New Approaches for the Treatment of Alzheimer's Disease
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Digest for Bioorg. Med. Chem. Lett. New Approaches for the Treatment of Alzheimer’s Disease Paul V. Fish,a,b,* David Steadman,a Elliott D. Bayle,a,b and Paul Whitinga,c a Alzheimer’s Research UK UCL Drug Discovery Institute, The Cruciform Building, University College London, Gower Street, London WC1N 1E 6BT, UK. b The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, UK. c The Dementia Research Institute, The Cruciform Building, University College London, Gower Street, London WC1N 1E 6BT, UK. Key words: Alzheimer’s disease, neurodegeneration, neuroinflammation, drug discovery pipeline, symptomatic treatments, disease modification. 1 Digest for Bioorg. Med. Chem. Lett. Graphical Abstract New Approaches for the Treatment of Alzheimer’s Disease Paul V. Fish, David Steadman, Elliott D. Bayle, Paul Whiting 2 Digest for Bioorg. Med. Chem. Lett. Abstract Alzheimer’s disease (AD) is the most prevalent chronic neurodegenerative disease. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target - amyloid (A) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the ‘A hypothesis’, there are a number of newer approaches to treat AD with neuroinflammation emerging as a very active area of research based on risk gene analysis. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD. 3 Digest for Bioorg. Med. Chem. Lett. 1. Introduction Alzheimer’s disease (AD) is the most prevalent chronic neurodegenerative disease with 5.7 million people living with the disease in the USA alone and this is projected to increase to 13.8 million people by 2050.1 Globally, the number of people currently suffering with dementia is estimated to be 50 million of which 30-35 million have AD.2 The risk of developing the disease is influenced by both genetic and environmental factors, however the biggest risk factor by far is age; the older you are the more likely you are to develop the disease but it is not an inevitable part of ageing. For instance, about one in 50 people aged between 65 to 69 have dementia, and this figure rises to one in five for those aged between 85 to 89.2 Given the global increase in life expectancy, this represents a huge societal and economic challenge with the impact extending to those living with AD, along with their caregivers and family. The disease often manifests itself initially as short term memory loss and as the disease progresses symptoms include language problems, disorientation, mood swings and behavioural issues (agitation, sleep changes, psychosis). Eventually the disease progresses to loss of bodily function and ultimately to death. Aβ Ta u Figure 1: Postmortem tissue samples from Alzheimer’s disease (AD) patient brains reveal AD pathology including amyloid- (A) plaques and Tau tangles. Photographic image courtesy of Dr. Tammaryn Lashley at the Queen Square Brain Bank for Neurological Disorders (UCL Queen Square Institute of Neurology). Copyright Tammaryn Lashley 2018. There are two pathological hallmarks of the disease found in the brain of individuals with AD: extracellular amyloid plaques and intracellular neurofibrillary tangles (Figure 1).3 These were first recognised in 1906 by Alois Alzheimer after whom the disease is named.3b We now recognise that the plaques are largely composed of -amyloid peptides (A) derived from amyloid precursor protein (APP), while the neurofibrillary tangles are composed of the tau protein (microtubule associated protein). As the disease advances, these pathologies progress along with brain shrinkage due to neuronal atrophy. (Figure 2). 4 Digest for Bioorg. Med. Chem. Lett. Figure 2: Comparison of MRI scans of healthy volunteer (left, control) and Alzheimer’s disease patient (right). The AD brain shows significant atrophy, dilation of the lateral ventricle and a smaller hippocampus. Images courtesy of Nick Fox (UCL Queen Square Institute of Neurology). Copyright Nick Fox. Human genetics has significantly enabled our understanding of the disease and the approaches that have been taken to discover new therapies. Rare autosomal dominant mutations in three genes, APP, presenilin 1 (PSEN1) and presenilin 2 (PSEN2) cause familial Alzheimer’s disease (FAD). FAD accounts for 2-3% of AD cases and usually has an earlier onset with symptoms developing in people in their 30s or 40s. In 1992, Hardy and Higgins postulated that the “deposition of amyloid protein (AβP) … is the causative agent of Alzheimer’s pathology and that neurofibrillary tangles, cell loss, vascular damage, and dementia follow as a direct result of this deposition”.4 Given that the APP protein is the source of A found in plaques, and that it subsequently became clear that the PSEN genes encode the catalytic subunit of the - secretase enzyme that cleaves APP (along with -secretase) leading to the generation of A peptides, this led to the molecular basis of the “-amyloid hypothesis of AD”.4 How A peptides (be that soluble, oligomeric, or plaque) leads to cell