Failing animal research is delaying cures for alzheimer’s disease, says new paper in Drug Discovery Today
A decade of Alzheimer’s disease research dominated by artificially creating symptoms in genetically modified mice has failed to find a single cure that works in human patients, and could be delaying progress towards effective treatments, says a new paper published in Drug Discovery Today.
The paper by Dr Gill Langley, senior science adviser to Humane Society International, calls for a fundamental paradigm shift in Alzheimer’s disease research – utilising state-of-the-art techniques based on human rather than non-human biology. Next-generation tools such as functioning human brain cells in a test tube, neuroimaging and genomics must form the basis of a new framework for research that analyses the disease ‘pathways’ leading to Alzheimer’s, from the cell and tissue level to the whole body scenario.
Dr Langley said: “Alzheimer’s is one of those disease research areas still very much dominated by the standard approach: studying the wrong condition in the wrong animal. The legacy of that approach is that despite a decade of effort using genetically modified mice, more than 300 potential treatments have been successful in animals but not a single one has proved effective in human patients. With one and a half million people in the UK alone projected to have Alzheimer’s in the next 40 years, continuing to focus on failing animal models is a waste of time and resources that is simply unsustainable.
“If we want to improve our chances of cracking this debilitating brain disease, we must embark on a new research roadmap that applies the very latest research tools to study the processes involved in the development of Alzheimer’s. From patient-derived human brain cells in culture, to powerful neuroimaging machines, and super-computers combining multiple data to reconstruct the disease pathways, Alzheimer’s can be mapped within the framework of human biology in order to understand why and how the illness occurs and how best to treat it. These advanced techniques will allow a complexity of understanding of this uniquely human disease never before achieved using animal models.”
A number of different animal species have featured in Alzheimer’s research, including rabbits, dogs and monkeys. But for the last two decades, the dominant animal ‘model’ has been transgenic mice – mice with inserted faulty human genes that produce a few symptoms similar to the real disease. The problem is that the sum of a few artificially induced symptoms is not true Alzheimer’s, and so the condition developed in these mice differs from the human disease in how it is caused, how the disease progresses, and the sequence of symptoms that occur.
Despite basic similarities in all mammalian brains, the different evolutionary paths of mice and humans mean that our brains differ in genetics, proteins, chemistry and physiology. One key example of this is a protein called apolipoprotein E. It is the only protein proven to be a risk factor for common (late onset) Alzheimer’s disease, but it has a different structure and function in mice than in humans. Efforts to predict drug effects in patients based on memory tests in transgenic mice have also failed repeatedly, often because the results are very variable and difficult to interpret.
A change in conceptual thinking and practice is long overdue. Focusing on human biology will eliminate problems of species differences, and patient-derived cells offer a true human disease model. Identifying underlying disease pathways and their key events will provide ‘targets’ for novel drug development, as well as demonstrating links between different illnesses such as Alzheimer’s and Parkinson’s disease.
Personalised medicine tailored to maximise benefits to individual patients – highly unlikely with animal-based research – could also become a real possibility. Funding needs to be re-directed away from costly efforts to improve animal ‘models’, and towards further developing, finessing and integrating 21st-century scientific models and techniques in order to offer real hope for patients with Alzheimer’s disease.
Considering a new paradigm for Alzheimer’s disease research, Langley, G.R., Drug Discovery Today, DOI: 10.1016/j.drudis.2014.03.013, published online 21 March 2014.