder affecting the upper and lower motor neurons (UMNs/LMNs), brain stem and spinal cord. This leads to progressive muscular weakness and atrophy, paralysis, and eventually death, usually within three to five years after the onset of symptoms. Decades of failed drug development mean that MND/ALS is still incurable; only two FDA-approved drugs exist (riluzole, and more recently, edaravone), but these only slow down disease progression.
Human iPSC-Derived Motor Neurons: Expert tips on best cell-culture practices to enhance your research
Despite intensive research, there is still no known cure or standard treatment for Amyotrophic Lateral Sclerosis (ALS), a Motor Neuron Disease (MND) subtype. Researchers have traditionally used animal models (usually mice) to screen candidate compounds, but these models are now known to lack physiological relevance to the human pathology, which could limit translational drug development.
Kidneys play a key role in removing waste and toxins from the body, as well as having essential endocrinological and homeostatic functions. If certain pharmaceuticals are abused, administered incorrectly or taken regularly, they can induce toxicity in the kidneys (nephrotoxicity). This can result in impaired renal function, and even death in the most severe cases. For example, nephrotoxic drugs (NDs) are responsible for 19-25% of acute kidney injury in critically ill patients.
Enhancing Amyotrophic Lateral Sclerosis (ALS) drug discovery using physiologically relevant hiPSC-Derived Motor Neurons
Amyotrophic Lateral Sclerosis (ALS), a Motor Neurone Disease (MND) subtype is characterised by the degeneration and death of nerves (motor neurons) in the brain and the spinal cord that control essential voluntary muscle activity. Affecting over 400,000 patients worldwide each year, MND/ALS progressively causes difficulties in speaking, walking, breathing, and swallowing, with the disease eventually being fatal in about a quarter of all patients affected each year.
The brain is the most complex organ in the body, controlling our highest functions, as well as regulating myriad processes which incorporate the entire physiological system. There is a significant risk that a novel therapeutic agent might impact brain structure and function, resulting in serious pathologies and even death. Therefore, CNS testing forms part of the 'core battery' of safety pharmacology studies .