death remains controversial. Similarly, how tau tangles affect neural function, the relationship between -amyloid and tau tangles, and the apparent inter-neuronal spread of tau, are all areas of intense research. The recent clinical failures (discussed below) of a number of therapeutics that attempt to test the “- amyloid hypothesis of AD” might lead to the suggestion that this hypothesis has been disproven. However, it is our view that the A hypothesis is still central to causation of the disease and has yet to be adequately tested either because of flaws in the various therapeutics tested or because the clinical trials need to be performed on subjects much earlier in the disease process. Whether A or tau are the better drug target is unknown at this moment, and perhaps a moot point; both appear to be central to the disease process and so it is likely that combination therapies modulating both pathologies will ultimately be most successful. 5 Digest for Bioorg. Med. Chem. Lett. As well as the identification of autosomal dominant mutations, extensive genome wide association studies (GWAS) in AD have led to the identification of numerous risk alleles.5 The most significant of these is apolipoprotein E4 (ApoE4) with homozygosity leading to an 8 fold increase in risk of AD. However, despite a significant effort, the biology that underpins this increased risk conferred by ApoE4 remains to be fully understood. In the absence of this knowledge, it remains unclear if positive or negative modulation of ApoE4 would be beneficial. Furthermore, ApoE is a lipid-binding protein and is likely to be a challenging drug target for a small molecule even when there is an understanding as to the required modulation of function. A group of other genes identified through GWAS all point towards a role for neuroinflammation and microglial cells in AD. This is becoming an important area of research. Therapeutic approaches to AD, like most chronic degenerative diseases, can be broadly divided into three categories: symptomatic, disease modifying, and regenerative. Current approved therapies (cholinesterase inhibitors and glutamate antagonists) are symptomatic having some effect on cognitive function. There remains a significant unmet medical need for symptomatic treatments that impact more effectively the cognitive domain and also the other distressing symptoms such as agitation, psychosis and sleep disturbance.6 Most ongoing efforts to find new therapies are focussing on disease modification/disease progression; the premise is that if the onset of the disease can be delayed, or the progression of the disease slowed, then people will live longer without the developing AD. To date approaches have largely focussed around intervention in the A cascade and tau biology. The third category, regeneration, remains very much a hypothetical approach. Regenerating a diseased brain, replacing lost neurons and circuitry, is arguably a step too far for AD at this time. Clinical trials for AD have proven challenging, largely because the rate of disease progression is many months (meaning the trials often last 18 months or more), and the registerable endpoints recognised by the regulatory agencies are measures of cognitive performance.7 These are generally considered less robust an endpoint than biochemical or physiological measures. Good strides have however been made with pharmacodynamic endpoints. For instance, cerebrospinal fluid (CSF) A concentrations are routinely used as a biomarker for assessing compounds whose mechanism is inhibition of the enzymes that generate A from APP.8 Similarly, there are now good positron emission tomography (PET) ligands available that support visualisation and quantification of both A plaques and tau tangles. This is beginning to enable the correlation of the change in these classical pathological markers of the disease with disease progression as measured by the cognitive scales.9 For example florbetaben (1), flutemetamol (2) and florbetapir (3) are diagnostic radiotracers developed for routine clinical application to visualize A plaques in the brain. 18F-Flutemetamol (2, Vizamyl) is indicated for PET imaging of A neuritic plaque 6 Digest for Bioorg. Med. Chem. Lett. density in the brains of adult patients with cognitive impairment who are being evaluated for AD (Figure 3). florbetaben F-18 (1) flutemetamol F-18 (2) florbetapir F-18 (3) Figure 3: Axial view of negative (left) and positive (right) Vizamyl scans. Frontal (f), lateral temporal (it) and striatal (s) regions of the brain. Image taken from Vizamyl prescribing information, revised 02/2017. http://www.gevizamyl.com/us/wp-content/uploads/2017/02/43-1067C-Vizamyl1.pdf. Copyright GE Healthcare. 2. Approved Therapies There are currently no approved therapies which directly target AD pathology. Existing treatments are symptomatic, aimed at ameliorating cognitive function through two different modes of action: agonism of the cholinergic system and antagonism of the N-methyl-D-aspartate receptor (NMDA-receptor).